Michel Boivin

Gastric feeding with erythromycin is equivalent to transpyloric feeding in the critically ill

ObjectiveTo determine whether adding erythromycin to a gastric feeding regimen could render it as effective in meeting nutritional needs as transpyloric feeding. DesignRandomized, controlled study. SettingUniversity hospital medical, surgical, and neurologic care intensive care units. PatientsCritically ill patients, requiring a projected 96 hrs of enteral feeding, who had no specific indication for tube location (gastric or transpyloric). Eighty patients were randomized. InterventionsPatients were randomized to gastric feeding with erythromycin (200 mg iv) given every 8 hrs or feeding through a transpylorically placed feeding tube. Goal rate and feeding advancement were determined by protocol. Measurements and Main Results During the 96-hr period, the gastric group received 74% of their goal calories and the transpyloric group received 67%. The only day on which gastric feedings were superior was the first study day, where the gastric group attained 55% of their goal, compared with 44% in the transpyloric group. This 1-day difference was the result of an initial failure of tube placement in some subjects. Exclusion of these patients did not change overall results. Nutritional indexes, length of stay in the intensive care unit, ventilator dependence, and survival were not different between the two groups. ConclusionsGastric feeding with erythromycin as a prokinetic is equivalent to transpyloric feeding in meeting the nutritional goals of the critically ill.

Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene.

Defective intestinal epithelial tight junction (TJ) barrier has been shown to be a pathogenic factor in the development of intestinal inflammation. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which plays an important role in promoting inflammatory response in the gut and in the systemic circulation. Despite its key role in mediating variety inflammatory response, the effect of IL-6 on intestinal epithelial barrier remains unclear. The purpose of this study was to investigate the effect of IL-6 on intestinal epithelial TJ barrier and to delineate the intracellular mechanisms involved using in-vitro (filter-grown Caco-2 monolayers) and in-vivo model (mouse intestinal perfusion) systems. Our results indicated that IL-6 causes a site-selective increase in Caco-2 intestinal epithelia TJ permeability, causing an increase in flux of small-sized molecules having molecular radius <4 Å. The size-selective increase in Caco-2 TJ permeability was regulated by protein-specific increase in claudin-2 expression. The IL-6 increase in TJ permeability required activation of JNK signaling cascade. The JNK pathway activation of AP-1 resulted in AP-1 binding to its binding sequence on the claudin-2 promoter region, leading to promoter activation and subsequent increase in claudin-2 gene transcription and protein synthesis and TJ permeability. Our in-vivo mouse perfusion showed that IL-6 modulation of mouse intestinal permeability was also mediated by AP-1 dependent increase in claudin-2 expression. In conclusion, our studies show for the first time that the IL-6 modulation of intestinal TJ permeability was regulated by JNK activation of AP-1 and AP-1 activation of claudin-2 gene.

Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects.

Study Objectives. To evaluate whether a dose‐response curve exists for erythromycin, determine the lowest effective dose of erythromycin needed to improve gastric motility, and compare erythromycins effectiveness with that of metoclopramide in improving gastric emptying.

Haemodialysis induces mitochondrial dysfunction and apoptosis.

Background  Mitochondria play a crucial role in the regulation of the endogenous pathways of apoptosis activated by oxidant stress. Nuclear factor‐κB (NF‐κB) is a central integration site for pro‐inflammatory signals and oxidative stress.

A Multicenter, Prospective Study of the Placement of Transpyloric Feeding Tubes with Assistance of a Magnetic Device

BACKGROUND Placement of feeding tubes in the transpyloric position can be helpful in the management of enterally fed patients with pancreatitis, gastric atony, enterocutaneous fistulae, or pulmonary aspiration risk. The attainment of transpyloric position is difficult, and numerous techniques have been proposed to help in achieving this location. Recently, the use of a magnet-tipped feeding tube, dragged into proper position with an external magnet, has been described with an excellent success rate. METHODS At 10 participating institutions, practitioners were trained in the use of the device. Successful tube placement was determined by abdominal radiograph. RESULTS One hundred fifty-six tube placements were attempted. Transpyloric position was obtained in 60%. Placement into the third portion of the duodenum or distal was obtained in only 32%. Analysis of the data did not reveal a learning curve at the institutions, and 7 of 10 had a 50% or lower success rate. CONCLUSIONS Placement of feeding tubes with the assistance of a magnetic device was infrequently successful at the majority of institutions where it was attempted. We report a lower success rate than the original article, which described an 88% success rate of transpyloric intubation. Although this technique has a high failure rate, some individuals seem to be very successful using it, which could reduce the need for endoscopy or transport for the placement of feeding tubes.

