Exit Examination Gastroenterology & Hepatology

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Exit Examination Gastroenterology & Hepatology Title Somatostatin in the prevention of post ERCP Pancreatitis Candidate Dr. Chi Pang HO Department of Medicine & Geriatrics Princess Margaret Hospital Supervisor
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Exit Examination Gastroenterology & Hepatology Title Somatostatin in the prevention of post ERCP Pancreatitis Candidate Dr. Chi Pang HO Department of Medicine & Geriatrics Princess Margaret Hospital Supervisor Dr. Ambrose, Chi Pong KWAN Department of Medicine & Geriatrics Princess Margaret Hospital Content ABSTRACT...2 INTRODUCTION...4 PATIENT AND METHODS...6 STATISTICAL ANALYSIS...7 RESULTS...8 DEMOGRAPHIC DATA:...8 PATIENTS WITH PANCREATITIS:...8 PATIENTS WITH HYPERAMYLASEMIA:...9 PATIENTS WITH PERSISTENT ABDOMINAL PAIN:...9 RISK FACTORS FOR POST ERCP PANCREATITIS:...9 SIDE EFFECTS OF MEDICATION:...10 DISCUSSION...11 INCIDENCE OF PANCREATITIS...11 EFFECT OF BOLUS SOMATOSTATIN...11 RISK FACTORS FOR POST ERCP PANCREATITIS...12 PATHOPHYSIOLOGY OF POST ERCP PANCREATITIS...13 SOMATOSTATIN...14 SOMATOSTATIN IN PREVENTION OF POST ERCP PANCREATITIS...15 OTHER POSSIBLE THERAPEUTIC MODALITIES IN PREVENTION OF POST ERCP PANCREATITIS...16 FUTURE TRENDS...19 REFERENCES: Abstract Background: Acute pancreatitis is the most common complication after ERCP. Prophylactic somatostatin infusion has been demonstrated to reduce the incidence of post ERCP pancreatitis. However, the cost for continuous intravenous infusion and in-patient treatment to deliver somatostatin is high. Bolus somatostatin injection has also been shown to inhibit pancreatic exocrine secretion and reduce the incidence of post ERCP pancreatitis. Aim: The aim of this study was to see if bolus somatostatin injection could prevent post ERCP pancreatitis in our local population. Possible patient and procedure related risk factors for post ERCP pancreatitis were also studied. Patient and methods: A single centred, randomized, double-blind, placebo controlled, prospective study was carried out in patients undergoing diagnostic +/- therapeutic ERCP. Patients were randomized to receive bolus injection of 250mcg somatostatin (group A) or the same volume of normal saline injection as placebo (group B) just before the cannulation of the papilla. The incidence of pancreatitis was compared between the two groups by Fisher s Exact test. Possible risk factors were identified by comparing patients with or without pancreatitis using student t-test, chi square test (or Fisher s Exact test), or Mann Whitney test. Independent risk factors were then identified by backward stepwise multiple logistic regression. Results: From 8/1/1999 to 13/2/2001, 160 patients were recruited for study with 80 patients in each group. Mean age of patients was , with a male to female ratio of 1.3: patients (6.3%) developed post ERCP pancreatitis, 4 patients (5%) in the somatostatin group (3 mild and 1 moderately severe) and 6 patients (7.5%) in the placebo group (5 mild and 1 moderately severe). The difference did not reach statistical significance (P=0.75). All pancreatitis were self-limiting and uncomplicated. 120 patients (75%) developed hyperamylasemia. There was no significant difference between the two groups in terms of the incidence of hyperamylasemia (P=0.72), significant hyperamylasemia (amylase 3x ULN) (P=0.41), mean amylase level at 4 hours (P=0.51) and 18 hours (P=0.53) after ERCP, and persistent abdominal pain (P=1.0). Longer procedure time (P=0.002), difficult selective biliary cannulation (P=0.016), multiple pancreatic duct cannulation (P=0.024), secondary or higher degree of opacification of pancreatic duct (P=0.035) were associated with post ERCP pancreatitis in univariate analysis. Longer procedure time was found to be the only independent risk factor for post ERCP pancreatitis in multivariate model. Therapeutic procedures performed in the study (papillotomy, stone extraction, biliary stenting, cytology brushings) were not associated with increased post ERCP pancreatitis (P=0.319) Conclusion: Prophylactic bolus somatostatin injection did not significantly reduce the incidence of post ERCP pancreatitis in unselected patients. Longer procedure time, difficult selective biliary cannulation, increased number of pancreatic duct cannulation, and secondary 2 or higher degree of opacification of pancreatic duct were associated with increased risk of post ERCP pancreatitis. Only longer procedure time was found to be an independent risk factor for post ERCP pancreatitis. 