Juhani Sand

Early treatment with antibiotics reduces the need for surgery in acute necrotizing pancreatitis—a single-center randomized study☆

Pancreatic infection is the main indication for surgery and the principal determinant of prognosis in acute necrotizing pancreatitis. Previous studies on the effects of antibiotics have not, however, uniformly demonstrated any reduction in the need for surgery or any decrease in mortality among these patients, although the incidence of pancreatic infections was significantly reduced. This single-center randomized study was designed to compare early vs. delayed imipenem treatment for acute necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis (C-reactive protein >150 mg/L, necrosis on CT) were randomized within 48 hours either to a group receiving imipenem (1.0 g plus cilastatin intravenously 3 times a day) or a control group. Not included were those who had been started on antibiotics at the referring clinic, those who were taken directly to the intensive care unit for multiorgan failure, and those who refused antibiotics or might have had adverse reactions. Thirty-two patients were excluded because they were over 70 years of age (not potentionally operable) or for any study violation. There were 25 patients in the imipenem group and 33 patients in the control group. The main end point was the indication for necrosectomy due to infection (i.e., after the initial increase and decrease, there was a second continuous increase in temperature, white blood cell count [>30%] and C-reactive protein [>30%], with other infections ruled out, or bacteria were found on Gram stain of the pancreatic fine-needle aspirate). In the control group, imipenem was started when the operative indication was fulfilled. Conservative treatment was continued for at least 5 days before necrosectomy. The study groups did not differ from each other with regard to sex distribution, patient age, etiology, C-reactive protein concentration, and extent of pancreatic necrosis on CT. Two (8%) of 25 patients in the imipenem group compared to 14 (42%) of 33 in the control group fulfilled the operative indications (P = 0.003). Nine patients in the control group responded to delayed antibiotics but five had to undergo surgery. Of those receiving antibiotics, 2 (8%) of 25 in the early antibiotic (imipenem) group needed surgery compared to 5 (36%) of 14 in the delayed antibiotic (control) group (P = 0.04). Two (8%) of 25 patients in the imipenem group and 5(15%) of 13 patients in the control group died (P = NS [no significant difference]). Seven (28%) of 25 in the imipenem group and 25 (76%) of 33 in the control group had major organ complications (P = 0.0003). Based on the preceding criteria, early imipenem-cilastatin therapy appears to significantly reduce the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis, and reduces by half the mortality rate; this is not, however, statistically significant in a series of this size.

Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial

IMPORTANCE An increasing amount of evidence supports the use of antibiotics instead of surgery for treating patients with uncomplicated acute appendicitis. OBJECTIVE To compare antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis confirmed by computed tomography (CT). DESIGN, SETTING, AND PARTICIPANTS The Appendicitis Acuta (APPAC) multicenter, open-label, noninferiority randomized clinical trial was conducted from November 2009 until June 2012 in Finland. The trial enrolled 530 patients aged 18 to 60 years with uncomplicated acute appendicitis confirmed by a CT scan. Patients were randomly assigned to early appendectomy or antibiotic treatment with a 1-year follow-up period. INTERVENTIONS Patients randomized to antibiotic therapy received intravenous ertapenem (1 g/d) for 3 days followed by 7 days of oral levofloxacin (500 mg once daily) and metronidazole (500 mg 3 times per day). Patients randomized to the surgical treatment group were assigned to undergo standard open appendectomy. MAIN OUTCOMES AND MEASURES The primary end point for the surgical intervention was the successful completion of an appendectomy. The primary end point for antibiotic-treated patients was discharge from the hospital without the need for surgery and no recurrent appendicitis during a 1-year follow-up period. RESULTS There were 273 patients in the surgical group and 257 in the antibiotic group. Of 273 patients in the surgical group, all but 1 underwent successful appendectomy, resulting in a success rate of 99.6% (95% CI, 98.0% to 100.0%). In the antibiotic group, 70 patients (27.3%; 95% CI, 22.0% to 33.2%) underwent appendectomy within 1 year of initial presentation for appendicitis. Of the 256 patients available for follow-up in the antibiotic group, 186 (72.7%; 95% CI, 66.8% to 78.0%) did not require surgery. The intention-to-treat analysis yielded a difference in treatment efficacy between groups of -27.0% (95% CI, -31.6% to ∞) (P = .89). Given the prespecified noninferiority margin of 24%, we were unable to demonstrate noninferiority of antibiotic treatment relative to surgery. Of the 70 patients randomized to antibiotic treatment who subsequently underwent appendectomy, 58 (82.9%; 95% CI, 72.0% to 90.8%) had uncomplicated appendicitis, 7 (10.0%; 95% CI, 4.1% to 19.5%) had complicated acute appendicitis, and 5 (7.1%; 95% CI, 2.4% to 15.9%) did not have appendicitis but received appendectomy for suspected recurrence. There were no intra-abdominal abscesses or other major complications associated with delayed appendectomy in patients randomized to antibiotic treatment. CONCLUSIONS AND RELEVANCE Among patients with CT-proven, uncomplicated appendicitis, antibiotic treatment did not meet the prespecified criterion for noninferiority compared with appendectomy. Most patients randomized to antibiotic treatment for uncomplicated appendicitis did not require appendectomy during the 1-year follow-up period, and those who required appendectomy did not experience significant complications. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01022567.

