Intra-abdominal vagal blocking (VBLOC therapy): clinical results with a new implantable medical device.

BACKGROUND: A new medical device uses high-frequency electrical algorithms to create intermittent vagal blocking (VBLOC therapy). The aim is to assess the effects of vagal blocking on excess weight loss (EWL), safety, dietary intake, and vagal function. METHODS: An open-label, 3-center study was conducted in obese subjects (body mass index [BMI] 35-50 kg/m(2)). Electrodes were implanted laparoscopically on both vagi near the esophagogastric junction to provide electrical block. Patients were followed for 6 months for body weight, safety, electrocardiogram, dietary intake, satiation, satiety, and plasma pancreatic polypeptide (PP) response to sham feeding. To specifically assess device effects alone, no diet or exercise programs were instituted. RESULTS: Thirty-one patients (mean BMI, 41.2 +/- 1.4 kg/m(2)) received the device. Mean EWL at 4 and 12 weeks and 6 months after implant was 7.5%, 11.6%, and 14.2%, respectively (all P < .001); 25% of patients lost >25% EWL at 6 months (maximum, 36.8%). There were no deaths or device-related serious adverse events (AEs). Calorie intake decreased by >30% at 4 and 12 weeks and 6 months (all P 25 pg/mL (P = .02). Three patients had serious AEs that required brief hospitalization, 1 each for lower respiratory tract, subcutaneous implant site seroma, and Clostridium difficile diarrhea. CONCLUSIONS: Intermittent, intra-abdominal vagal blocking is associated with significant EWL and a desirable safety profile.

Inducible nitric oxide synthase mediates gut ischemia/reperfusion-induced ileus only after severe insults.

Inducible nitric oxide synthase (NOS 2) is thought to play a role in gut motility disorders that occur under proinflammatory conditions. Clinically, ileus occurs after sepsis and shock-induced gut ischemia/reperfusion (I/R). The purpose of this study was to determine if NOS 2 mediates impaired intestinal transit in well-established models of both moderate and severe gut ischemia/reperfusion. At laparotomy, Sprague-Dawley rats had duodenal catheters placed. Small intestinal transit was determined by quantitating the percentage tracer (FITC-dextran) in 10 equal segments of intestine 30 min after catheter injection [expressed as the mean geometric center (MGC) of distribution]. Transit was assessed at 6 and 24 h after gut ischemia [45 or 75 min of superior mesenteric artery occlusion (SMAO) with sham laparotomy as control]. In a separate set of experiments, N(6)-(iminoethyl)-L-lysine (L-NIL), a selective NOS 2 antagonist, was administered 1 h prior to laparotomy and transit was determined after 6 h as described above. Ileal NOS 2 expression was assessed by Western immunoblot and quantitative "real-time" RT-PCR. We observed that both 45 and 75 min of SMAO decreased intestinal transit at 6 h of reperfusion compared to sham. Ileal NOS 2 mRNA and protein were increased after 75, but not 45, min of SMAO. In addition, L-NIL improved transit after 75, but not 45, min of SMAO. We conclude that (1) NOS 2 is upregulated in the gut only after more severe ischemic insults, and (2) ileus is mediated, at least in part, by NOS 2 under these conditions.

Post-injury multiple organ failure: the role of the gut.

Despite intensive investigation, the pathogenesis of post-injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas-Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post-injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis-associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

Ileal mucosal response to bacterial toxin challenge.

