Christophe A. Müller

Acute Necrotizing Pancreatitis: Treatment Strategy According to the Status of Infection

ObjectiveTo determine benefits of conservative versus surgical treatment in patients with necrotizing pancreatitis. Summary Background DataInfection of pancreatic necrosis is the most important risk factor contributing to death in severe acute pancreatitis, and it is generally accepted that infected pancreatic necrosis should be managed surgically. In contrast, the management of sterile pancreatic necrosis accompanied by organ failure is controversial. Recent clinical experience has provided evidence that conservative management of sterile pancreatic necrosis including early antibiotic administration seems promising. MethodsA prospective single-center trial evaluated the role of nonsurgical management including early antibiotic treatment in patients with necrotizing pancreatitis. Pancreatic infection, if confirmed by fine-needle aspiration, was considered an indication for surgery, whereas patients without signs of pancreatic infection were treated without surgery. ResultsBetween January 1994 and June 1999, 204 consecutive patients with acute pancreatitis were recruited. Eighty-six (42%) had necrotizing disease, of whom 57 (66%) had sterile and 29 (34%) infected necrosis. Patients with infected necrosis had more organ failures and a greater extent of necrosis compared with those with sterile necrosis. When early antibiotic treatment was used in all patients with necrotizing pancreatitis (imipenem/cilastatin), the characteristics of pancreatic infection changed to predominantly gram-positive and fungal infections. Fine-needle aspiration showed a sensitivity of 96% for detecting pancreatic infection. The death rate was 1.8% (1/56) in patients with sterile necrosis managed without surgery versus 24% (7/29) in patients with infected necrosis (P <.01). Two patients whose infected necrosis could not be diagnosed in a timely fashion died while receiving nonsurgical treatment. Thus, an intent-to-treat analysis (nonsurgical vs. surgical treatment) revealed a death rate of 5% (3/58) with conservative management versus 21% (6/28) with surgery. ConclusionsThese results support nonsurgical management, including early antibiotic treatment, in patients with sterile pancreatic necrosis. Patients with infected necrosis still represent a high-risk group in severe acute pancreatitis, and for them surgical treatment seems preferable.

Partial Pancreatectomy in Adult Humans Does Not Provoke β-Cell Regeneration

OBJECTIVE—β-Cell regeneration has been proposed as a possible treatment for diabetes, but the capacity for new β-cell formation in humans is yet unclear. In young rats, partial pancreatectomy prompts new β-cell formation to restore β-cell mass. We addressed the following questions: In adult humans: 1) Does partial pancreatectomy provoke new β-cell formation and increased β-cell mass? 2) Is β-cell turnover increased after partial pancreatectomy? RESEARCH DESIGN AND METHODS—Protocol 1: human pancreatic tissue was collected from 13 patients who underwent two consecutive partial pancreas resections, and markers of cell turnover were determined in both tissue samples, respectively. Protocol 2: pancreas volumes were determined from abdominal computer tomography scans, performed in 17 patients on two separate occasions after partial pancreatectomy. RESULTS—Protocol 1: fasting glucose concentrations increased significantly after the 50% pancreatectomy (P = 0.01), but the fractional β-cell area of the pancreas remained unchanged (P = 0.11). β-Cell proliferation, the overall replication index (Ki67 staining), and the percentage of duct cells expressing insulin were similar before and after the partial pancreatectomy. The overall frequency of apoptosis (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling) was slightly increased following the partial pancreatectomy (P = 0.02). Protocol 2: pancreatic volume was ∼50% reduced to 35.6 ± 2.6 ccm3 by the partial pancreatectomy. The total pancreatic volume was unchanged after an interval of 247 ± 160 days (35.4 ± 2.7 ccm3; P = 0.51). CONCLUSIONS—Unlike in rodents, a 50% pancreatectomy does not prompt β-cell regeneration in adult humans. This explains the high incidence of diabetes after pancreatic resections. Such differences in β-cell turnover between rodents and humans should be born in mind when evaluating new treatment options aiming to restore β-cell mass in patients with diabetes.

