Benoy I. Babu

Open pancreatic necrosectomy in the multidisciplinary management of postinflammatory necrosis.

Objective:To examine clinical outcome in a consecutive cohort of patients undergoing open necrosectomy for postinflammatory necrosis. Background Information:The last decade has witnessed major developments in the surgical management of pancreatic necrosis. Minimally invasive approaches have become established. However, there are limited data from contemporary open necrosectomy, in particular where multidisciplinary care and aggressive interventional radiology are used. This report provides data on outcome from open necrosectomy in a tertiary referral Hepatobiliary unit over the last decade. Methods:During the period January 1, 2000 to July 31, 2008, 1535 patients were admitted with a final discharge code of acute pancreatitis. Twenty-eight (1.8%) of all admissions underwent open surgical necrosectomy. Twenty-four (86%) were tertiary referral patients. Results:The median APACHE II score on admission was 10.5 (5–26). Median logistic organ dysfunction score on admission was 3 (0–10). Median LODS score after surgery was 2 (0–8). Twenty patients (71%) underwent radiologically guided drainage of collections before surgery. Thirty-day mortality occurred in 2 (7%), 4 further deaths occurred in patients after discharge from intensive care resulting in a total of 6 (22%) episode-related deaths. Conclusions:Modern open necrosectomy can be performed without the procedure-related deterioration in organ dysfunction associated with major debridement. Multidisciplinary care with an emphasis on aggressive radiologic intervention before and after surgery results in acceptable outcomes in this cohort of critically ill patients. Newer laparoscopic techniques must demonstrate similar outcomes in the setting of stage-matched severity before wider acceptance.

Current status of minimally invasive necrosectomy for post-inflammatory pancreatic necrosis

OBJECTIVE This paper reviews current knowledge on minimally invasive pancreatic necrosectomy. BACKGROUND Blunt (non-anatomical) debridement of necrotic tissue at laparotomy is the standard method of treatment of infected post-inflammatory pancreatic necrosis. Recognition that laparotomy may add to morbidity by increasing postoperative organ dysfunction has led to the development of alternative, minimally invasive methods for debridement. This study reports the status of minimally invasive necrosectomy by different approaches. METHODS Searches of MEDLINE and EMBASE for the period 1996-2008 were undertaken. Only studies with original data and information on outcome were included. This produced a final population of 28 studies reporting on 344 patients undergoing minimally invasive necrosectomy, with a median (range) number of patients per study of nine (1-53). Procedures were categorized as retroperitoneal, endoscopic or laparoscopic. RESULTS A total of 141 patients underwent retroperitoneal necrosectomy, of whom 58 (41%) had complications and 18 (13%) required laparotomy. There were 22 (16%) deaths. Overall, 157 patients underwent endoscopic necrosectomy; major complications were reported in 31 (20%) and death in seven (5%). Laparoscopic necrosectomy was carried out in 46 patients, of whom five (11%) required laparotomy and three (7%) died. CONCLUSIONS Minimally invasive necrosectomy is technically feasible and a body of evidence now suggests that acceptable outcomes can be achieved. There are no comparisons of results, either with open surgery or among different minimally invasive techniques.

Green tea polyphenols ameliorate pancreatic injury in cerulein-induced murine acute pancreatitis.

Objective: Green tea polyphenols (GTPs) are naturally occurring antioxidants acting through pathways that include reactive oxygen species and nuclear factor kappa B (NF-&kgr;B). This study investigates the effect of GTPs in a cerulein-induced murine model of acute pancreatitis (AP). Methods: Male CD mice (median weight, 37.7 g) were divided into 4 groups: mice administered with cerulein alone, cerulein and GTP, saline alone (sham), and GTP alone. Acute pancreatitis was induced by serial intraperitoneal administration of cerulein (50 &mgr;g/kg, ×6). Green tea polyphenol was administered intraperitoneally at 25 mg/kg on the first, third, and sixth hours after pancreatitis induction. We analyzed histologic and biochemical features of AP, NF-&kgr;B pathway activity, leukocyte-mediated damage, cytokine levels, oxidative stress injury, lipid peroxidation, expression of poly-(adenosine diphosphate-ribose) synthetase, and presence of apoptosis. Results: Treatment with GTP reduced the histologic and biochemical features of AP. Western blot revealed significant NF-&kgr;B inactivation. Immunostaining for P selectin and intercellular adhesion molecule 1, tumor necrosis factor &agr;, transforming growth factor &bgr;, vascular endothelial growth factor, nitrotirosine, poly-(adenosine diphosphate ribose) synthetase, and malondialdheide levels were significantly reduced. There was a significant down-regulation of apoptotic markers. Conclusions: Our results demonstrated that GTP significantly ameliorated the effects of cerulein-induced AP in mice. These effects of GTP are mediated by actions at the NF-&kgr;B/IkB (inhibitor kB) proteins and oxidative stress pathways.

