Biomedical subjects

Paul J Matheson

Publications and source records attributed to Paul J Matheson.

11 recordsLinked to original sources

PubMed2006

Immune-enhancing diet and cytokine expression during chronic sepsis: an immune-enhancing diet containing L-arginine, fish oil, and RNA fragments promotes intestinal cytokine expression during chronic sepsis in rats.

Chronic feeding with enteral immune-enhancing diets (IEDs) provides benefits based on composition of the diet, route of feeding, and timing of feeding in relation to timing of trauma or surgery. Our prior studies of acute feeding in naïve rats demonstrated that IED promotes blood flow and proinflammatory cytokines in the ileum. We hypothesized that chronic feeding with IED would shift gut immune status to an anti-inflammatory state during chronic sepsis, resulting in an altered state of cytokine expression in the gut. Five days prior to feeding, gauze was implanted subcutaneously in the backs of male Sprague-Dawley rats, which were fed for 3 days with either control diet (CD, Boost; Mead-Johnson, Evansville, IL) or IED (Impact; Novartis) and randomly assigned to one of four groups: saline control (NS) + control diet (CD), sepsis (EC) + CD, NS + IED, or EC + IED. EC rats were inoculated with 10(9) CFU Escherichia coli and 10(9) CFU Bacteroides fragilis in 2 ml normal saline into the back sponge while NS rats received 2 mL normal saline alone. After 3 days, animals were anesthetized and gut tissue samples were harvested and frozen at -80 degrees C. Tissue protein was extracted and ELISA was performed for interleukin (IL-1beta, IL-5, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. In saline controls, IED feeding decreased IL-1beta, IL-5, IL-6, TNF-alpha, and IFN-gamma and increased IL-10 compared with CD-fed animals. In septic animals, IED feeding increased IL-5 and IL-6, while decreasing IFN-gamma and IL-10 in the distal third of the small intestine compared with CD-fed septic rats, whereas IL-1beta and TNF-alpha levels were unchanged. Chronic IED feeding produced a anti-inflammatory state via decreased IFN-gamma and increased IL-5 and IL-6, which both promote gut IgA class switching, suggesting that the gut is shifted toward humoral immunity during chronic IED feeding in septic rats.

Animals↗

PubMed2005

Intravital intestinal videomicroscopy: techniques and experiences.

Intravital videomicroscopy (IVM) of the gastrointestinal (GI) tract is a sophisticated and powerful technique to directly observe the neurologically intact microvasculature of rats in naive and pathological conditions. We combine IVM with other techniques (i.e., vascular ring tension analysis and colorimetric microsphere determination of whole organ blood flow) to develop a strategy for the systematic analysis of the regulation of GI blood flow in healthy animals and in models of systemic sepsis and resuscitated hemorrhagic shock. We also study the molecular biology of the GI tract (enzyme- or radio-linked immunosorbent assays, fluorescent Greiss assay, and immunoblots) to correlate expression and levels of vascular mediators in tissue and arterial, venous, and portal blood with functional activity of the GI microvascular tree. When combined, these techniques develop a picture of gut pathophysiology at the level of the endothelium, vascular smooth muscle cells, and blood cells in the microcirculation. Our work led us to the general hypothesis that altered microcirculatory function in disease states lies primarily at the level of the interface between vascular and tissue physiology, i.e., the endothelial cell. This review focuses on methods and techniques for studying microvascular function, and concludes with focused reviews of pertinent findings.

Animals↗

PubMed2005

Poor validity of residual volumes as a marker for risk of aspiration in critically ill patients.

