Endocannabinoids and endocannabinoid-like compounds modulate hypoxia-induced permeability in CaCo-2 cells via CB1, TRPV1, and PPARα.

BACKGROUND AND PURPOSE: We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion. EXPERIMENTAL APPROACH: Caco-2 cells were grown on cell culture inserts to confluence. Trans-epithelial electrical resistance (TEER) was used to measure permeability. To generate hypoxia (0% O2), a GasPak™ EZ anaerobe pouch system was used. Endocannabinoids were applied to the apical or basolateral membrane in the presence or absence of receptor antagonists. KEY RESULTS: Complete hypoxia decreased TEER (increased permeability) by ~35% after 4 h (recoverable) and ~50% after 6 h (non-recoverable). When applied either pre- or post-hypoxia, apical application of N-arachidonoyl-dopamine (NADA, via TRPV1), oleamide (OA, via TRPV1) and oleoylethanolamine (OEA, via TRPV1) inhibited the increase in permeability. Apical administration of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) worsened the permeability effect of hypoxia (both via CB1). Basolateral application of NADA (via TRPV1), OA (via CB1 and TRPV1), noladin ether (NE, via PPARα), and palmitoylethanolamine (PEA, via PPARα) restored permeability after 4 h hypoxia, whereas OEA increased permeability (via PPARα). After 6 h hypoxia, where permeability does not recover, only basolateral application PEA sustainably decreased permeability, and NE decreased permeability. CONCLUSIONS AND IMPLICATIONS: A variety of endocannabinoids and endocannabinoid-like compounds modulate Caco-2 permeability in hypoxia/reoxygenation, which involves multiple targets, depending on whether the compounds are applied to the basolateral or apical membrane. CB1 antagonism and TRPV1 or PPARα agonism may represent novel therapeutic targets against several intestinal disorders associated with increased permeability.

Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability.

BACKGROUND AND PURPOSE: Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro. EXPERIMENTAL APPROACH: Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL(-1) ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB(1) , CB(2) , TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids. KEY RESULTS: Δ(9) -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB(1) receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB(1) antagonism. No role for the CB(2) receptor was identified in these studies. Co-application of THC, cannabidiol or a CB(1) antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation. CONCLUSIONS AND IMPLICATIONS: These findings suggest that locally produced endocannabinoids, acting via CB(1) receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability.

Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion, and intestinal motility. However, the effects of cannabinoids on intestinal permeability have not yet been established. The aim of the present study is to examine the effects of cannabinoids on intestinal permeability in an in vitro model. Caco-2 cells were grown until fully confluent on inserts in 12-well plates. Transepithelial electrical resistance (TEER) measurements were made as a measure of permeability. EDTA (50 µM) was applied to reversibly increase permeability (reduce TEER). The effects of cannabinoids on permeability in combination with EDTA, or alone, were assessed. Potential target sites of action were investigated using antagonists of the cannabinoid (CB)(1) receptor, CB(2) receptor, transient receptor potential vanilloid subtype 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)γ, PPARα, and a proposed cannabinoid receptor. When applied to the apical or basolateral membrane of Caco-2 cells, Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) enhanced the speed of recovery of EDTA-induced increased permeability. This effect was sensitive to cannabinoid CB(1) receptor antagonism only. Apical application of endocannabinoids caused increased permeability, sensitive to cannabinoid CB(1) receptor antagonism. By contrast, when endocannabinoids were applied basolaterally, they enhanced the recovery of EDTA-induced increased permeability, and this involved additional activation of TRPV1. All cannabinoids tested increased the mRNA of the tight junction protein zona occludens-1, but only endocannabinoids also decreased the mRNA of claudin-1. These findings suggest that endocannabinoids may play a role in modulating intestinal permeability and that plant-derived cannabinoids, such as THC and CBD, may have therapeutic potential in conditions associated with abnormally permeable intestinal epithelium.

A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer.

AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

A review article on gastric volvulus: a challenge to diagnosis and management.

Acute gastric volvulus is a life-threatening condition, but its intermittent nature and vague symptoms may make diagnosis difficult. Imaging is usually only diagnostic if carried out when patients are symptomatic. The population affected ranges from paediatric age group to elderly with multiple co-morbidities. Laparoscopic repair is advisable once a diagnosis is reached. This review on gastric volvulus focuses on the diagnostic and management challenges encountered, together with strategies for dealing with them. Lessons have emerged which may assist in dealing with such a rare presentation in future.

Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis.