3 Introduction With the improvement in technology, instruments and techniques, ERCP has evolved from purely a diagnostic study to providing a variety of therapeutic modalities. However, it is not without risk, especially many more invasive procedures are now being performed (1). Subclinical pancreatic injury signified by isolated raised pancreatic enzymes is very common after ERCP. The incidence of hyperamylasemia ranged from 44% to 94% (2-6). Pancreatitis is the most common complication of ERCP, with the incidence ranging from 2.8% to 10.2% in recent, large prospective studies (7-10). A recent prospective study on somatostatin infusion in prevention of post ERCP pancreatitis in Hong Kong (11) revealed an incidence of pancreatitis of 10% in the placebo group. In a large clinical audit on ERCP, M.L. Szeto et al. (12) retrospectively reviewed 732 ERCPs from 13 hospitals in Hong Kong and found an incidence of post ERCP pancreatitis of 1.4%. Although clinical pancreatitis after ERCP is usually mild and self-limiting, it still incurs significant morbidity in terms of abdominal pain and prolonged hospitalization. It becomes clinically even more important in severe cases, when pancreatic necrosis, secondary infection with abscess formation, systemic multi-organ failure occur. Even deaths have been reported. A study on major complications of ERCP noted moderate to severe pancreatitis in 1.3% of patients (13). Two recent studies by M.L. Freeman et al. revealed that the incidence of severe pancreatitis was 0.4% and 0.3% for biliary sphincterotomy (14) and ERCP (10) respectively. Two United States centres retrospectively reviewed more than seven thousand five hundred cases of ERCP (15). They found an incidence of 0.5% and 1% for severe complications and a death rate of 0.07% and 0.11% for diagnostic and therapeutic ERCP respectively. Besides causing significant morbidity and mortality to patients, there can also be potential medico-legal consequences. A study on malpractice claims in gastrointestinal endoscopy in United States (16) revealed that 1.8% of claims were related to ERCP. The relative risk of claims for ERCP was 1.6 when compared to sigmoidoscopy, which was ranked second after colonoscopy (relative risk 1.7). Treatment, or preferably, prevention of post ERCP pancreatitis is therefore clinically important. Unfortunately, medical therapy for acute pancreatitis has not been promising and treatment at present is mainly supportive. Lexipafant, a platelet activating factor antagonist, has been studied for treatment of acute non-iatrogenic pancreatitis. But results were disappointing (17). Somatostatin and its analogues have shown some evidence of reducing the severity of pancreatitis in animal (18) and human studies (19). But the effect is, expectedly, difficult to be elicited because the drug is usually given late in the course of the disease when the cascade of 4 systemic inflammatory response has already been triggered. Thus, a search for effective therapy that can prevent post ERCP pancreatitis is imminent. Prophylactic somatostatin bolus injection has been shown in previous studies to protect against post ERCP pancreatitis (20) and reduce enzyme elevation (4,20). It works by minimizing pancreatic acinar injury through inhibition of pancreatic enzyme production (21). Its effect on relaxation of the sphincter of Oddi (22) may also help reduce the risk of post ERCP pancreatitis, possibly by allowing easier cannulation, reduction of pressure in the pancreatic duct, improved drainage of contrast and activated pancreatic enzymes. Although the plasma level of somatostatin is short in half-life, its effect on the pancreas may last longer. Pancreatic secretion remains reduced for more than ten minutes after a bolus injection of somatostatin (20). Prophylactic somatostatin infusion has also been demonstrated in a prospective, randomized, placebo controlled study to reduce incidence of post-ercp pancreatitis from 10% to 3% (11). However, a bolus dose rather than continuous infusion would be more advantageous in reducing drug costs and in obviating the need for hospital stay for drug treatment. This prospective study would like to address the question whether a bolus dose of somatostatin can reduce the incidence of post ERCP pancreatitis in our local population. Various possible risk factors associated with post ERCP pancreatitis were also studied. 5 Patient and methods Starting from 8/1/1999, all patients undergoing ERCP would be eligible. Exclusion criteria were as follows: 1) age 18 or 80 2) history of allergy to somatostatin 3) pregnancy 4) serious medical disorders 5) previous papillotomy 6) acute pancreatitis* *Patients with acute pancreatitis after the acute stage were also included into the study provided that they had no more abdominal pain and their amylase level normalised before the study. Informed written consent was obtained from patient. The study was approved by the hospital ethics committee. The drugs were supplied by the Serono Pharmaceutical Company. Patients were randomised into group A: receiving intravenously bolus somatostatin 250mcg just before cannulation of the major papilla, or group B: same amount of normal saline intravenously as placebo. Patients, doctors and nurses in the endoscopy suite were blinded to the drug given. The drugs were prepared into unlabelled identical syringes outside the endoscopy suite. By opening sealed envelopes, which contained information on randomised treatment arm to be allocated, the corresponding medication was prepared. Patients