The performance of organ dysfunction scores for the early prediction and management of severity in acute pancreatitis: an exploratory phase diagnostic study.

Objective: To evaluate contemporary organ dysfunction scoring systems for early prediction of severity in acute pancreatitis (AP). Methods: In a consecutive cohort of 181 patients with AP, organ dysfunction scores (logistic organ dysfunction system [LODS] score, Marshall organ dysfunction score, and sequential organ failure assessment score) were collected at 24 and 48 hours. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated on admission and 24 and 48 hours and C-reactive protein level measured at 48 hours. Patients who died or used critical care facilities (level 2/3) during admission were classed as severe. Results: Area under curve for APACHE II score at admission was 0.78 (95% confidence interval, 0.69-0.86). At 24 hours, area under curve for LODS, Marshall organ dysfunction system, sequential organ failure assessment, and APACHE II scores were 0.82, 0.80, 0.80, and 0.82, respectively. The LODS score at cutoff of 1 achieved 90% sensitivity and 69% specificity, corresponding to a positive predictive value of 38%. Acute Physiology and Chronic Health Evaluation II score as a rule-out for selection of mild cases at a test threshold of 9 (scores ≤ 8 being selected) gives homogeneity of 91% and efficiency of 79%. Conclusions: Contemporary organ dysfunction scoring systems provides an objective guide to stratification of management, but there is no perfect score. All scores evaluated here perform equivalently at 24 hours. Acute Physiology and Chronic Health Evaluation II may have practical clinical value as a rule-out test.

Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: Systematic review of current evidence

BACKGROUND The severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review. METHODS A literature review of published material identified from MEDLINE and EMBASE databases, for the period from January 1985 to January 2011, reporting rhAPC usage in AP. RESULTS 3 of 4 experimental studies reported an improvement in outcome in animals with AP given rhAPC. The clinical randomized trial showed no improvement in outcome in the treatment arm. CONCLUSION The experimental evidence of disease amelioration in AP following intervention with rhAPC has not translated to the small clinical RCT. Given that there were only 16 patients in the treatment arm, further clinical evaluation is justified.

Recombinant human activated protein C (Xigris) attenuates murine cerulein-induced acute pancreatitis via regulation of nuclear factor κB and apoptotic pathways.

Objectives Microvascular thrombosis occurs in severe acute pancreatitis (AP). Exploiting this knowledge, we used human recombinant activated protein C (Xigris; Eli Lilly, Indianapolis, Ind) known to preserve microvascular patency, in evaluating the role of Xigris in experimental AP. Methods In accordance with European union experimentation regulations, AP was induced by hourly injection of cerulein 50 &mgr;g/kg body weight over 6 hours. Male rats of median weight of 231 g (range, 176-312 g) were allocated at random into groups: group 1, control; group 2, vehicle; group 3, AP; group 4, cerulein + Xigris at induction of AP and killing at 24 h; and group 5, cerulein + Xigris 24 hours after induction and killing at 48 hours. In addition to enzymatic and histological markers of pancreatic injury, apoptosis, nuclear factor &kgr;B (NF-&kgr;B) p65/I&kgr;B, cytokine response, and endothelial injury were assessed. Western blot quantified by densitometry was used to assess marker of apoptosis and endothelial injury. Results Cerulein injection resulted in acute necrotizing pancreatitis. Intervention with recombinant human activated protein C did not modify coagulation parameters or lead to hemorrhage but ameliorated pancreatic injury with preservation of I&kgr;B and reduction of NF-&kgr;B p65 and modulation of apoptosis. Conclusions Our study indicates that recombinant human activated protein C ameliorates experimental cerulein-induced pancreatitis through apoptotic and NF-&kgr;B pathways without causing pancreatic hemorrhage.