BACKGROUND: The cause of postinjury intestinal mucosal barrier disruption remains obscure. The present study examines the hypothesis that the bacterial toxin formyl-methionyl leucyl phenylalanine (FMLP) plays an initial role in this process. METHODS: Mucosal permeability to fluorescein isothiocyanate-labeled dextran (4,400 molecular weight) was measured in perfused distal rat ileum with and without FMLP. Dextran and myeloperoxidase appearance in the lumenal perfusate was assessed in response to surrogates of traumatic stress: ischemia/reperfusion, total abdominal irradiation, and total parenteral nutrition. Recovery of FMLP in the effluent of static closed and perfused ileal loops was determined by mass spectrometry. Release of mast cell mediators in the presence of FMLP was determined in ileal everted sacs. RESULTS: Seventy-five percent of FMLP was recovered in perfusion effluent in contrast to 5% in closed loops. There was a transient increase in ileal permeability in FMLP/perfused, untreated rats, and in ischemia/reperfusion and total parenteral nutrition treated rats that was recorded with a concomitant increment in myeloperoxidase (inflammatory marker) in all experimental models except irradiated rats, which were unresponsive to FMLP. FMLP responsiveness was associ. ated with a significant rise in release of serotonin (mast cell mediator). CONCLUSION: These results suggest that mast cells and other resident inflammatory cells within the gut wall are involved in FMLP-induced changes in mucosal barrier permeability and raise the possibility that under conditions of traumatic stress, proinflammatory mediators within the gut wall might be activated by toxic factors in the gut lumen.

Pathogenesis and presentation of common bile duct stones.

Common bile duct stones are generally classified as primary or secondary stones based on the locations of origin. The vast majority of the stones found in the biliary tree are secondary stones. The current review discusses the pathogenesis and presentations of primary and secondary biliary stones. Based on discussion of disease pathogenesis and presentation, recommendations for the evaluation and management of common and uncommon disease processes associated with choledocholithiasis are proposed.

Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide.

Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean +/- SE) from 508 +/- 55 (control) to 355 +/- 33 g/cm2 (P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold (P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra (P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.

Regional intestinal blood flow and nitric oxide synthase inhibition during sepsis in the rat.

OBJECTIVE: Regional circulatory changes in intestinal mucosa were evaluated after the onset of septic shock and the effect of nitric oxide (NO) inhibition on mucosal blood flow was investigated at different locations along the intestine. SUMMARY BACKGROUND DATA: The response of intestinal blood flow to different physiologic and pharmacologic stimuli is known to vary along the intestine, but limited data are available on regional alterations in intestinal blood flow during septic shock. These regional variations in intestinal blood flow could become important because NO inhibition might restore the circulation of one segment of the gut or exacerbate ischemia that may be occurring concomitantly in another segment of the intestine. METHODS: Mucosal blood flow was studied with fluorescent microspheres in conscious unrestrained rats before and 2, 4, and 6 hours after lipopolysaccharide (LPS, 20 mg/kg intraperitoneally) induced sepsis in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-argininemethylester (L-NAME, 5 mg/kg subcutaneously). RESULTS: Control mucosal blood flow was significantly higher in the ileum than in the duodenum, jejunum, or colon. During LPS-induced sepsis, mucosal blood flow to the ileum decreased and perfusion to the remaining gut was preserved. This was accompanied by hypotension throughout the experiment. L-NAME administration during sepsis prevented hypotension and decreased mucosal blood flow to all segments of small intestine at 2 hours. In this group, mucosal blood flow to the proximal small intestine but not to the ileum returned to baseline levels at 4 and 6 hours. L-NAME alone decreased mucosal blood flow to the small intestine throughout the experiment. CONCLUSIONS: This study indicates that mucosal blood flow alterations during septic shock vary along the intestine, with a significant change only in the ileum, suggesting that perfusion in the small intestine is dependent on physiologic NO production.

Hypotension during septic shock does not correlate with plasma levels of nitric oxide metabolites in the conscious rat.