Clinical assessment compared with cyst fluid analysis in the differential diagnosis of cystic lesions in the pancreas

BACKGROUND In adults 80% to 90% of cystic lesions in the pancreas are pseudocysts and the remainder are mostly neoplastic cysts. To choose optimal treatment for an individual patient, exact nonoperative diagnosis would be preferable. This study was done to assess the value of cyst fluid analysis, compared with clinical and radiologic findings, in the differential diagnosis of pancreatic cystic lesions. METHODS Twenty-two patients with a cystic lesion in the pancreas underwent operation, cyst wall biopsy, and aspiration of cyst fluid. Carcinoembryonic antigen (CEA), CA 19-9, pancreatitis-associated protein (PAP), and total protein concentration, amylase activity, and cytologic findings were studied. Final diagnosis was pseudocyst in 14 patients, serous cystadenoma in two, mucinous cystadenoma in two, and mucinous cystadenocarcinoma in four patients. RESULTS Clinical and radiologic judgment correctly differentiated pseudocysts and neoplastic cysts. Cyst fluid aspiration did not succeed in two patients with mucinous cystadenocarcinomas because of the high fluid viscosity. Cyst fluid amylase activity was high (greater than 16,000 IU/ml) in all but one pseudocyst and low (less than 83 IU/ml) in all but one neoplastic cyst. CEA level was lower in pseudocysts than in neoplastic cysts, but with an overlapping value between the groups. Mean CA 19-9 concentration was higher in pseudocysts than in neoplastic cysts, but with wide overlap between the groups. Pancreatitis-associated protein and total protein concentration and cystic fluid cytologic findings did not differ between various types of cysts. CONCLUSIONS Clinical judgment including careful history and radiologic studies seems to be the most reliable method of differentiating neoplastic pancreatic cysts from pseudocysts. Amylase and CEA levels give suggestive information, but cyst fluid analysis may be misleading in an individual patient.

The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial.

BACKGROUND & AIMS In the long term, half of patients with their first alcohol-associated acute pancreatitis (AP) develop acute recurrence, alcohol consumption being the main risk factor. None of the recent national or international guidelines for treatment include recommendations aimed to decrease recurrences, possibly because of a lack of studies. This study investigated whether AP recurrences can be reduced. METHODS One hundred and twenty patients admitted to a university hospital for their first alcohol-associated AP were randomized either to repeated intervention (n = 59) or initial intervention only (n = 61). The patients in the 2 groups did not differ. A registered nurse performed an intervention in both groups before discharge, after which it was repeated in the study group at 6-month intervals at the gastrointestinal outpatient clinic. Acute recurrences during the next 2 years were monitored. RESULTS There were 9 recurrent AP episodes in 5 patients in the repeated-intervention group compared with 20 episodes (P = .02) in 13 patients (P = .04) in the control group. The recurrence rates were similar during the first 6 months (4 vs 5 episodes), after which the repeated-intervention group had fewer recurrences than the control group (5 vs 15 episodes; P = .02). CONCLUSIONS The repeated visits at 6-month intervals at the gastrointestinal outpatient clinic, consisting of an intervention against alcohol consumption, appear to be better than the single standardized intervention alone during hospitalization in reducing the development of recurrent AP during a 2-year period.

Post-ERCP pancreatitis: reduction by routine antibiotics.