Useful markers for predicting severity and monitoring progression of acute pancreatitis.

Background: The main problem in staging acute pancreatitis is the lack of accurate predictors of disease severity and of markers for progression of acute pancreatitis. Methods: We reviewed the literature for all candidate markers of acute pancreatitis and graded their usefulness and practicability for prediction of severe pancreatitis and for monitoring disease progression. Results: Several markers can differentiate mild and severe cases of acute pancreatitis with a high positive predictive value. Trypsinogen activation peptide and procalcitonin show significant differences in patients with mild and severe disease already on admission. While most parameters peak early and decrease rapidly thereafter, C-reactive protein (CRP), phospholipase A2, procalcitonin and serum amyloid A are reliable predictors with persistently elevated levels in severe disease. CRP is still the reference parameter of all predictors indicating severe disease and pancreatic necrosis. So far, no single parameter has been developed which is suitable for early prediction of infected pancreatic necrosis. Conclusion: Of all markers available today, CRP is the ‘gold standard’ in predicting the severity of acute pancreatitis, but procalcitonin seems to be a promising tool to monitor the progression of the disease. CRP has already been established in clinical routine. For procalcitonin, a practicable assay is also available and could easily be adopted into clinical routine.

Functional Assessment of Pancreatic β-Cell Area in Humans

OBJECTIVE β-Cell mass declines progressively during the course of diabetes, and various antidiabetic treatment regimens have been suggested to modulate β-cell mass. However, imaging methods allowing the monitoring of changes in β-cell mass in vivo have not yet become available. We address whether pancreatic β-cell area can be assessed by functional test of insulin secretion in humans. RESEARCH DESIGN AND METHODS A total of 33 patients with chronic pancreatitis (n = 17), benign pancreatic adenomas (n = 13), and tumors of the ampulla of Vater (n = 3) at various stages of glucose tolerance were examined with an oral glucose load before undergoing pancreatic surgery. Indexes of insulin secretion were calculated and compared with the fractional β-cell area of the pancreas. RESULTS β-Cell area was related to fasting glucose concentrations in an inverse linear fashion (r = −0.53, P = 0.0014) and to 120-min postchallenge glycemia in an inverse exponential fashion (r = −0.89). β-Cell area was best predicted by a C-peptide–to–glucose ratio determined 15 min after the glucose drink (r = 0.72, P < 0.0001). However, a fasting C-peptide–to–glucose ratio already yielded a reasonably close correlation (r = 0.63, P < 0.0001). Homeostasis model assessment (HOMA) β-cell function was unrelated to β-cell area. CONCLUSIONS Glucose control is closely related to pancreatic β-cell area in humans. A C-peptide–to–glucose ratio after oral glucose ingestion appears to better predict β-cell area than fasting measures, such as the HOMA index.

Influence of contrast-enhanced computed tomography on course and outcome in patients with acute pancreatitis.

Introduction Many of the complications in severe acute pancreatitis result from the amplifying effects of microcirculatory disruption. Contrast medium may cause significant additional reductions of capillary flow, which has been shown to aggravate acute pancreatitis in experimental studies. Aim To investigate the role of serial contrast-enhanced computed tomography (CECT) in patients with acute pancreatitis. Methodology A retrospective analysis evaluated 302 patients with moderate to severe acute pancreatitis. Among these patients, 264 underwent CECT within 96 hours of the onset of symptoms and again during the course, but in 38 patients no serial CECT was performed. Outcome measurement was analyzed by comparison of hospital stay and mortality rate between the two patient groups. Influences of contrast medium on severity of disease were detected by monitoring complications during the course of treatment, C-reactive protein, and APACHE II score. Results The 1-month mortality rate was less in patients with CECT (6.4% versus 15.8%, p <0.05). There were no significant differences considering the incidence of additional complications, and hospital stay was not significantly longer (29 ± 36 versus 19 ± 13 days). C-reactive protein and APACHE II score had similar time courses. Conclusion Contrast-enhanced computed tomography remains crucial in identifying patients with acute pancreatitis at high risk to develop necrosis of the pancreas and systemic complications. Contrast medium has been found to aggravate acute pancreatitis in animal models. As compared with the patient group without being exposed to contrast medium, however, this study did not show a deterioration of acute pancreatitis by administration of contrast medium in men.