Hypotension following administration of lipopolysaccharide may be due to excessive production of the potent vasodilator nitric oxide brought about by induction of nitric oxide synthase. The purpose of this study was to determine in conscious, fasted rats what role nitric oxide played in lipopolysaccharide-induced hypotension. When examined by Western immunoblot analysis, inducible nitric oxide synthase immunoreactivity was detected in the aorta at 3 hours and increased over time following administration of intraperitoneal lipopolysaccharide (20 mg/kg). When compared with saline-treated control rats, significant hypotension was observed at 2, 4, and 6 hours following lipopolysaccharide treatment. Blood pressure at 2 hours did not differ significantly from that at 6 hours. Using the Griess reaction to quantify plasma levels of nitrates and nitrites as an index of systemic nitric oxide production, an augmentation in the formation of these nitric oxide metabolites was demonstrated at 4 and 6 hours but not at 2 hours. Subcutaneous administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (5 mg/kg) prevented lipopolysaccharide-induced hypotension, an effect reversed by subcutaneous L-arginine but not D-arginine (350 mg/kg). However, nitric oxide synthase inhibition did not attenuate the ability of lipopolysaccharide to increase plasma nitrate/nitrite levels. These data indicate that lipopolysaccharide-induced production of nitric oxide metabolites does not correlate with lipopolysaccharide-induced hypotension.

Ileo-cecal junction: a valve or a sphincter? An experimental study in the opossum.

The characteristics of the ileo-junction (UIC) were examined in seven opossums in vivo, and the effect of the UIC on colo-ileal reflux in eight opossums in vitro. Electromyography and intraluminal manometry were studied during intestinal distensions, and administration of phenylephrine, isoproterenol and carbachol. In vitro studies used preparations of ileum, UIC, and colon, attached to a propulsion evaluation system. Fluid flow across the UIC was studied basally and after phenylephrine, isoproterenol and carbachol. A high pressure zone in the UIC was not observed in vivo. Colonic distension increased the pressure and electrical spike bursts in the ileum and UIC, while ileal distension had the opposite effect. Myoelectric and contractile activities were inhibited by adrenergic agonists and stimulated by carbachol. In vitro studies demonstrated aborally migrating ileal contractions initiated by fluid injections into the ileum, and cecal contractions elicited by fluid injections into the colon. The UIC only prevented colo-ileal reflux when it was undergoing contraction as part of ileal or colonic activity. These findings suggest that the opossum UIC does not have valvular properties and ileal fluid propulsion is the main factor in the prevention of colo-ileal reflux.

Decreased ileal muscle contractility and increased NOS II expression induced by lipopolysaccharide.

This study was designed to determine if an increase in nitric oxide synthase (NOS) activity induced by lipopolysaccharide (LPS) is associated with increases in NOS II protein and mRNA abundance and with altered ileal longitudinal muscle contractility. Strips of muscle taken from LPS-treated, but not control, animals exhibited reduced in vitro contractility when L-arginine was a component of the physiological salt solution. This reduction was reversed by N omega-nitro-L-arginine (L-NNA), a competitive inhibitor of NOS. Full-thickness segments of jejunum, ileum, and colon taken 5 h after LPS injection exhibited increased NOS activity, NOS II immunoreactivity, and NOS II mRNA abundance. Increased NOS II immunoreactivity and mRNA abundance also were detected in ileal muscle strips taken from LPS-treated animals. These data confirm the reported effects of LPS on intestinal NOS activity and indicate that it can be attributed, at least in part, to an increase in NOS II mRNA and protein abundance. Furthermore, the data suggest that an LPS-induced increase in NOS II may lead to a decrease in ileal muscle contractility.

Omental transposition in chronic spinal cord injury.