BACKGROUND: Acute pancreatitis is a common abdominal emergency with no specific treatment. Pancreatic necrosis may complicate severe attacks, detectable by computed tomography (CT). Necrosis can become infected, making surgical intervention necessary and increasing mortality to more than 40%. Experimental studies suggest that antibiotic therapy may prevent infection, but could promote resistance and fungal infection. OBJECTIVES: To determine the effectiveness and safety of prophylactic antibiotics in acute pancreatitis complicated by pancreatic necrosis. SEARCH STRATEGY: The Cochrane Library (Issue 1, 2006), MEDLINE (January 1966-December 2005), EMBASE (January 1980-December 2005) and CINAHL (January 1982-December 2005) were searched. We also examined Conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing antibiotics versus placebo in acute pancreatitis with CT proven necrosis were sought using a detailed search strategy without linguistic limitation. RCTs. Initial searching was undertaken in November 2001. Latest update: December 2005. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently for rates of primary end-points: mortality and pancreatic infection rates. Secondary end-points included: non pancreatic infection and operative rates. Adverse events: antibiotic resistance and fungal infections. Subgroup analyses: antibiotic regimen. MAIN RESULTS: Five evaluable studies randomised 294 patients. Analysis suggested significantly less mortality with therapy (6%) versus controls (15.3%), odds ratio 0.37 (95% CI 0.17, 0.83). Infected pancreatic necrosis rates were not significantly different (therapy 20%, controls 27.8%), odds ratio 0.62 (95% CI 0.35, 1.09), and neither were operative treatment rates or non-pancreatic infection rates. Fungal infections were not significantly different at 4% with therapy versus 4.9% in controls, odds ratio 0.83 (95% CI 0.30, 2.27). There were no evaluable data on antibiotic resistance. Sub-group analysis was performed for antibiotic regimen: beta lactam (192 patients), and quinolone plus imidazole (102 patients). With beta lactam prophylaxis there was significantly less mortality (6.3%) versus controls (16.7%), odds ratio 0.34 (95% CI 0.13, 0.91), and infected pancreatic necrosis (15.6%) versus (29.2%) in controls, odds ratio 0.41 (95% CI 0.20, 0.85), but there were no significant differences in operative treatment rates or non-pancreatic infections. No significant differences were seen with quinolone plus imidazole. AUTHORS' CONCLUSIONS: Antibiotic prophylaxis appeared to be associated with significantly decreased mortality but not infected pancreatic necrosis. Beta lactams were associated with significantly decreased mortality and infected pancreatic necrosis, but quinolone plus imidazole regimens were not. There were variations in methodological quality, treatment regimens, and a lack of data on adverse effects. Further better designed studies are needed to support antibiotic prophylaxis and, should these prove beneficial, to compare beta-lactams with quinolones directly.

Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis.

BACKGROUND: Acute pancreatitis is a common acute abdominal emergency which lacks specific therapy. In severe attacks, areas of the pancreas may become necrotic. The mortality risk rises to >40% if sterile necrosis becomes superinfected, usually with gut derived aerobic organisms. Experimental and clinical studies indicate a window of opportunity of 1-2 weeks, when superinfection, and thus high-risk surgical debridement, may be prevented by administering systemic antibiotics to 'sterilise' tissues adjacent to necrotic areas. There are theoretical risks of encouraging antibacterial resistance and opportunistic fungal infections. OBJECTIVES: To determine the effectiveness and safety of prophylactic antibiotic therapy in patients with severe acute pancreatitis who have developed pancreatic necrosis. SEARCH STRATEGY: MEDLINE, EMBASE, and the Cochrane Library were searched. We also examined other sources including Conference Abstracts (published and unpublished data). SELECTION CRITERIA: Randomised controlled trials (RCT) were sought using the search strategy detailed below. No linguistic limitations were applied. RCTs were selected in which antibacterial therapy was evaluated in patients with severe acute pancreatitis associated with pancreatic necrosis proven by intravenous contrast-enhanced computed tomography (CT). No linguistic limitations were applied. Searching was undertaken initially in November 2001 and updated in March 2003. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data from trial publications independently, concerning rates for the primary end-points: with respect to: all cause mortality and rates of infection of pancreatic necrosis (proven by microbiological examination of fine needle aspirate or operative specimens). In addition, secondary end-points included peri-pancreatic sepsis, remote sepsis (respiratory, urinary, central venous line sources), operative rates, length of hospital stay, adverse events including the incidence of drug resistant microorganisms and opportunistic fungal infection. MAIN RESULTS: It was possible to evaluate mortality in all four included studies, and it demonstrated a survival advantage for antibiotic therapy (Odds ratio 0.32, p=0.02). Pancreatic sepsis (infected necrosis) was also measurable in all four studies and showed an advantage for therapy (Odds ratio 0.51, p=0.04). Extra-pancreatic infection could be evaluated in three studies, but showed no significant advantage for therapy (Odds ratio 0.47, p=0.05).Operative treatment data was available in three studies, but surgery rates were not significantly reduced (Odds ratio 0.55, p=0.08). Fungal infections showed no strongly increased preponderance with therapy (Odds ratio 0.83, p=0.7), but there were no data on infection with resistant organisms. Length of hospital stay could only be evaluated in two studies and was not significantly different. Sub-group analyses planned for the influence on outcome measures of the antibiotic regimen, the time of commencement of therapy in relation to symptom onset and/or hospitalisation, duration of therapy, and aetiology could not be performed as no data were available. REVIEWER'S CONCLUSIONS: Despite variations in drug agent, case mix, duration of treatment and methodological quality (especially the lack of double blinded studies), there was strong evidence that intravenous antibiotic prophylactic therapy for 10 to 14 days decreased the risk of superinfection of necrotic tissue and mortality in patients with severe acute pancreatitis with proven pancreatic necrosis at CT. Further studies are required to confirm all of the benefits suggested (in particular the need for operative debridement), to provide more adequate data on adverse effects, to address the choice of antibacterial agents and effects of varying duration of therapy, and whether outcome is related to aetiology.