BACKGROUND AND AIMS: Elevated residual volumes (RV), considered a marker for the risk of aspiration, are used to regulate the delivery of enteral tube feeding. We designed this prospective study to validate such use. METHODS: Critically ill patients undergoing mechanical ventilation in the medical, coronary, or surgical intensive care units in a university-based tertiary care hospital, placed on intragastric enteral tube feeding through nasogastric or percutaneous endoscopic gastrostomy tubes, were included in this study. Patients were fed Probalance (Nestle USA) to provide 25 kcal/kg per day (to which 10 yellow microscopic beads and 4.5 mL of blue food coloring per 1,500 mL was added). Patients were randomized to one of two groups based on management of RV: cessation of enteral tube feeding for RV >400 mL in study patients or for RV >200 mL in controls. Acute Physiology and Chronic Health Evaluation (APACHE) III, bowel function score, and aspiration risk score were determined. Bedside evaluations were done every 4 hrs for 3 days to measure RV, to detect blue food coloring, to check patient position, and to collect secretions from the trachea and oropharynx. Aspiration/regurgitation events were defined by the detection of yellow color in tracheal/oropharyngeal samples by fluorometry. Analysis was done by analysis of variance, Spearman's correlation, Student's t-test, Tukey's method, and Cochran-Armitage test. RESULTS: Forty patients (mean age, 44.6 yrs; range, 18-88 yrs; 70% male; mean APACHE III score, 40.9 [range, 12-85]) were evaluated (21 on nasogastric, 19 on percutaneous endoscopic gastrostomy feeds) and entered into the study. Based on 1,118 samples (531 oral, 587 tracheal), the mean frequency of regurgitation per patient was 31.3% (range, 0% to 94%), with a mean RV for all regurgitation events of 35.1 mL (range, 0-700 mL). The mean frequency of aspiration per patient was 22.1% (range, 0% to 94%), with a mean RV for all aspiration events of 30.6 mL (range, 0-700 mL). The median RV for both regurgitation and aspiration events was 5 mL. Over a wide range of RV, increasing from 0 mL to >400 mL, the frequency of regurgitation and aspiration did not change appreciably. Aspiration risk and bowel function scores did not correlate with the incidence of aspiration or regurgitation. Blue food coloring was detected on only three of the 1,118 (0.27%) samples. RV was < or =50 mL on 84.1% and >400 mL on 1.4% of bedside evaluations. Sensitivities for detecting aspiration per designated RV were as follows: 400 mL = 1.5%; 300 mL = 2.3%; 200 mL = 3.0%; and 150 mL = 4.5%. Low RV did not assure the absence of events, because the frequency of aspiration was 23.0% when RV was <150 mL. Raising the designated RV for cessation of enteral tube feeding from 200 mL to 400 mL did not increase the risk, because the frequency of aspiration was no different between controls (21.6%) and study patients (22.6%). The frequency of regurgitation was significantly less for patients with percutaneous endoscopic gastrostomy tubes compared with those with nasogastric tubes (20.3% vs. 40.7%, respectively; p = .046). There was no correlation between the incidence of pneumonia and the frequency of regurgitation or aspiration. CONCLUSIONS: Blue food coloring should not be used as a clinical monitor. Converting nasogastric tubes to percutaneous endoscopic gastrostomy tubes may be a successful strategy to reduce the risk of aspiration. No appropriate designated RV level to identify aspiration could be derived as a result of poor sensitivity over a wide range of RV. Study results do not support the conventional use of RV as a marker for the risk of aspiration.

APACHE↗

PubMed2004

Microvascular responses to adenosine help explain functional and pathologic differences between intestinal segments.

BACKGROUND: Many physiologic (post-prandial hyperemia), pathologic (inflammatory bowel disease), and clinical (enteral feeding) phenomena involve changes in microvascular blood flow to the intestine. Adenosine (Ado) derived from energy metabolism causes vasodilation and appears to be involved in some of these events. The Ado-mediated control mechanisms appear to vary with the diameter of the microvessels and the function of the tissue. This suggests the possibility that Ado-based microvascular control varies between anatomic intestinal segments and microvascular levels in those intestinal segments. METHODS: In vivo digital intravital microscopy was used to measure the responses of larger distributing (A1) and smaller premucosal (A3) vessels to Ado in intact neurovascular loops of jejunum and terminal ileum of the rat. Dose-response curves to Ado were determined. RESULTS: Microvascular dilation and augmented blood flow to Ado were significantly greater in the jejunum than in the terminal ileum. Ado-induced dilation was greater in the smaller A3 than in the larger A1 microvessels. DISCUSSION: These data indicate (1) different vasodilator mechanisms for the jejunum and the terminal ileum, (2) a greater role for Ado-related microvascular control in the jejunum compared with the ileum, and (3) a greater Ado-related control in the premucosal (A3) vessels. These findings suggest that Ado-mediated microvascular effects could explain why some clinical phenomena vary in intensity in selective intestinal segments, and are likely to involve different microvascular control mechanisms in the different segments. Knowledge of these Ado mechanisms could be beneficial in certain clinical scenarios to control blood flow during pathologic conditions.

Adenosine↗

PubMed2003

Tempol, an antioxidant, restores endothelium-derived hyperpolarizing factor-mediated vasodilation during hypertension.