The results of omental transposition in chronic spinal cord injury have been reported in 160 patients operated upon in the United States, Great Britain, China, Japan, India and Mexico, with detailed outcomes reported in few studies. Recovery of function to a greater degree than expected by natural history has been reported. In this series, 15 patients with chronic traumatic spinal cord injury (> 1.5 years from injury) underwent transposition of pedicled omentum to the area of the spinal cord injury. Of the first series of four patients who were operated upon in 1988, one died, one was lost to follow-up and two were followed with sequential neurological examinations and Magnetic Resonance Imaging (MRI) scans preoperatively, at 1 year post injury and 4 1/2 years post injury. Another 11 patients were operated in 1992 and underwent detailed neurological and neurophysiological examinations and had MRI scans preoperatively and every 4 months for at least 1 year after surgery. All patients completed a detailed self-report form. Of the total of 13 operated patients in both series followed for 1-4 1/2 years, six reported some enhanced function at 1 year and five of these felt the changes justified surgery primarily because of improved truncal control and decreased spasticity. MRI scans showed enlargement of the spinal cord as compared to preoperative scans in seven patients. Increased T2 signal intensity of the spinal cord was found by 1 year after surgery in eight of 13 operated patients. Neurophysiological examinations of 11 patients in the second series agreed with self-reports of increases or decreases in spasticity (r = 0.65, P < 0.03). Somatosensory evoked potentials and motor evoked potentials at 4 month intervals up to 1 year in these patients showed no change after surgery. Neurological testing, using the American Spinal Injury Association (ASIA) and International Medical Society of Paraplegia (IMSOP) international scoring standards, failed to show any significant changes when the 1-year post operative examination was compared to the first preoperative examination except for decreased sensory function after surgery which approached statistical significance. When the 11 patients in the second series were compared to eight non-operated matched patients, followed for a similar length of time, no significant differences were found. Complications encountered in the operated patients from both series included one postoperative death from a pulmonary embolus, one postoperative pneumonia, three chronic subcutaneous cerebrospinal fluid (CSF) fistulae requiring wound revision, and one patient who developed biceps and wrist extensor weakness bilaterally requiring graft removal. We conclude that the omental graft remains viable over time and this operation can induce anatomical changes in the spinal cord as judged by MRI. Some patients reported subjective improvement but this was not supported by objective testing. We, therefore, find no justification for further clinical trials of this procedure in patients who have complete or sensory incomplete lesions. Further testing in motor incomplete patients would seem appropriate only with compelling supportive data.

Aberrant biliopancreatic duct. A probable cause of acute pancreatitis?

Abnormal biliopancreatic ducts are very uncommon in adults with the exception of those associated with abnormalities of either the pancreatic or the bile ducts. The case presented herein is unique in that a biliopancreatic connection occurred proximal to the papilla of Vater and the patient was symptomatic because of the aberrant connection. The surgical therapy consisted of cholecystectomy and ligation of the aberrant duct, with complete relief of severe, debilitating symptoms. This interesting clinical observation is discussed in the light of Opie's theory of biliary reflux into the pancreatic duct as a pathogenetic mechanism for acute pancreatitis.

Intestinal transit and bacterial translocation in obstructive pancreatitis.

Pancreatic infection from gut-derived bacteria has emerged as the major cause of death in necrotizing pancreatitis. Bacterial overgrowth of indigenous enteric organisms as a consequence of guts stasis (ileus) represents a potential initial event in this process. The present study was designed to examine the interrelationships between intestinal transit, enteric bacteriology, and the translocation of bacteria from the gut lumen to mesenteric lymph nodes and splanchnic viscera during experimentally induced acute pancreatitis. Male rats underwent pancreaticobiliary duct ligation (PBDL) or sham surgery and were sacrificed after 24, 48, or 96 hr. Severity of pancreatitis was assessed with histology, tissue water content, and amylase and lipase levels. Intestinal transit was measured with fluorescent tracers. Blood, mesenteric lymph nodes (MLNs), splanchnic organs, and gut luminal contents were subjected to bacteriologic analysis. PBDL was followed by biochemical and histologic evidence of progressive pancreatic injury at each time interval. Enteric bacteria within the gut and in adjacent MLNs increased as intestinal transit decreased after PBDL-induced pancreatic inflammation. Surprisingly, all parameters returned to control levels by 96 hr in spite of progression of pancreatic inflammation.

Mechanisms of sepsis in acute pancreatitis in opossums.