Calcitonin precursors: early markers of gut barrier dysfunction in patients with acute pancreatitis.

BACKGROUND: Severe acute pancreatitis is associated with an early increase in intestinal permeability and endotoxemia. Endotoxin is a potent stimulator for the production and release of procalcitonin and its components (calcitonin precursors; [CTpr]). The aim of this study is to evaluate the role of plasma CTpr as an early marker for gut barrier dysfunction in patients with acute pancreatitis. METHODS: Intestinal permeability to macromolecules (polyethylene glycol 3350), serum endotoxin and antiendotoxin core antibodies, plasma CTpr, and serum C-reactive protein (CRP) were measured on admission in 60 patients with acute pancreatitis. Attacks were classified as mild (n = 48) or severe (n = 12) according to the Atlanta criteria. RESULTS: Compared with mild attacks of acute pancreatitis, severe attacks were significantly associated with an increase in intestinal permeability index (median: 0.02 vs. 0.006, P < 0.001), the frequency of endotoxemia (73% vs. 41%, P = 0.04), and the extent of depletion of serum IgM antiendotoxin antibodies (median: 43 MMU vs. 100 MMU, P = 0.004). Plasma CTpr levels were significantly elevated in patients with severe attacks compared with mild attacks on both the day of admission and on day 3 (median: 64 vs. 22 fmol/mL, P = 0.03; and 90 vs. 29 fmol/mL, P = 0.003 respectively). A positive and significant correlation was observed between the admission serum endotoxin and plasma CTpr levels on admission (r = 0.7, P < 0.0001) and on day 3 (r = 0.96, P < 0.0001), and between plasma CTpr on day 7 and the intestinal permeability index (r = 0.85, P = 0.0001). In contrast, only a weak positive correlation was observed between peak serum levels of CRP and plasma CTpr on admission (r = 0.3, P = 0.017) and on day 7 (r = 0.471, P = 0.049), as well as between CRP and each of the admission serum endotoxin (r = 0.3, P = 0.03) and the intestinal permeability index (r = 0.375, P = 0.007). CONCLUSIONS: In patients with acute pancreatitis, plasma concentrations of CTpr appear to reflect more closely the derangement in gut barrier function rather than the extent of systemic inflammation.

Micropuncture cholecystectomy vs conventional laparoscopic cholecystectomy: a randomized controlled trial.