Modern Phase-Specific Management of Acute Pancreatitis

The management of acute necrotizing pancreatitis has changed significantly over the past years. In contrast to the early surgical intervention of the past, there is now a strong tendency towards a more conservative approach. Initially, severe acute pancreatitis is characterized by the systemic inflammatory response syndrome. Early management is non-surgically and solely supportive. A specific treatment still does not exist. In cases of necrotizing disease, prophylactic antibiotics should be applied to reduce late septic complications. Today, more patients survive the first phase of severe pancreatitis due to improvements of intensive care medicine, thus increasing the risk of later sepsis. Pancreatic infection is the major risk factor with regard to morbidity and mortality in the second phase of severe acute pancreatitis. Whereas early surgery and surgery for sterile necrosis can only be recommended in selected cases, pancreatic infection is a well-accepted indication for surgical treatment in the second phase of the disease. Surgery should ideally be postponed until 4 weeks after the onset of symptoms, as necrosis is well demarcated at that time. Three surgical techniques can be performed with comparable results regarding mortality: necrosectomy combined with the (1) open packing technique, (2) planned staged relaparotomies with repeated lavage, or (3) closed continuous lavage of the retroperitoneum. However, the latter method seems to be associated with the lowest morbidity compared to the other approaches.

Intraductal papillary mucinous neoplasms of the pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are now a well-recognized category of slowly growing tumors with a remarkably better prognosis, even when malignant, than pancreatic ductal adenocarcinoma. Their clinical and pathohistologic features have been increasingly attracting the attention of clinicians since their first description 25 years ago. Despite its burgeoning volume recently, accumulated literature devoted to IPMN still provides a low level of evidence with regard to diagnosis, treatment, and prognosis. Therefore, we performed a Medline-based systematic review of the literature aimed at clearly defining the clinicopathologic characteristics of pancreatic IPMN and determining the best currently available evidence-based principles of diagnosis and management of patients with this disease.

Role of endogenous glucocorticoid metabolism in human acute pancreatitis

Objective:This study aimed to observe how levels of total cortisol, calculated free cortisol, corticosteroid-binding globulin, and adrenocorticotropic hormone change during the early course of human acute pancreatitis and to describe how these changes affect the development of pancreatic necrosis. Design and Patients:In a total of 109 consecutive patients with acute pancreatitis (74 with edematous pancreatitis, 35 with necrotizing pancreatitis), serial daily blood monitoring of total and free cortisol, adrenocorticotropic hormone, and corticosteroid-binding globulin was done after hospital admission, up to day 6 after the onset of pain; 30 healthy individuals served as controls. Measurements:Corticosteroid-binding globulin and total cortisol were measured by immunoassays, and free cortisol was calculated according to Coolens et al. The adrenocorticotropic hormone was measured with an enzyme-linked immunoassay. Results:Initially, highly elevated levels of calculated free cortisol (median, 86.2 ng/mL; quartile ranges, 50.6–106.7 ng/mL) and total cortisol (41.2 &mgr;g/dL, 30.4–51.1 &mgr;g/dL) and depressed levels of adrenocorticotropic hormone (0.2 pg/mL, 0.1–2.0 pg/mL) and corticosteroid-binding globulin (30.6 &mgr;g/mL, 24.1–35.5 &mgr;g/mL) were observed. Further, daily measurements revealed increasing adrenocorticotropic hormone levels, whereas cortisol levels decreased. Conclusions:Although an increase in adrenocorticotropic hormone levels is suggested to increase corresponding cortisol levels, cortisol levels decreased during the development of necrotizing acute pancreatitis. This phenomenon, along with the continuously decreasing corticosteroid-binding globulin levels, brings up the hypothesis of a relative adrenal insufficiency, which favors acinar cell apoptosis and hence may trigger the development of necrosis in the initial vulnerable phase of acute pancreatitis.