PURPOSE: To study the incidence and pathways of colonization of the pancreas by specific bacteria in a model of necrotizing pancreatitis. METHODS: Bacteremia and splanchnic organ colonization were studied in the early course of necrotizing pancreatitis following common biliopancreatic duct ligation (BPDL) of the opossum. Nonoperated animals served as controls. Intestinal lymph nodes, liver, spleen, and pancreas were cultured following bacteremia or sacrifice. RESULTS: In opossums with sterile bile, bacteria were recovered from 28.6% of blood cultures after BPDL (n = 10) and from 12.0% in controls (n = 10, P < 0.05). Animals that underwent BPDL revealed enteric microorganisms in intestinal lymph nodes (6), liver (3), spleen (4), and pancreas (4). Ten animals carried Salmonella within their bile (5 controls, 5 BPDL animals). Following BPDL, they developed rapid bacteremia and colonization of organs, pancreatic ductal rupture, and extravasation of bacteria and bile into the interstitium. CONCLUSION: There are two possible mechanisms for the development of bacterial colonization in opossum pancreatitis: bacterial translocation of enteric organisms from gut lumen to mesenteric lymph nodes and subsequent hematogenous dissemination and transductal infestation from the biliary tract.

Gallbladder contractility in aspirin- and cholesterol-fed prairie dogs.

BACKGROUND/AIMS: Whether aspirin prevents cholesterol gallstone formation is controversial. This study aimed to investigate this issue and determine the depression of gallbladder smooth muscle contractility associated with cholesterol feeding in the prairie dog. METHODS: Prairie dogs were divided into four subgroups. Animals were fed control or 1.2% cholesterol diet and treated with placebo or aspirin for 2 weeks. The presence of crystals and stones was determined, and contractile force in response to cholecystokinin octapeptide (CCK-8) of gallbladder muscle strips was measured. RESULTS: Maximal stress of 2.66 +/- 0.23 x 10(4) N/m2 was measured in muscle strips from animals on control diet. Maximal stress was significantly lower in strips from animals on high-cholesterol diet, being 1.49 +/- 0.16 x 10(4) N/m2 with placebo and 1.62 +/- 0.23 x 10(4) N/m2 with aspirin. The difference in maximal stress between aspirin-treated and placebo-treated animals was not significant. Although none of the animals on control diet had crystals or stones, all animals on the high-cholesterol diet, whether receiving placebo or aspirin, had crystals in the bile, and more than 65% had cholesterol stones. CONCLUSIONS: Aspirin has no effect on stone formation, nor does it prevent the decrease in contractility despite a profound decrease in endogenous gallbladder prostanoid synthesis.

Nitric oxide is involved in muscle relaxation but not in changes in short-circuit current in rat ileum.

L-Arginine (L-Arg)-nitric oxide (NO) pathways in rat ileum were studied in an Ussing chamber modified so that a strain gauge transducer could be attached longitudinally on the serosal side of the intestine. Ileal segments from 22 rats were mounted as flat sheets and voltage clamped at zero transmural potential (PD). Changes in short-circuit current (delta ISC) in the absence of carbachol and longitudinal muscle relaxations in the presence of carbachol in response to transmural field stimulation (TMS; 5-s trains of impulses, 0.4-ms impulse duration, 1-10 Hz) were recorded during a control period, in the presence of N omega-nitro-L-arginine (L-NNA; 10(-4) M), and in the presence of L-Arg after treatment with L-NNA. In the control period, the delta ISC and muscle relaxation were frequency dependent with maximal responses generated at a frequency of 10 Hz. Tetrodotoxin (5 x 10(-6) M) blocked muscle relaxation and decreased delta ISC by 94% during TMS at 10 Hz. L-NNA blocked the muscle relaxation induced by TMS but failed to alter delta ISC. Muscle relaxation to TMS was restored dose dependently by L-Arg. In segments from another group of eight rats, saturated NO solutions relaxed the muscle but failed to change ISC either in the presence or absence of carbachol. These results support a role for NO as a neurotransmitter mediating relaxation of ileal smooth muscle but not mediating changes in epithelial ISC.