Acetylcholine releases a non-prostanoid endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide from physiological salt solution perfused rat mesenteric arteries. This study reports an impairment in EDHF-mediated vasodilation in deoxycorticosterone acetate (DOCA)-salt hypertensive versus control normotensive rats. Nitric oxide-mediated vasodilation to acetylcholine was not altered in the animals. We hypothesize that free radical species generated as by-products of arachidonic acid metabolism contribute to impaired EDHF-mediated dilation in DOCA-salt hypertension. With or without reduced nicotinamide adenine dinucleotide phosphate (NADPH) as co-factor, arterial microsomes generate free radical species upon incubation with arachidonic acid. The production of free radicals was significantly higher in DOCA-salt versus control rat microsomes, and was totally eliminated by addition of cyclooxygenase-2 inhibitors NS-398 or celecoxib at 30 microM. Treatment of DOCA-salt rats with tempol (an antioxidant; 15 mg/kg, i.p., 21 days) alleviates hypertension; improves acetylcholine-induced EDHF-mediated vasodilation in DOCA-salt rats, and decreases arachidonic acid-driven microsomal free radical production. Serum level of 8-isoprostanes is elevated in DOCA-salt hypertension versus control or sham-salt rats, and the increase was reversed by tempol treatment. These results show that EDHF-mediated dilation of rat mesenteric arteries is impaired in DOCA-salt induced hypertension. Our data also suggest that cyclooxygenase-2 mediates free radical production, and that free radicals modulate the EDHF-mediated vascular response in DOCA-salt induced hypertension.

Acetylcholine↗

PubMed2003

A novel method of peritoneal resuscitation improves organ perfusion after hemorrhagic shock.

BACKGROUND: After resuscitation from hemorrhagic shock, intestinal microvessels constrict leading to impairment of blood flow. This occurs despite restoration and maintenance of central hemodynamics. Our recent studies have demonstrated that topical and continuous exposure of the gut microvasculature to a clinical solution (Delflex; Fresenius Medical Care), as a technique of direct peritoneal resuscitation (DPR), reverses the postresuscitation vasoconstriction and hypoperfusion to a sustained dilation and hyperperfusion. We hypothesize that initiation of DPR simultaneously with resuscitation from hemorrhagic shock enhance organ blood flow to all tissues surrounding the peritoneal cavity as well as distant organs. METHODS: Male Sprague-Dawley rats were anesthetized, intubated and cannulated for monitoring of hemodynamics and for withdrawal of blood. Rats were hemorrhaged to 50% of mean blood pressure for 60 minutes prior to resuscitation with shed blood plus 2 volumes of saline. Animals were randomized for intraperitoneal therapy with 30 mL saline (group 1, n = 9), or Delflex (group 2, n = 9). Whole organ blood flow was measured by colorimetric microsphere technique with phantom organ at baseline, after completion of resuscitation, and at 120 minutes postresuscitation. Replenishment of the dwelling intraperitoneal saline or Delflex was performed in (group 3, n = 8), and (group 4, n = 8), respectively at 90 minutes postresuscitation, and a single whole organ blood flow was performed at 120 minutes postresuscitation. RESULTS: Direct peritoneal resuscitation caused a significant increase in blood flow to the jejunum (35%), ileum (33%), spleen (48%), and pancreas (57%), whereas a marked increase in blood flow was detected in the lung (111%), psoas major muscle (115%), and diaphragm (132%), as compared with the saline treated animals in group 1. At 120 minutes postresuscitation, organ blood flow returned to the prehemorrhagic shock baseline level in all organs irrespective of peritoneal therapy. Replenishment of the intraperitoneal solution in group 3 and 4, enhanced blood flow to the liver, kidneys, and diaphragm. CONCLUSIONS: Direct peritoneal resuscitation enhanced blood flow to organs incited in the pathogenesis of multiple organ failure that follows hemorrhagic shock.

Animals↗

PubMed2003

Adrenomedullin is increased in the portal circulation during chronic sepsis in rats.