BACKGROUND: The aim of this study was to compare micropuncture laparoscopic cholecystectomy (MPLC), with three 3.3-mm cannulas and one 10-mm cannula with conventional laparoscopic cholecystectomy (CLC). METHODS: Patients were randomized to undergo either CLC or MPLC. The duration of each operative stage and the procedure were recorded. Interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), and vasopressin were sampled for 24 h. Visual analogue pain scores (VAPS) and analgesic consumption were recorded for 1 week. Pulmonary function and quality of life (EQ-5D) were monitored for 4 weeks. Statistical analysis was performed using the Mann-Whitney test or Fisher's exact test. Results are expressed as median (interquartile range). RESULTS: Forty-four patients entered the study, but four were excluded due to unsuspected choledocholithiasis (n = 3) or the need to reschedule surgery (n = 1). The groups were comparable in terms of age, duration of symptoms, and indications for surgery. Total operative time was similar (CLC, 63 [52-81] min vs MPLC 74 [58-95] min; p = 0.126). However, time to place the cannulas after skin incision (CLC, 5:42 [3:45-6:37] min vs MPLC, 7:38 [5:57-10:15] min; p = 0.015) and to clip the cystic duct after cholangiography (CLC, 1:05 [0:40-1:35] min vs MPLC, 3:45 [2:26-7:49] min; p <0.001) were significantly longer for MPLC. Six CLC patients and one MPLC patient required postoperative parenteral opiates (p = 0.04). Oral analgesic consumption was similar in both groups (p = 0.217). Median VAPS were lower at all time points for MPLC, but this finding was not significant (p = 0.431). There were no significant differences in postoperative stay, IL-6, ACTH or vasopressin responses, pulmonary function, or EQ-5D scores. CONCLUSIONS: The thinner instruments did not significantly increase the total duration of the procedure. MPLC reduced the use of parenteral analgesia postoperatively, which may prove beneficial for day case patients, but it did not have a significant impact on laboratory variables, lung function or quality of life.

Calcitonin precursors in the prediction of severity of acute pancreatitis on the day of admission.

BACKGROUND: Calcitonin precursors are sensitive markers of inflammation and infection. The aim of this study was to evaluate the role of plasma calcitonin precursor levels on the day of admission in the prediction of severity of acute pancreatitis, and to compare this with the Acute Physiology And Chronic Health Evaluation (APACHE) II scoring system. METHODS: Plasma concentrations of calcitonin precursors were determined on admission in 69 patients with acute pancreatitis. APACHE II scores were calculated on admission. Attacks were classified as mild (n = 55) or severe (n = 14) according to the Atlanta criteria. Plasma calcitonin precursor levels were determined with a sensitive radioimmunoassay. RESULTS: On the day of hospital admission, plasma levels of calcitonin precursors were significantly greater in patients with a severe attack compared with levels in those with a mild attack of pancreatitis (median 64 versus 25 fmol/ml; P = 0.014), but the APACHE II scores were no different (median 9 versus 8; P = 0.2). The sensitivity, specificity, positive predictive and negative predictive values, and accuracy for the prediction of severe acute pancreatitis were 67, 89, 57, 93 and 85 per cent respectively for plasma calcitonin precursor levels higher than 48 fmol/ml, and 69, 45, 23, 86 and 50 per cent respectively for an APACHE II score greater than 7. Differences in the specificity and accuracy of the two prognostic indicators were significant (P < 0.001 and P = 0.001 respectively). A plasma calcitonin precursor concentration of more than 160 fmol/ml on admission was highly accurate (94 per cent) in predicting the development of septic complications and death. CONCLUSION: The assay of plasma calcitonin precursors on the day of admission to hospital has the potential to provide a more accurate prediction of the severity of acute pancreatitis than the APACHE II scoring system.

Increased nitric oxide excretion in patients with severe acute pancreatitis: evidence of an endotoxin mediated inflammatory response?

BACKGROUND AND AIMS: Nitric oxide represents a potential key mediator of the local and systemic manifestations of acute pancreatitis (AP) in experimental models but its role in human disease is uncertain. We therefore sought to assess if systemic nitric oxide (NO) production is elevated in severe AP and determine whether this is a reflection of biochemical severity or endotoxin exposure. PATIENTS AND METHODS: Patients were recruited within 72 hours of pain onset. NO derived nitrite excretion determined from a 24 hour sterile urine collection was correlated with intestinal macromolecular permeability (polyethylene glycol excretion ratio), markers of systemic endotoxin exposure (IgG:IgM endotoxin core antibody (EndoCAb) ratio), disease severity, and the magnitude of systemic inflammation (peak C reactive protein (CRP) and Acute Physiology and Chronic Health Evaluation score II (APACHE-II)). RESULTS: In patients with a severe attack (n=20), nitrite excretion was increased significantly compared with patients with a mild attack (n=45, 20.6 micro g v 15.65 micro g; p<0.00) and the latter with healthy controls (n=20, p=0.004). Nitrite excretion correlated strongly with both intestinal permeability (r=0.7, p=0.006) and EndoCAb ratio (r=0.7, p<0.01) but not with CRP or APACHE-II scores (p>0.1). CONCLUSIONS: Total urinary nitrite excretion is increased in patients with severe AP, and may not be simply a reflection of systemic inflammation, but potentially a consequence of endotoxin mediated upregulation of inducible NO synthase activity.