were kept fast for at least 6 hours before ERCP. They were given pharyngeal anesthesia with xylocaine and conscious sedation with intravenous diazemuls and pethidine. Intravenous ciprofloxacin 200mg was given as prophylactic antibiotic for patients with obstructive jaundice. ERCP were performed by trainees in gastroenterology under supervision or by experienced endoscopists themselves. Pancreatic duct cannulation was not routinely performed unless clinically indicated. Conray (Meglumine lothalamate 60%), a high osmolality ionic contrast, was used for opacification. Papillotomy, if required, was performed using a blended current. The number of pancreatic duct cannulation and pancreatic duct injection, the degree and extent of pancreatic duct opacification was recorded. The number of pancreatic duct injection referred to the number of times any volume of contrast was injected into the pancreatic duct. The degree was graded as primary if only the main pancreatic duct was shown, as secondary if pancreatic side ducts were shown, or as acinarization if any focal or diffuse parenchymal blush 6 was shown. The extent was graded as 1 if opacification was only up to the head of pancreas, as 2 if opacification was up to the body, as 3 if the whole pancreatic duct was opacified. The difficulty of selective biliary cannulation was graded as easy or difficult by the endoscopist. Failed cases were considered as difficult. The indications for ERCP, bilirubin level before ERCP, ERCP diagnoses, therapeutic procedures and procedure time were also recorded. The procedure time was measured from the commencement of papilla cannulation to the time of withdrawal of endoscope from the patient. Serum amylase levels were checked before ERCP, 4 hours and 18 hours after ERCP. Lipase measurement was not available in our hospital. Patients were assessed by endoscopists before ERCP for obtaining consent and examine for abdominal signs. They were reassessed 4 hours and 18 hours after the procedure for abdominal pain, the need for analgesia, and complications. Hyperamylasemia was defined as amylase level above the upper limit of normal. Significant hyperamylasemia was defined as amylase level more than 3 times above the upper limit of normal. Persistent abdominal pain was defined as new onset abdominal pain that persisted till 18 hours after ERCP. Pancreatitis was defined as significant hyperamylasemia in the presence of persistent abdominal pain (i.e. new onset abdominal pain after ERCP that persisted till 18 hours after ERCP with a rise in amylase level to more than 3 times the upper limit of normal.) (20). The severity of pancreatitis was graded according to the consensus criteria in 1991(23): mild if prolonged hospitalisation for 4 days; moderate if prolonged hospitalisation for 4-10 days; severe if prolonged hospitalisation for 10 days, or haemorrhagic pancreatitis, or complications like pseudocyst, abscess, or intervention required (percutaneous drainage or surgery), or the patient died. Statistical analysis Numerical data were expressed as mean + standard deviation. Amylase levels were compared by student t-test. Frequency of pancreatitis, hyperamylasemia, and persistent abdominal pain were compared by chi-square test (or Fisher s exact test if appropriate). Risk factors for pancreatitis were identified in univariate analysis by Student t-test for numerical variables, chi-square test for nominal variables, and Mann Whitney test for ordinal variables. Significant factors noted in univariate analysis were then included in a backward stepwise multiple logistic regression to identify independent risk factors. A P-value of 0.05 was considered statistically significant (2-tailed). 7 Results From 8/1/1999 to 13/2/2001, 451 ERCPs were performed. Many patients were excluded because of previous papillotomy, consent not obtainable, or refusal to enter into study. A total of 161 patients were recruited for study. One patient was excluded from the study because the correct medication was not given according to the information provided in the envelope. Demographic data: The mean age was , range (28-80). Male to female ratio was 1.3: 1 (90/70). The age, sex, indications for ERCP, patients with raised bilirubin level, the endoscopic diagnoses, the number of diagnostic and therapeutic ERCP, and the procedure time were all comparable in somatostatin treated and placebo group. (Table 1) Failed bile duct cannulation occurred in 11 cases (6.9%) due to technical difficulty. 66 patients (41.2%) had a normal ERCP. 61 patients (38.1%) had stone disease and 15 patients (9.4%) had biliary stricture. The remaining 7 patients (4.4%) had dilated bile ducts of unknown significance. (Fig. 1) Therapeutic procedure was required in 65 patients (40.6%). These included 56 papillotomies (35%), 36 stone extractions (22.5%), 31 insertion of plastic stents (19.4%), and 12 cytology brushings (7.5%). (Fig. 2) No pre-cut papillotomy was performed in the patients studied. Patients with pancreatitis: Overall, 10 patients (6.3%) developed post ERCP pancreatitis. 