Rainer Isenmann

Human pancreatic tissue concentration of bactericidal antibiotics

Pancreatic infection represents the most important cause of fatal outcome in human acute pancreatitis. In a comparative analysis, human pancreatic tissue concentrations of 10 different bactericidal antibiotics were determined in 89 patients undergoing pancreatic surgery. Concentrations of the antibiotics were determined in the blood and pancreatic tissue using high-pressure liquid chromatography. Pancreatic tissue concentrations 120 minutes after intravenous administration were as follows: mezlocillin, 19.0 mg/kg; piperacillin, 20.3 mg/kg; cefotaxime, 9.1 mg/kg; ceftizoxime, 7.9 mg/kg; netilmicin, 0.4 mg/kg; tobramycin, 0.4 mg/kg; ofloxacin, 1.7 mg/kg; ciprofloxacin, 0.9 mg/kg; imipenem, 6.0 mg/kg; metronidazole, 3.5 mg/kg. Three groups of antibiotics were established: group A, substances with low tissue concentrations (netilmicin, tobramycin), which were below the minimal inhibitory concentrations of most bacteria found in pancreatic infection; group B, antibiotics with pancreatic tissue concentrations which were sufficient to inhibit some but not all bacteria in pancreatic infection (mezlocillin, piperacillin, ceftizoxime, cefotaxime); group C, substances with high pancreatic tissue levels as well as high bactericidal activity against most of the germs present in pancreatic infection (ciprofloxacin, ofloxacin, imipenem). These data could serve as the basis for adequate antibiotic prophylaxis or treatment of pancreatic infection.

Early severe acute pancreatitis: characteristics of a new subgroup.

This study focuses on patients with severe acute pancreatitis complicated by organ failure within the initial phase of the disease. Data of 158 patients with severe acute pancreatitis (SAP) admitted to hospital within 72 hours after onset of symptoms were prospectively documented and analyzed for the occurrence of early severe acute pancreatitis (ESAP). ESAP was defined as presence of organ failure (OF) at admission. Forty-seven (30%) patients had ESAP, compared with 111 patients without OF (SAP group). In a multivariate analysis, the main factor predisposing to ESAP was the presence of extended pancreatic necrosis (odds ratio, 3.8), whereas biliary pancreatitis was associated with a slightly lower risk compared with alcoholic pancreatitis (odds ratio, 0.34). Compared with SAP, patients with ESAP more frequently developed intractable organ failure, which posed the indication for surgical treatment. Surgical necrosectomy due to progressive OF had to be performed in 89% of the ESAP patients and in 60% of the SAP patients. The incidence of infected pancreatic necrosis did not differ between both groups (23 vs. 21%). Mortality was significantly higher in ESAP (42 vs. 14%;p = 0.0003). ESAP is characterized by the presence of extended pancreatic necrosis and a complicated clinical course. Intractable organ failure is a frequent finding. Given the poor prognosis of ESAP, these patients should be treated in specialized intensive care units.

SURGICAL MANAGEMENT OF NECROTIZING PANCREATITIS

The most important diagnostic step in the management of patients with severe acute pancreatitis is the discrimination between acute interstitial and necrotizing pancreatitis. Measurement of C-reactive protein, lactic acid dehydrogenase, alpha-1-antitrypsin, and alpha-2-macroglobulin and contrast-enhanced CT are useful in detecting the necrotizing course of acute pancreatitis. C-reactive protein, lactic acid dehydrogenase, and contrast-enhanced CT offer detection rates of 85 per cent to more than 90 per cent for pancreatic necrosis. Surgical decision-making in necrotizing pancreatitis should be based on clinical, morphologic, and bacteriologic data. Patients with focal pancreatic necrosis, in general, respond well to medical treatment and do not need surgery. Extended (50 per cent or more) pancreatic necroses, infected necroses, and intrapancreatic parenchymal necroses plus extrapancreatic fatty tissue necroses are indicators for surgical management. The decision for the timing of operation in patients with proved necrotizing pancreatitis should be based on clinical criteria: the development of an acute surgical abdomen, generalized sepsis, shock, persisting or increasing organ dysfunction, or some combination thereof despite maximum intensive care treatment for at least 3 days. Major pancreatic resection for the treatment of necrotizing pancreatitis appears disadvantageous. Necrosectomy and continuous local lavage allow debridement of devitalized tissue and preservation of vital pancreatic tissue. Postoperative local lavage thus results in an atraumatic evacuation of necrotic tissue, the bacterial material, and biologically active substances. The hospital mortality rate of patients treated with necrosectomy and continuous local lavage (the Ulm protocol) is below 10 per cent. Nevertheless, controlled prospective clinical trials should be performed in order to bring more precision to our clinical decisions in respect to the role of surgery for this disease.