Laparoscopic cholecystectomy: are patients with biliary pancreatitis at increased operative risk?

BACKGROUND: Previous reports of laparoscopic cholecystectomy (LC) in patients with biliary pancreatitis suggested increased operative difficulty, high rates of conversion, and greater morbidity and mortality. METHODS: Between 1990 and 1997, LC was performed for biliary pancreatitis in 63 patients (Group I) and for other causes in 829 patients (Group II). RESULTS: Patients with biliary pancreatitis were significantly older (median age 57 vs 50 years, p = 0.009), with greater co-morbidity (ASA III/IV 24% vs 11%, p = 0.008). The groups were comparable with respect to the frequency of previous abdominal operations, acute inflammation of the gallbladder, and the frequency of bile duct calculi detected by intraoperative cholangiography. Moderate to severe adhesions involving the gallbladder were significantly more frequent in patients with biliary pancreatitis (46% vs 29%, p = 0.004). No significant differences were observed between the two groups with respect to intraoperative (1.5% Group I vs 6.0% Group II, p = 0.109) or postoperative complications (10% vs 8%, p = 0.426), conversion rate (0 vs 2.7%, p = 0.181), or duration of operation (median 92 vs 85 min, p = 0.33). CONCLUSION: Despite increased age and co-morbidity and more frequent adhesions, our data showed no evidence that intraoperative or postoperative complications were more frequent in patients with biliary pancreatitis than in other patients undergoing LC.

Does pneumatic dilatation affect the outcome of laparoscopic cardiomyotomy?

BACKGROUND: Controversy surrounds the choice of laparoscopic cardiomyotomy as the primary treatment for achalasia or a second-line treatment following the failure of nonsurgical treatment. Laparoscopic cardiomyotomy can be more difficult technically following pneumatic dilatations. The aim of this study was to compare the outcome obtained with primary laparoscopic cardiomyotomy to that achieved when the procedure is performed following failed pneumatic dilatation. METHODS: Laparoscopic cardiomyotomy was performed in seven patients following a median of four pneumatic dilatations (group A) and in five patients as their primary treatment (group B). Outcome was measured using manometry, a modified DeMeester symptom scoring system, and a quality-of-life questionnaire. RESULTS: There were no significant differences between groups A and B in sex, age, preoperative modified DeMeester score, or mean barrier pressure. Six of seven group A patients had evidence of periesophageal and submucosal fibrosis at surgery, but this condition was not seen in group B patients. The operative time was slightly longer in group A patients. There was no difference in complication rates (one primary hemorrhage in group A and one esophageal perforation in group B), and both groups had a significantly improved modified DeMeester score at 6 weeks and at long-term follow-up (median, 26 months). Eleven of 12 patients said that they would choose laparoscopic cardiomyotomy as their primary treatment if newly diagnosed with achalasia. CONCLUSIONS: Laparoscopic cardiomyotomy is safe and effective as a primary or second-line treatment following pneumatic dilatations in patients with achalasia.

Laparoscopic cholecystectomy in morbidly obese patients.

BACKGROUND: Morbid obesity is generally regarded as a risk factor for laparoscopic cholecystectomy due to increases in operative time, morbidity, and conversion rate to open cholecystectomy. The aim of this study was to evaluate the feasibility and outcome of laparoscopic cholecystectomy (LC) in morbidly obese patients. METHODS: A total of 864 consecutive patients underwent LC at our institution between 1990 and 1997. This series represents a continuing policy of LC for all comers. Data were collected prospectively. There were 659 nonobese (NO: BMI 40 kg/m2). Laparoscopic bile duct exploration was performed in 28 (4.2%), nine (4.8%), and one (5.9%) patients, respectively. RESULTS: Obesity and morbid obesity were associated with trends toward an increased conversion rate (2.3% NO; 4.3% OB; 5.9% MO), a longer operative time (median, 80, 85, and 107 mins, respectively), greater postoperative morbidity (4.7%, 5.9%, and 11.8%, respectively), and a reduced ability to obtain cholangiography (86.1%, 80.1%, and 71.4%, respectively). None of these differences, however, were statistically significant (c2 test, p > 0.05). Postoperative hospital stay for LC was similar for all three groups (median, 1 day). CONCLUSION: LC in morbidly obese patients is a safe procedure, but it may be associated with increased operative difficulty and morbidity, as compared with nonobese and obese patients.