BACKGROUND: A clinical hallmark of sepsis is an early, hyperdynamic cardiac phase (increased cardiac output) that degrades to a hypodynamic phase, which results in poor gut perfusion and subsequent gastrointestinal (GI) hypoxemia, tissue ischemia, necrosis and loss of gut barrier function. Studies in rat cecal-ligation and puncture suggest that the potent vasodilator adrenomedullin (AM) might initiate or maintain the hypodynamic phase. We hypothesize that AM expression is increased in acute Escherichia coli bacteremia and chronic E coli-Bacteroides fragilis sepsis. METHODS: Acute bacteremia: male Sprague-Dawley rats were anesthetized (urethane/alpha-chloralose), tracheotomized, and cannulated for monitoring blood pressure (MABP) and heart rate (HR) and for infusion of E coli (10(9) colony-forming units [CFU] E coli per 1 mL normal saline) and blood sampling. Arterial blood was withdrawn for arterial blood gas (ABG) measurements every 60 minutes. After 6 hours, we harvested lung, liver, kidney, spleen, and small intestine tissue samples and drew arterial and portal blood for AM enzyme-linked immunosorbent assay (ELISA). Chronic sepsis: a sterile gauze pad was implanted and animals recovered for 5 days. Twenty-four hours (10(9) CFU E coli and 10(9) CFU B fragilis per 1 mL normal saline; 1 injection) or 72 hours (2 injections) after the inoculation of the back sponge, rats were anesthetized, intubated, and cannulated as above. MABP, HR, and ABG were measured for 1 hour before tissue and serum harvest for AM ELISA. RESULTS: Sepsis increased HR and MABP in all groups. Acute sepsis caused a respiratory alkalosis and pH was also elevated in chronic sepsis. Serum AM levels were increased in all groups compared with baseline and remained elevated at every time point, but were not different between saline controls and septic animals at any time point, except for the portal serum from the 72-hour chronic sepsis, which was elevated. CONCLUSIONS: These data suggest that surgical manipulation alone is sufficient to stimulate AM secretion, most probably from endothelial cells. While the AM levels were decreasing at 72 hours compared with 6 hours or 24 hours in the arterial blood and the saline control portal blood, it remained elevated in the septic portal samples, suggesting that the sepsis-induced increase of AM was derived from the gut by a different mechanism than that which elevated arterial serum levels.

Acute Disease↗

PubMed2003

Immune-enhancing enteral diet increases blood flow and proinflammatory cytokines in the rat ileum.

BACKGROUND: Enteral feeding improves outcome following surgery. Benefits depend on timing, route (enteral vs parenteral), and nutrient composition (standard vs immune-enhancing diets; IED). IED augments intestinal immunity and stimulates gut blood flow during absorption in a nutrient-specific manner. We hypothesize that a mechanism for the gut protective effect of IED is augmentation of blood flow to the gut-associated lymphoid tissue (GALT) in the terminal ileum. METHODS: Male Sprague-Dawley rats (200-230 g) were fed for 5 days either an IED (Impact, Novartis) or an isocaloric, isonitrogenous control diet (CD, Boost, Mead-Johnson) matched to the daily caloric intake (rat chow). Rats were then anesthetized and cannulated for microsphere determination of whole organ blood flow. Blood glucose levels and blood flow to abdominal organs were determined at baseline and 30, 60, 90, and 120 min after gastric gavage (2 ml) with IED or CD. Intestinal tissues were harvested for cytokine levels (ELISA: IL-4, IL-10, IFN-gamma, and IgA). RESULTS: Chronic IED increased baseline blood flow in the distal third of the small intestine compared to chow-fed and CD. Baseline blood flow was comparable between IED and CD in all other organs. CD and IED produced different blood flow patterns after gavage. CD increased blood flow compared to baseline and IED in antrum, duodenum, and jejunum. Ileal blood flow remained elevated in IED rats for 2 h, perhaps suggesting maximal blood flow. IED increased blood glucose compared to CD. Chronic IED increased IL-4 and decreased IL-10 in the terminal ileum. CONCLUSIONS: Chronic IED exposure increases and sustains ileal blood flow compared to CD with altered proinflammatory cytokine expression. Our data suggest that a mechanism for the IED effect involves the selective perfusion of the terminal ileum and contiguous GALT during IED nutrient absorption.

Animals↗

PubMed2003

Intraperitoneal resuscitation improves intestinal blood flow following hemorrhagic shock.

OBJECTIVE: To study the effects of peritoneal resuscitation from hemorrhagic shock. SUMMARY BACKGROUND DATA: Methods for conventional resuscitation (CR) from hemorrhagic shock (HS) often fail to restore adequate intestinal blood flow, and intestinal ischemia has been implicated in the activation of the inflammatory response. There is clinical evidence that intestinal hypoperfusion is a major factor in progressive organ failure following HS. This study presents a novel technique of peritoneal resuscitation (PR) that improves visceral perfusion. METHODS: Male Sprague-Dawley rats were bled to 50% of baseline mean arterial pressure (MAP) and resuscitated with shed blood plus 2 equal volumes of saline (CR). Groups were 1) sham, 2) HS + CR, and 3) HS + CR + PR with a hyperosmolar dextrose-based solution (Delflex 2.5%). Groups 1 and 2 had normal saline PR. In vivo videomicroscopy and Doppler velocimetry were used to assess terminal ileal microvascular blood flow. Endothelial cell function was assessed by the endothelium-dependent vasodilator acetylcholine. RESULTS: Despite restored heart rate and MAP to baseline values, CR animals developed a progressive intestinal vasoconstriction and tissue hypoperfusion compared to baseline flow. PR induced an immediate and sustained vasodilation compared to baseline and a marked increase in average intestinal blood flow during the entire 2-hour post-resuscitation period. Endothelial-dependent dilator function was preserved with PR. CONCLUSIONS: Despite the restoration of MAP with blood and saline infusions, progressive vasoconstriction and compromised intestinal blood flow occurs following HS/CR. Hyperosmolar PR during CR maintains intestinal blood flow and endothelial function. This is thought to be a direct effect of hyperosmolar solutions on the visceral microvessels. The addition of PR to a CR protocol prevents the splanchnic ischemia that initiates systemic inflammation.