Cholangitis and pancreatitis are severe complications of endoscopic retrograde cholangiopancreatography (ERCP). Antibiotics have been considered important in preventing cholangitis, especially in those with jaundice. Some have suggested that bacteria may play a role in the induction of post-ERCP pancreatitis. It is not clear, however, whether the incidence of post-ERCP pancreatitis could be reduced by antibiotic prophylaxis, as is the case with septic complications. In this prospective study, a total of 321 consecutive patients were randomized to the following two groups: (1) a prophylaxis group (n = 161) that was given 2 g of cephtazidime intravenously 30 minutes before ERCP, and (2) a control group (n = 160) that received no antibiotics. All patients admitted to the hospital for ERCP who had not taken any antibiotics during the preceding week were included. Patients who were allergic to cephalosporins, patients with immune deficiency or any other condition requiring antibiotic prophylaxis, patients with clinical jaundice, and pregnant patients were excluded. In the final analysis six patients were excluded because of a diagnosis of bile duct obstruction but with unsuccessful biliary drainage that required immediate antibiotic treatment. The diagnosis of cholangitis was based on a rising fever, an increase in the C-reactive protein (CRP) level, and increases in leukocyte count and liver function values, which were associated with bacteremia in some. The diagnosis of acute pancreatitis was based on clinical findings, and increases in the serum amylase level (>900 IU/L), CRP level, and leukocyte count with no increase in liver chemical values. The control group had significantly more patients with post-ERCP pancreatitis (15 of 160 in the prophylaxis group vs. 4 of 155 in the control group; P = 0.009) and cholangitis (7 of 160 vs. 0 of 155; P = 0.009) compared to the prophylaxis group. Nine patients in the prophylaxis group (6%) and 15 patients in the control group (9%) had remarkably increased serum amylase levels (>900 III/L) after ERCP, but clinical signs of acute pancreatitis with leukocytosis, CRF’ reaction, and pain developed in four of nine patients in the prophylaxis group compared to 15 of 15 patients with hyperamylasemia in the control group (P = 0.003). In a multivariate analysis, the lack of antibiotic prophylaxis (odds ratio 6.63, P = 0.03) and sphincterotomy (odds ratio 5.60, P = 0.05) were independent risk factors for the development of post-ERCP pancreatitis. We conclude that antibiotic prophylaxis effectively decreases the risk of pancreatitis, in addition to cholangitis after ERCP, and can thus be routinely recommended prior to ERCP These results suggest that bacteria could play a role in the pathogenesis of post-ERCP pancreatitis.

Prospective Randomized Trial of the Effect of Nifedipine on Pancreatic Irritation after Endoscopic Retrograde Cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) is complicated by acute pancreatitis in up to 12% of the examinations. One possible mechanism for this complication is the cannulation-induced sphincter of Oddi spasm with temporary pancreatic duct obstruction. Nifedipine is known to relax the sphincter of Oddi, thus possibly inhibiting or reducing post-ERCP +/- endoscopic sphincterotomy (EST) pancreatic irritation. To test this hypothesis 166 adult patients undergoing ERCP +/- EST were randomized to receive nifedipine (n = 82) 20 mg 3 times at 8-hour intervals during the day of ERCP +/- EST or placebo (n = 84) in a double-blind manner. Clinical pancreatitis developed in 6 patients (4%), in 3 patients in each group. Necrotizing pancreatitis developed in 3 patients, 2 (2%) in the nifedipine group and 1 (1%) in the placebo group. Overall 60 patients (36%) needed medication for post-ERCP +/- EST epigastric pain, 27 (33%) in the nifedipine group and 33 (39%) in the placebo group. Of the 87 patients, who did not need any pain medication before ERCP +/- EST, 34 (39%) needed pain medication after ERCP +/- EST. 14/47 (30%) in the nifedipine group and 20/40 (50%) in the placebo group (p = 0.044). Serum total amylase activity (median) increased from 189 U/l (range 39-11,950 U/l) before ERCP +/- EST to 299 U/l (range 43-11,824 U/l) at 12 h (p < 0.001) and 247 U/l (range 34-15,950 U/l) at 24 h (p < 0.001), with no differences between the two groups. Median serum C-reactive protein concentration and blood leukocyte count remained unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-Term Follow-up after the First Episode of Acute Alcoholic Pancreatitis: Time Course and Risk Factors for Recurrence