Practical Strategies for Case Selection in Minimally Invasive Necrosectomy

Background: Minimally invasive necrosectomy is an umbrella term encapsulating the retroperitoneal, endoscopic and laparoscopic approaches. However, current evidence is unclear in terms of which approach to select in any particular setting. Methods/Results: This leading article provides a pragmatic guide to approach selection in treating pancreatic necrosis with particular reference to the use of minimally invasive approaches. Current evidence in relation to timing of surgery, use of fine-needle aspiration and detailed imaging by magnetic resonance scanning is incorporated into a modern treatment algorithm. Conclusion: The era of minimally invasive necrosectomy has arrived. In the absence of randomised trial evidence, the keys to contemporary management of pancreatic necrosis are good multidisciplinary care, adequate high-quality imaging and careful consideration of all available treatment options including traditional open approaches.

Twenty-four hour infusion of human recombinant activated protein C (Xigris) early in severe acute pancreatitis: The XIG-AP 1 trial.

OBJECTIVE Patients with severe acute pancreatitis were excluded from major trials of human recombinant activated protein C (Xigris) because of concern about pancreatic haemorrhage although these individuals have an intense systemic inflammatory response that may benefit from treatment. The object of this study was to provide initial safety data evaluating Xigris in severe acute pancreatitis. DESIGN Prospective clinical trial recruiting between November 2009 and October 2011. Patients received human recombinant activated protein C (Xigris) for 24 h by intravenous infusion (24 μg/kg/h) in addition to standard clinical care. A matched historical control group treated within the same hospital unit were used to compare outcomes. Of 166 consecutive admitted patients, 43 met the screening criteria for severe acute pancreatitis and 19 were recruited, all contributing to the analyses. RESULTS Compared to historical controls, there were fewer bleeding events in the Xigris group although the finding did not reach significance (Xigris 0% vs. Control 21%, p = 0.13), similarly further intervention appeared less frequent (11% vs. 47%, p = 0.07) in the treatment group. Length of stay was shorter for patients receiving Xigris (19 vs. 41 days, p = 0.03) as was inotrope use (5% vs. 32%, p = 0.02); mortality and incidence of infections in both groups were similar. Biomarker protein C increased while IL-6 decreased following infusion. CONCLUSIONS A 24-hr infusion of Xigris appears safe when used in patients with severe acute pancreatitis. TRIAL REGISTRATION Eudract Number 2007-003635-23.

Administration of Human Recombinant Activated Protein C Is Not Associated with Pancreatic Parenchymal Haemorrhage in L-Arginine-Induced Experimental Acute Pancreatitis

CONTEXT Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C (Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathways and maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from the inflamed pancreas. OBJECTIVE This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitis without causing pancreatic haemorrhage. METHODS Sprague Dawley rats were allocated as follows: Group 1: control (n=7); Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 µg/kg body weight before induction of acute pancreatitis (n=6); and Group 4: Administration of Xigris® 500 µg/kg body weight 30 minutes after induction of acute pancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g body weight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatic haemorrhage and inflammation assessed. RESULTS Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® both before (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. control group) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was no histological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associated with a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction of acute pancreatitis. CONCLUSION Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis. Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect was not seen with administration of Xigris® after induction of acute pancreatitis.

Functional protein C levels during the early phase of clinical acute pancreatitis.

Objective: Protein C modulates microvascular thrombosis in sepsis, with levels being depleted in severe cases. Similar changes occur in necrotizing acute pancreatitis (AP). However, little is known of the pathophysiological characteristics of endogenous protein C early in the disease course of AP. This study undertakes an evaluation of protein C levels in AP. Methods: In a consecutive series of 57 patients with AP, the chromogenic substrate method was used to determine functional protein C levels in plasma. Protein C activity and variables required for the calculation of Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were assessed at admission and 24 and 48 hours after admission. Results: The median functional protein C level was 97 U/dL (range, 41-178 U/dL) on admission and 96 U/dL (range, 46-170 U/dL) 24 hours after admission. There was no significant difference in the functional protein C levels between the patients with an admission APACHE score of 8 or higher and those with lower APACHE II scores. Linear regression plots showed a nonsignificant trend to the lower levels of functional protein C activity in those patients with higher APACHE II scores. Conclusions: In human AP, functional protein C levels are conserved in mild disease. However, there is evidence that levels are depleted early in severe disease, suggesting a parallel between the pathophysiology of severe sepsis and that of severe AP.