Influence of Etiology on the Course and Outcome of Acute Pancreatitis

It has been supposed that there are differences with regard to clinical course and outcome due to the underlying etiological factor in acute pancreatitis. Therefore, the objective of this study was to analyze the severity of the disease, serum enzymes, indicators of necrosis, systemic complications, and mortality in acute pancreatitis with regard to the etiology. One hundred ninety patients with acute pancreatitis (127 male, 63 female) were studied prospectively and subdivided into three etiological groups: (i) alcohol, (ii) gallstones, and (iii) other causes and idiopathic acute pancreatitis. Severity scores (Ranson and Bank) and findings by contrast-enhanced computed tomography were similar in all three groups. Analysis of serum enzymes [lipase, aspartate aminotransferase (ASAT)] and indicators of necrosis (C-reactive protein, alpha 1-antitrypsin, alpha 2-macroglobulin, and lactate dehydrogenase) showed only for ASAT within 24 h significantly higher levels in biliary acute pancreatitis in comparison with the other groups. There were no differences in the rate of infected pancreatic necrosis and mortality in alcohol-related acute pancreatitis (31 and 5.3%), biliary acute pancreatitis (38 and 10%) and acute pancreatitis due to other etiological factors (43 and 5.5%). In conclusion, this study clearly showed that once the pathogenetic mechanisms have initiated the disease, the course and outcome of acute pancreatitis are not influenced by the underlying etiological factor.

Pancreatic necrosis: an early finding in severe acute pancreatitis.

Despite the clinical importance of pancreatic necrosis in the course of acute pancreatitis, little is known about when it develops. Serum C-reactive protein (CRP) is a reliable parameter with a high detection rate for pancreatic necrosis. We analyzed 199 patients with acute pancreatitis. The development of pancreatic necrosis was ascertained by a daily measurement of serum CRP in 45 patients with contrast-enhanced computed tomographic proven necrotizing pancreatitis. In all 45 cases, the criteria for pancreatic necrosis were satisfied within the first 4 days of the onset of symptoms. This indicates that pancreatic necrosis is an early finding that develops within hours.

Characteristics of infection with Candida species in patients with necrotizing pancreatitis.

This study focuses on the relevance of Candida infection (albicans andnon-albicans) in patients with necrotizing pancreatitis.Altogether, 92 patients with infected pancreatic necrosis were reviewedfor Candida infection. All patients underwent surgicalnecrosectomy for infected pancreatic necrosis. Data from patients withCandida growth in intraoperative smears were compared tothose obtained from patients without Candida infection.There were 22 patients (24%) with Candida infection.Patients with or without Candida infection were comparableregarding age, gender, etiology, and severity scores at admission.Candida patients suffered a higher mortality (64% vs.19%, p = 0.0001) and experienced more systemiccomplications (3.2 ± 1.6 vs. 2.1 ± 1.4; p= 0.004) than patients without Candida. Preoperativeantibiotics were given significantly longer prior toCandida infection (19.0 ± 13.2 vs. 6.4 ± 10.3days; p < 0.0001). With regard to the concomitantspectrum of bacteria, solitary gram-negative infection was rare inCandida patients (5% vs. 43%, p =0.0006). The presence of Candida in patients with infectedpancreatic necrosis is associated with increased mortality. Our dataprovide evidence that application of antibiotics contributes to thedevelopment of Candida infection and to changes in thebacterial spectrum of infected necrosis with an increase in theincidence of gram-positive infection.