Bacteribilia after preoperative bile duct stenting: a prospective study.

Study Design A prospective analysis of intraoperative bile duct cultures in patients undergoing surgery for both, malignant or benign periampullary diseases at the Department of Surgery, St Josef Hospital, Bochum, Germany, during a period of 18 months, between January 2004 and June 2005. Goals The goals of the presented study were to investigate the effects of preoperative bile duct stenting on intraoperative bile duct cultures and postoperative outcome in patients undergoing pancreatic surgery. Background In pancreatic surgery, bile duct stenting is often aimed at improving postoperative outcome. As implantation of xenograft material in the main bile duct facilitates bacterial contamination and cholangitis, a critical evaluation of stenting is mandatory. Study In all patients with a hepaticojejunostomy (n=80), a bile duct culture was collected during the operation. All patients received antibiotic prophylaxis perioperatively and a retrograde flushing of bile ducts with warm saline after bile duct resection. Fifty-one percent (41/80) patients had biliary drainage before surgery, whereas 49% (39/80) were operated without preoperative draining procedures. Results After bile duct stenting, 98% of patients had a positive bile culture, whereas only 21% of infected bile was seen in patients without drainage (P<0.001). Despite infected bile, only 2% stented patients developed acute cholangitis postoperatively, versus 13% patients in the group without stent (P=0.231). After stenting, major complications occurred in 12%, versus 8% in patients without stent (P=0.817). Conclusions Preoperative biliary drainage leads to an almost 100% bacterial contamination of bile ducts. With hospital-adjusted antibiotic prophylaxis and retrograde flushing of bile ducts, the postoperative rate of acute cholangitis and morbidity is not elevated. A critical evaluation of benefits from preoperative biliary drainage for each patient is necessary.

Predictive value of complement activation fragments C3a and sC5b-9 for development of severe disease in patients with acute pancreatitis.

Background: Complement activation has been shown to occur in patients with acute pancreatitis. However, the diagnostic potential of complement activation products in plasma for predicting severe disease remains unclear to date. Methods: The daily levels of the complement anaphylatoxin C3a and the soluble terminal complement complex sC5b‐9 were determined by ELISA in plasma of patients with mild (n = 16) or severe (n = 14) acute pancreatitis during the first week after onset of symptoms, and in healthy control subjects (n = 14). Results: Both C3a and sC5b‐9 were significantly elevated during the first 7 days in plasma of patients with severe acute pancreatitis (C3a: 459.3 ± 407.5 ng/mL (mean ± s); sC5b‐9: 617.9 ± 297.7 ng/mL), as compared to patients with mild disease (C3a: 172 ± 149.5 ng/mL; sC5b‐9: 306.7 ± 167.3 ng/mL) or controls (C3a: 102.3 ± 19.7 ng/mL; sC5b‐9: 40.64 ± 19.7 ng/mL; P < 0.001, repeated measures ANOVA). The analysis of both parameters in combination during the first week after onset of symptoms revealed a high sensitivity (0.93) and specificity (0.88) as well as high negative and positive predictive values (0.93 and 0.87, respectively) with an odds ratio of 91.0 for the development of pancreatic necrosis (P < 0.0001, Fisher exact test). Conclusion: In patients with acute pancreatitis, the plasma levels of complement C3a and sC5b‐9 measured daily during the first week after onset of symptoms represent highly specific and sensitive parameters for the prediction of severe acute pancreatitis.