Activation of caspase-3 in the skeletal muscle during haemodialysis

Eur J Clin Invest 2010; 40 (10): 903–910

Comparison of available gum-elastic bougies

INTRODUCTION The purpose of this study was to compare 4 different gum-elastic bougies (GEBs) for differences in success rate, speed of intubation, and device preference. METHODS This was a randomized study of 4 different GEBs (Sunmed, Portex, Greenfield, and Eschmann) used by emergency medicine (EM) and anesthesiology residents and attending physicians on a simulated difficult airway model. Success, time to intubation, and personal preference were recorded for each participant. Data were compared with analysis of variance, chi(2) and t tests, and 95% confidence intervals (95% CIs) where appropriate. P < .05 was considered significant. RESULTS Twenty-one participants from EM (16 residents, 5 faculty) and 13 from anesthesia (9 residents, 4 faculty) were entered into the study. Overall success rates were 88% for Sunmed, 68% for Portex, 88% for Greenfield, and 79% for Eschmann. Participants were significantly more likely to be successful when using either the Sunmed or the Greenfield GEB compared with the Portex GEB (relative risk [RR] = 1.3, 95% CI = 1.0-15.6). Success rate by specialty was significantly different with 60 (71%) of 84 for EM physicians and 50 (96%) of 52 for anesthesiologists. Speed of intubation was a mean +/- SD of 22.5 +/- 9.7 seconds, with no significant difference by GEB or specialty. Participants were significantly more likely to prefer the Sunmed over the Greenfield (P = .001, RR = 6.9, 95% CI = 1.5-24.8) and the Eschmann over the Greenfield (P = .003, RR = 6.1, 95% CI = 1.6-63.0). CONCLUSION Emergency medicine physicians had better success rates using the Sunmed and Greenfield GEBs but low preference for the Greenfield GEB.

Etiology of decreased gastric nitric oxide in the critically ill.

Background Nitric oxide (NO) is present in the gas phase of the normal human stomach at a high concentration (1-10 ppm). The majority of this NO is produced from the reduction of dietary nitrate to nitrite and finally NO. Generation of this nonenzymatically produced gastric NO occurs only in an acidic environment. We examined NO concentrations in critically ill subjects and the mechanism for the observed perturbations. Methods Seven critically ill, intubated intensive care unit (ICU) patients (mean APACHE II score 16) and seven control patients were studied. Gastric NO concentrations were measured with a Sievers NO analyzer (GE, Boulder, CO). Nitrate and nitrite concentrations were determined by a modified Griess assay. Bacterial counts were determined by optical density at 600 nm. Results Gastric NO concentration was significantly lower in the critically ill group (102.7 ppb) compared with the control group (953.2 ppb), although this difference was abolished by treating the control group with omeprazole (54 ppb). Gastric nitrate and nitrite concentrations were similar in the control and ICU groups, suggesting that substrate deficiency was not a cause of the low intragastric NO. Gastric pH was significantly lower in the control subjects (3.0) compared with the ICU patients (6.3) and the control subjects after receiving omeprazole (6.5). ICU patients had a trend toward higher gastric bacterial load. Conclusion In critically ill patients, markedly decreased NO concentrations are found in the gas of the stomach owing to a failure of gastric acidification.