8 cases were mild and 2 cases were moderate. All pancreatitis were self-limiting and uncomplicated. For cases with mild pancreatitis, hospitalization was prolonged for 2 days in 3 patients and 3 days in 5 patients. None of them required analgesics for relief of abdominal pain. For cases with moderate pancreatitis, one patient had CBD stones with papillotomy and stone extraction performed. He required prolonged hospitalization for 7 days and 2 doses of analgesic for relief of abdominal pain during his stay. The remaining patient had a normal ERCP. CT scan abdomen on day 3 pancreatitis revealed only oedema of pancreas without necrosis or abscess formation. Hospitalization was prolonged for 8 days and 2 doses of analgesic were given for pain relief. Concerning the underlying diagnosis, 5 patients had common bile ductal stones. Of those 5 patients, 4 patients had therapeutic procedures performed and one of them developed moderate pancreatitis. Bile duct access and drainage was failed in the remaining patient which was subsequently successful in the repeated ERCP session. 3 patients had normal ERCP. One of them developed moderate pancreatitis. The remaining 2 patients had malignant bile duct stricture with drainage procedures performed. There were 4 patients (5%) in the somatostatin group and 6 patients (7.5%) in the placebo 8 group with pancreatitis. The difference was not statistically significant (P-value = 0.75). (Table 2) Each group has 1 patient with moderate pancreatitis (P-value =1.0). Patients with hyperamylasemia: 120 patients (75%) developed hyperamylasemia, 61 patients (76%) in the somatostatin group and 59 patients (74%) in the placebo group. The difference was not statistically significant (P-value = 0.72). When only hyperamylasemia of 3 times the upper limit of normal was considered, 31 and 26 patients in somatostatin and placebo group respectively developed significant hyperamylasemia. There was no statistical significant difference between the two groups (P-value =0.41). (Table 2) The amylase levels at 4-hour post ERCP were 488 (+/- 653) IU/L and 463 (+/- 642) IU/L in the somatostatin and placebo group respectively (P-value =0.51). The amylase levels at 18-hour post ERCP were 462 (+/- 765) IU/L and 409 (+/-619) IU/L in the somatostatin and placebo group respectively. (P-value =0.53). No statistical significant difference was present between the two groups at 4-hour or 18-hour amylase level. (Table 2) Patients with persistent abdominal pain: 16 patients (10%) developed persistent post ERCP abdominal pain. Equal number of patients occurred in either group (P-value =1.0). (Table 2) Risk factors for post ERCP pancreatitis: Patient related and procedure related factors were compared between the two groups of patients with or without pancreatitis. (Table 3) There was no statistical significant difference between the two groups in terms of age, sex, indications for ERCP, proportion of patients with raised bilirubin level, endoscopic diagnoses, proportion of patients requiring therapeutic ERCP, the different types of endoscopic procedures performed, and the number of pancreatic duct injections. Acute pancreatitis was an indication for ERCP in 5 patients. All of them were suspected to have biliary pancreatitis. Of those 5 patients, 4 patients had stone disease as underlying diagnosis with therapeutic procedures performed. The remaining patient had a normal ERCP. None of them developed post ERCP pancreatitis. Longer procedure time (P-value=0.002), difficult selective biliary cannulation (P-value=0.016), increased number of pancreatic duct cannulation (P-value=0.024), secondary or higher degree of opacification of pancreatic duct (P-value=0.035) were identified as risk factors for post ERCP pancreatitis on univariate analysis. (Table 3) 9 After multivariate analysis, only longer procedure time was found to be an independent risk factor for post ERCP pancreatitis (P-value=0.019). Secondary or higher degree of opacification of pancreatic duct had near statistical significance (P-value=0.055). (Table 4) Side effects of medication: No adverse side effects of medication (somatostatin or placebo) were reported. 10 Discussion Incidence of pancreatitis Our study revealed an incidence of pancreatitis of 7.5% in the placebo group. This is comparable to the incidence described in a recent prospective study from R Poon et al. in Hong Kong (11). They revealed an incidence of pancreatitis of 10% in the placebo group during a study on the effect of somatostatin infusion for preventing post ERCP pancreatitis. Another recent retrospective clinical audit on ERCP collected data from 13 different hospitals in Hong Kong from January to March in 1999 (12). The incidence of pancreatitis was 1.4% in the 732 ERCPs studied. Prospective studies from overseas reported an incidence ranging from 2.8% to 10.2% (7-10) for unselected cases, and 12.5% to up to 31% for high risk patients performing invasive procedures (8,24,25). The variation in incidence could be due to a number of reasons: 1) the dif
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