Natural History of Necrotizing Pancreatitis

The current definition of severe acute pancreatitis is based on a consensus found in Atlanta in 1992. The socalled Atlanta classification recognizes both the pathomorphologic and clinical characteristics of severe acute pancreatitis. In contrast to former classifications of acute pancreatitis, the Atlanta definition gives a number of clearly defined criteria that characterize a severe episode of the disease. Severe acute pancreatitis is associated with systemic complications such as pulmonary failure, renal insufficiency, shock or coagulation disorders [1]. Although the Atlanta system discriminates between local and systemic complications of the disease, there apparently is a close connection between these entities as it is a common observation that systemic complications are almost exclusively restricted to patients with pancreatic necrosis [2–4]. During the past years, we have learned that not all of the Atlanta criteria of severity really correlate with poor outcome. New criteria of severity such as advanced age and obesity have been identified that seem to be predictors of poor prognosis [5–7]. It will be the subject of future classification conferences to review and redefine the severity definition of this disease [8]. Acute pancreatitis is most commonly due either to gallstones or to alcohol overindulgence. Nevertheless, other etiologic causes can be observed, such as pancreatitis following endoscopic retrograde cholangiopancreatography or idiopathic disease. Alcoholic pancreatitis plays the leading role in central and northern Europe, whereas biliary pancreatitis seems to be more common in the United States.

Systematic review and meta-analysis of antibiotic prophylaxis in severe acute pancreatitis

Abstract Objective. The incidence of acute pancreatitis varies from 5 to 80 per 100,000 throughout the world. The most common cause of death in these patients is infection of pancreatic necrosis by enteric bacteria, spurring the discussion of whether or not prophylactic antibiotic administration could be a beneficial approach. In order to provide evidence of the effect of antibiotic prophylaxis in severe acute pancreatitis (SAP) we performed an updated systematic review and meta-analysis on this topic. Methods. The review of randomized controlled trials was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We conducted a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. For assessment of the treatment effects we calculated the risk ratios (RRs) for dichotomous data of included studies. Results. Fourteen trials were included with a total of 841 patients. The use of antibiotic prophylaxis was not associated with a statistically significant reduction in mortality (RR 0.74 [95% CI 0.50–1.07]), in the incidence of infected pancreatic necrosis (RR 0.78 [95% CI 0.60–1.02]), in the incidence of non-pancreatic infections (RR 0.70 [95% CI 0.46–1.06]), and in surgical interventions (RR 0.93 [95% CI 0.72–1.20]). Conclusion. In summary, to date there is no evidence that supports the routine use of antibiotic prophylaxis in patients with SAP.

Antibiotic Prophylaxis in Severe Acute Pancreatitis

Severe acute pancreatitis is considered to be a subgroup of acute pancreatitis with the development of local and/or systemic complications. A significant correlation exists between the development of pancreatic necrosis, the frequency of bacterial contamination of necrosis and the evolution of systemic complications. Bacterial infection and the extent of necrosis are determinants for the outcome of severe acute pancreatitis. The late course of necrotizing pancreatitis is determined by bacterial infection of pancreatic and peripancreatic necroses. Mortality increases from 5–25% in patients with sterile necrosis to 15–28% when infection has occurred. The use of prophylactic antibiotics has been recommended in patients with necrotizing pancreatitis. Several controlled clinical trials demonstrated a significant reduction in pancreatic infections or a significant reduction of hospital mortality. However, the results of these clinical trials are controversial and not convincing. Recently, the largest randomized placebo-controlled, double-blind trial has been able to demonstrate that antibiotic prophylaxis with ciprofloxacin and metronidazole has no beneficial effects with regard to the reduction of pancreatic infection and the decrease of hospital mortality. The clinical data from this placebo-controlled trial do not support antibiotic prophylaxis in all patients with necrotizing pancreatitis, but in specific subgroups of patients with pancreatic necrosis and a complicated course.

Management of Patients with Extended Pancreatic Necrosis

Background: Extended pancreatic necrosis pose a considerable therapeutic problem in patients with necrotizing pancreatitis. Aim: Factors that limit conservative treatment in patients with extended pancreatic necrosis were analyzed. Methods: The clinical course of 61 patients with an extent of necrosis of more than 50% of the gland (according to contrast-enhanced CT scan) were analysed with special regard to systemic complications. Indications for surgical treatment were either persistent organ failure or pancreatic infection. Results: 10 patients were managed by conservative treatment, 51 (84%) patients underwent operation. Indications for surgery were sepsis with or without organ failure in 17 patients, persistent organ failure in another 17 patients, persistent SIRS in 13 patients and local complications in 4 patients. Pancreatic infection was present in 25 patients. The incidence of systemic complications did not differ between infected and sterile necrosis, but they occurred earlier in sterile necrosis. Conclusions: Persistent organ failure is limiting conservative treatment during the early course in patients with sterile necrosis. The latter course is characterized by a high incidence of pancreatic infection and septic organ failure.