268 PREDNISOLONE BLOCKS NUCLEAR FACTOR KAPPA B TRANSCRIPTIONAL ACTIVATION THROUGH THE GLUCOCORTICOID RESPONSE ELEMENT.

Altered intestinal permeability is an important potential cause of Crohns disease. Cytokines, an important therapeutic target in Crohns disease, can cause disruption of the intestinal tight junction barrier, leading to increased permeability. Tumor necrosis factor alpha (TNF-α) activates nuclear factor kappa B (NF-κB), causing an increase in expression of the enzyme myosin light chain kinase (MLCK) that modulates the tight junction barrier defect. We have shown this increase in expression is due to NF-κB activating the MLCK promoter through specific NF-κB binding sites. Furthermore, prednisolone (an important treatment of Crohns disease) protects the intestinal epithelial tight junction barrier by blocking NF-κB-mediated MLCK promoter activation. In examining the MLCK promoter, we determined that it contained a sequence that matched the consensus for a glucocorticoid response element (GRE). In this abstract, we determine the mechanism through which glucocorticoids prevent NF-κB activation of the MLCK promoter. Methods Filter-grown epithelial Caco-2 cells were used as an in vitro model of the intestinal barrier. The 2 kb upstream of the MLCK translational start site was cloned into pGL3 vector and used for promoter activity studies. Results (1) Prednisolone blocked the TNF-α-induced increase in intestinal epithelial permeability. (2) Prednisolone inhibited the TNF-α-induced increase in MLCK expression. (3) Prednisolone did not inhibit NF-κB translocation to the nucleus. (4) Prednisolone caused translocation of glucocorticoid receptor (GR) to the nucleus. (5) Prednisolone increased binding of GR to its transcriptional factor binding site, the GRE. (6) Prednisolone blocked the TNF-α-induced up-regulation of MLCK promoter activity. (7) Prednisolone did not block the TNF-α up-regulation of MLCK promoter if (a) the GRE was rendered inactive through site-directed mutagenesis or (b) RU-486 (GRE binding antagonist) was present. (8) Mutation of the NF-κB site 30 bp downstream of the MLCK GRE site blocked TNF-α-induced promoter up-regulation. Conclusions For the first time, we demonstrate that glucocorticoids can block NF-κB-mediated promoter activation through a GRE site. Further studies will identify the interaction between the GRE site on the MLCK promoter and the nearby NF-κB binding site using mutagenesis, binding studies, and insertions.

408 GLUCORTICOIDS INHIBIT CYTOKINE-INDUCED INCREASES IN INTESTINAL PERMEABILITY THROUGH DECREASED EXPRESSION OF TIGHT JUNCTION PROTEINS

Background Glucocorticoid Hormones (GC) are an effective therapeutic agent for the treatment of the intestinal inflammation of Crohns disease. However, the precise anti-inflammatory mechanism of GC action in Crohns disease is unclear. Recently, we have shown that the pro-inflammatory cytokine TNF-α (which is markedly increased in IBD) causes an increase in intestinal epithelial tight junction(TJ) permeability. We hypothesize that GC have a direct effect in protecting the intestinal TJ barrier from TNF-α disruption. The purpose of this study is to test this hypothesis and examine the molecular mechanisms behind GC protection of the TNF-α induced defect of the intestinal epithelial barrier. Methods The epithelial TJ permeability of CaCo-2 intestinal cells was measured using trans-epithelial electrical resistance of filter grown monolayers. Mechanism of action was evaluated using EMSA, immunohistochemistry, Western blot and luciferase promoter assays. Results 1) TNF-α causes a decrease in TJ epithelial permeability across CaCo-2 monolayers. 2) TNF-α causes translocation of the p65 subunit of NF-κB from the cytoplasm to the nucleus, an increase in DNA binding to an NF-κB consensus oligonucleotide and activation of an NF-κB responsive promoter. 3) TNF-α causes down-regulation of Occludin protein expression, the key component of the extra-cellular TJ barrier. 4) Prednisolone (1-10μM) and Dexamethasone (0.25μM) pre-treatment completely inhibited the TNF-α induced decrease in CaCo-2 TJ permeability. 5) GC treatment did not affect TNF-α induced NF-κB nuclear translocation, DNA binding or NF-κB responsive promoter activation. 6) GC inhibited the TNF-α induced down-regulation of Occludin protein expression. Conclusion Prednisolone inhibits the increase in CaCo-2 TJ permeability caused by TNF-α. The mechanism of prednisolone action involved inhibition of the TNF-α induced decrease in TJ protein expression without altering NF-κB activation. Future studies will elucidate the mechanism of GC action on TNF-α responsive tight junction proteins.