BACKGROUND Owing to the current lack of long-term follow-up data on the recurrence of alcohol-induced acute pancreatitis (AP), we studied the pattern of recurrence and determined the characteristics of the disease to predict the recurrence. METHODS Between 1972 and 1991, 2678 AP episodes were detected; 1555 were induced by alcohol, and 591 of them were the first episode. During the first alcohol-induced AP 29 patients died and were excluded from further analysis. Of the 562 included, 503 were men, and 59 women. Admission serum tests, severity index, development of complications, intensive care unit and hospital stay, and need for surgery were assessed. Case records were studied. The national database was used to detect admissions to other hospitals. RESULTS Overall, 260 (46%) developed recurrent disease. Of the first relapses, 80% developed during 4 years. The recurrence rate has not changed with time. Age less than 45 years increased the risk (odds ratio (OR) = 2.42; 95% confidence interval (CI), 1.30-4.50). The risk factors of the first alcohol-induced AP associated with the development of multi-recurring pancreatitis are age <45 years (OR, 2.42; 95% CI, 1.59-13.0), 0-2 positive Glasgow criteria (OR, 2.45; 95% CI, 1.16-5.19), and arterial oxygen tension >60 mmHg (OR, 9.90; 95% CI, 1.32-74.3). CONCLUSIONS Fewer than half of the patients develop recurrent alcohol-induced AP. Younger patients are at the highest risk of recurrence. Those whose first alcohol-induced pancreatitis episode was not severe are at a higher risk of developing multi-recurring pancreatitis.Background: Owing to the current lack of long-term follow-up data on the recurrence of alcohol-induced acute pancreatitis (AP), we studied the pattern of recurrence and determined the characteristics of the disease to predict the recurrence. Methods: Between 1972 and 1991, 2678 AP episodes were detected; 1555 were induced by alcohol, and 591 of them were the first episode. During the first alcohol-induced AP 29 patients died and were excluded from further analysis. Of the 562 included, 503 were men, and 59 women. Admission serum tests, severity index, development of complications, intensive care unit and hospital stay, and need for surgery were assessed. Case records were studied. The national database was used to detect admissions to other hospitals. Results: Overall, 260 (46%) developed recurrent disease. Of the first relapses, 80% developed during 4 years. The recurrence rate has not changed with time. Age less than 45 years increased the risk (odds ratio (OR) = 2.42; 95% confidence interval (CI), 1.30-4.50). The risk factors of the first alcohol-induced AP associated with the development of multi-recurring pancreatitis are age <45 years (OR, 2.42; 95% CI, 1.59-13.0), 0-2 positive Glasgow criteria (OR, 2.45; 95% CI, 1.16-5.19), and arterial oxygen tension >60 mmHg (OR, 9.90; 95% CI, 1.32-74.3). Conclusions: Fewer than half of the patients develop recurrent alcohol-induced AP. Younger patients are at the highest risk of recurrence. Those whose first alcohol-induced pancreatitis episode was not severe are at a higher risk of developing multi-recurring pancreatitis.

Risk factors for recurrent acute alcohol-associated pancreatitis: a prospective analysis.

Objective. In an earlier retrospective study we showed that 46% of patients with acute alcoholic pancreatitis had recurrent attacks within 10–20 years, about 30% having a recurrence during the first 3 years. The aim of this prospective follow-up study was to determine the risk factors associated with recurrences. Material and methods. Sixty-eight patients, (59 M, 9 F, mean age 46 years, range 25–71 years) who survived their first acute alcohol-induced pancreatitis from January 2001 to January 2004 volunteered to participate in the study. The diagnostic criteria for acute pancreatitis were epigastric pain, serum amylase >3 times the upper normal range, elevated serum C-reactive protein (CRP), and signs of acute pancreatitis in imaging. Other etiologies were excluded. Alcohol consumption and dependency were detected by the Alcohol Use Disorders Identification Test (AUDIT) and the Short Alcohol Dependence Data (SADD), respectively, and by attempting to evaluate recent use in grams of pure alcohol. Social and demographic data of the patients, smoking, body mass index, and the severity of the pancreatitis were recorded. Serum and fecal markers of the endocrine and exocrine function and secretin-stimulated MRCP were studied. The patients were followed for a median 38 (25–61) months for recurrences, and at the 2-year time-point had a follow-up visit to investigate any changes in alcohol consumption. Results. Seventeen (25%) patients had recurrences of acute alcoholic pancreatitis during the follow-up. Pre-illness alcohol consumption, the severity of the pancreatitis, patients social or demographic data, pancreatic function tests or morphologic changes in MRCP, or smoking did not correlate with recurrence. None of the 13 patients with consistent total abstinence from alcohol at 2 years developed recurrent pancreatitis compared with 17 out of 51 (33%) patients with at least some alcohol consumption (p=0.02). Use of other sedatives than alcohol before the first attack of pancreatitis was an independent risk factor associated with recurrence (HR = 6.95, 95% CI 2.45–19.72, p<0.001). A lower reduction in dependency on alcohol (less decreased SADD points) during 2 years was associated with a higher recurrence rate (HR = 0.921/each reduced point, 95% CI 0.872–0.974, p=0.004). Conclusions. Contrary to chronic pancreatitis, smoking was not found to be a risk factor for recurrent episodes after the first attack of acute alcoholic pancreatitis. Abstinence from alcohol protects against recurrent pancreatitis. Patients who developed recurrent acute pancreatitis had increased dependency on alcohol, demonstrated by the use of other sedatives in addition to alcohol and supported by the less decreased dependency during the follow-up.