Elective laparoscopic cholecystectomy: preoperative prediction of duration of surgery.

BACKGROUND: Efficient use of operating time has become a key concern. The aim of this study was to determine preoperative factors that can predict extended duration of operating time (>90 min) for laparoscopic cholecystectomy (LC). METHODS: Data collected prospectively on 827 consecutive patients who underwent elective LC between 1990 and 1997 were analyzed. Factors evaluated included age, gender; body mass index; comorbidity; duration of symptoms; history of jaundice, pancreatitis, or abdominal surgery; dilated common bile duct or thick-walled gallbladder on ultrasound; preoperative endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (ES); and surgeon experience. Univariate and multivariate analyses were performed to identify factors predicting a long operation. RESULTS: Operating time was longer than 90 min in 276 patients (33%). Predictors of extended operation time were age older than 55 years (odds ratio [OR] = 9.7), preoperative ES (OR = 2.8), and a thick-walled gallbladder on ultrasound (OR = 2.5). CONCLUSION: These predictors may be useful in planning theater lists and anesthesia management, and in selecting patients for day surgery.

Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis.

BACKGROUND: Platelet activating factor (PAF) is believed to amplify the activity of key mediators of the systemic inflammatory response syndrome (SIRS) in acute pancreatitis, resulting in multiorgan dysfunction syndrome. We tested the hypothesis that a potent PAF antagonist, lexipafant, could dampen SIRS and reduce organ failure in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled, multicentre trial of lexipafant (100 mg/24 hours intravenously for seven days commenced within 72 hours of the onset of symptoms) involving 290 patients with an APACHE II score >6. Power calculations assumed that complications would be reduced from 40% to 24%. Secondary end points studied included severity of organ failure, markers of the inflammatory response, and mortality rate. FINDINGS: Overall, 80/138 (58%) patients in the placebo group and 85/148 (57%) in the lexipafant group developed one or more organ failures. The primary hypothesis was invalidated by the unexpected finding that 44% of patients had organ failure on entry into the study; only 39 (14%) developed new organ failure. Organ failure scores were reduced in the lexipafant group only on day 3: median change -1 (range -4 to +8) versus 0 (-4 to +10) in the placebo group (p=0.04). Systemic sepsis affected fewer patients in the lexipafant group (13/138 v 4/148; p=0.023). Local complications occurred in 41/138 (30%) patients in the placebo group and in 30/148 (20%) in the lexipafant group (20%; p=0.065); pseudocysts developed in 19 (14%) and eight (5%) patients, respectively (p=0.025). Deaths attributable to acute pancreatitis were not significantly different. Interleukin 8, a marker of neutrophil activation, and E-selectin, a marker of endothelial damage, decreased more rapidly in the lexipafant group (both p<0.05); however, absolute values were not different between the two groups. INTERPRETATION: The high incidence of organ failure within 72 hours of the onset of symptoms undermined the primary hypothesis, and power calculations for future studies in severe acute pancreatitis will need to allow for this. Lexipafant had no effect on new organ failure during treatment. This adequately powered study has shown that antagonism of PAF activity on its own is not sufficient to ameliorate SIRS in severe acute pancreatitis

Relaparoscopy for the detection and treatment of complications of laparoscopic cholecystectomy.

BACKGROUND: Laparotomy remains the commonest intervention in patients with abdominal complications of laparoscopic surgery. Our own policy is to employ relaparoscopy to avoid diagnostic delay and unnecessary laparotomy. The results of using this policy in patients with suspected intra-abdominal complications following laparoscopic cholecystectomy are reviewed. METHODS: Data were collected from laparoscopic cholecystectomies carried out by five consultant surgeons in one center. Details of relaparoscopy for complications were analyzed. RESULTS: Thirteen patients underwent relaparoscopy within 7 days of laparoscopic cholecystectomy for intra-abdominal bleeding (2 patients) or abdominal pain (11 patients). The causes of pain were subhepatic haematoma (1), acute pancreatitis (1), small bowel injury (1), and minor bile leakage (6). In 2 patients no cause was identified. Twelve patients were managed laparoscopically and 1 patient required laparotomy. Median stay after relaparoscopy was 7 days (range 2 to 19). CONCLUSIONS: Exploratory laparotomy can be avoided by prompt relaparoscopy in the majority of patients with abdominal complications of laparoscopic cholecystectomy.