Resection of the Head of the Pancreas in Finland: Effects of Hospital and Surgeon on Short-term and Long-term Results

Background: To study the effect of hospital volume and surgeon volume on postoperative hospital mortality, morbidity and long-term survival after resection of the head of the pancreas in a nationwide study (case record study), taking into a consideration risk factors found important in series based on experience in one hospital. Method: The case record investigation of 374 patients identified from the National Hospital Discharge Database as having undergone resection of the head of the pancreas between 1990 and 1994 in Finland. Results: The records of 350 patients were obtained for analysis. Operations were performed in 33 hospitals by 98 surgeons (average 2.1/year/hospital and 0.7/year/surgeon). Hospital mortality was 36/350 (10%), increasing from 4 and 7 to 13% with decreasing hospital volume from > 10 and 5-10 to < 5 respectively ( P < 0.05) and increasing from 3 and 10 to 14% with decreasing surgeon volume from > 3 and 1-3 to < 1, respectively ( P < 0.05). Most deaths were caused by surgical or technical complications (31/36 = 86%). Besides hospital mortality, postoperative complications, re-operations and hospital stay were also affected by surgeon volume. In the univariate analysis, also the age of the patient had an effect on the hospital mortality, and preoperative biliary stenting on the uncomplicated recovery, but in the multivariate analysis hospital mortality was independently affected by age (OR 0.94, P = 0.004) and surgeon volume (OR 1.3, P = 0.04), re-operations by surgeon volume (OR 1.10, P = 0.05) and hospital volume (OR 1.03, P = 0.05), postoperative complications by using the preoperative stent (OR 0.45, P = 0.02). Long-term survival was dependent on the histology of the specimen and by uncomplicated recovery, but not by hospital volume or surgeon volume. Conclusion: To decrease postoperative morbidity, mortality and hospital stay, pancreatic head surgery needs to be concentrated to only a few hospitals and to a few surgeons.

Postoperative acute pancreatitis as a major determinant of postoperative delayed gastric emptying after pancreaticoduodenectomy

The aim of this study was to prospectively analyze the possible association of delayed gastric emptying and postoperative pancreatic complications after pancreaticoduodenectomy. Although hospital mortality after pancreaticoduodenectomy is minimal, morbidity is still high; delayed gastric emptying is one of the most frequent complications. Thirty-nine consecutive patients undergoing pancreaticoduodenectomy were included in this study: 14 females and 25 males (median age 65 years; range, 7–82). Delayed gastric emptying was defined as the need for a nasogastric tube or recurrent vomiting that prevented normal feeding on the 10th postoperative day. Blood analysis was performed on postoperative days 4, 6, and 10; Gastrografin examination on day 6; CT scan on days 2 and 5; and drain amylases were measured on day 5. Pancreatitis was defined as pancreatitis changes in CT scan interpreted by an experienced radiologist without knowing other data. Pancreatic fistula was defined according to the recent international recommendations. We had no mortality. Twelve patients (31%) developed delayed gastric emptying. Surgical (9/12 vs. 5/27; P=0.001) but not medical complications occurred more often in the delayed gastric emptying group. Of the single complications, postoperative CT-detected pancreatitis (6/12 vs. 4/27; P=0.03) and postoperative pancreatic fistula (5/12 vs. 1/27; P=0.0007) were significantly associated with delayed gastric emptying compared with the patients without delayed gastric emptying. This pancreatitis was already detected in CT scan on day 2 in most patients (6/10, 60%). In delayed gastric emptying patients, the only parameters in blood analysis that differed significantly from patients without this complication were serum amylase activity (mean±SEM, 715±205 vs. 152±70 IU/L; P=0.02), blood leukocyte count (16±2 vs. 9±0.6 × 109/L; P=0.007) and serum C-reactive protein (CRP) concentration (144±28 vs. 51±14 mg/L, P=0.01). Postoperative pancreatic (subclinical) fistula was also associated with postoperative pancreatitis (6/10 vs. 0/29; P=0.003). Preoperative coronary artery disease (OR=16; 95% CI, 1.0-241; P=0.05) and soft pancreatic texture at operation (OR=9; 95% CI, 1.4-52; P=0.02) were significant risk factors for the development of postoperative pancreatitis. The diagnosis of delayed gastric emptying after pancreaticoduodenectomy often follows postoperative pancreatitis. Delayed gastric emptying is also associated with postoperative pancreatic fistula, for which this pancreatitis seems to be a risk factor. Preoperative coronary artery disease and soft texture of the pancreas are significant risk factors for postoperative CT-detected pancreatitis.