Animals↗

PubMed2002

Immune-enhancing enteral diet selectively augments ileal blood flow in the rat.

BACKGROUND: Clinical studies show that immune-enhancing enteral diets (IED; with L-arginine, fish oil, and RNA fragments) decrease the rate of sepsis and shorten the length of hospital stay after the start of enteral feeding. These beneficial effects are dependent on the route of administration (enteral vs parenteral) and on the nutrient composition (IED vs standard diets). Gut exposure to an IED seems to preserve and/or augment intestinal mucosal immunity. However, nutrient absorption stimulates gut blood flow in a nutrient-specific manner (i.e., postprandial hyperemia). We hypothesized that an IED would initiate a different pattern of whole organ blood flow compared to a standard diet. This suggests that a mechanism for the protective effect of IED might be the preferential augmentation of gut blood flow to gut-associated lymphoid tissue (GALT) or mucosa-associated lymphoid tissue (MALT). METHODS: Male Sprague-Dawley rats (200-225 g) were anesthetized and cannulated for colorimetric microsphere determination of blood flow distribution (with the phantom organ technique). Animals received gastric gavage (2 ml) of an IED (Impact; Novartis) or an isocaloric, isonitrogenous control diet (Boost; Mead-Johnson). Blood flow to the antrum, duodenum, jejunum, ileum, colon, liver, kidneys, and spleen was determined at baseline and 30, 60, 90, and 120 min after gavage. RESULTS: Baseline blood flows to the left and right kidneys were within 10%, indicating the technical integrity of the microsphere technique and assay. Control diet augmented blood flow compared to IED in the antrum, duodenum, jejunum, and spleen. Conversely, IED gavage stimulated a delayed and sustained hyperemic response in the ileum. IED also increased hepatic blood flow early (30 min). IED increased blood glucose levels compared to control diet at 30, 60, and 90 min, suggesting enhanced nutrient absorption. CONCLUSIONS: These data show that blood flow distribution depends on nutrient composition and that IED preferentially augments blood flow to the ileum. Since the terminal jejunum and ileum contain much of the GALT, our data suggest that a mechanism for enterally stimulated mucosal immunity involves selective perfusion of the terminal ileum during IED nutrient absorption.

Animal Nutritional Physiological Phenomena↗

PubMed2002

Omega-3 fatty acids in immune-enhancing enteral diets selectively increase blood flow to the ileum by a bile acid dependent mechanism.

BACKGROUND: The immune-enhancing diet (IED) (Impact, Novartis Corp, Minneapolis, Minn) initiates a delayed and sustained increase in blood flow to the ileum and gut-associated lymphoid tissue. The immune-enhancing benefits of Impact (Novartis Corp) are attributed to the addition of L-arginine, fish oil (FO), and RNA fragments to a standard enteral diet. The sustained increase in blood flow to the gut-associated lymphoid tissue during IED exposure might account for these immune effects. We hypothesized that the increase in ileal blood flow with IED might be a result of ileal omega-3 fatty acid absorption in the ileum by a bile-dependent mechanism. METHODS: Male Sprague-Dawley rats (200 g-230 g) were anesthetized and cannulated for microsphere measurement of whole organ blood flow. Rats received gastric gavage (2 mL) with either IED, an isocaloric, isonitrogenous control diet (CD) (Boost, Mead-Johnson, Evansville, Ind), CD plus menhaden FO (CD+FO), or CD+FO plus bile duct ligation (BDL). Blood flow was determined at baseline and 30, 60, and 120 minutes after short-term gavage. RESULTS: Baseline blood flow and central hemodynamics were comparable in all groups. In the ileum, at 120 minutes postgavage, blood flow was increased by IED and CD+FO compared with baseline and CD. BDL prevented the increase in blood flow in the CD+FO+BDL rats. All groups exhibited differences in splanchnic blood flow distribution after gavage: CD and CD+FO+BDL increased blood flow compared with baseline early in the proximal gut and spleen. IED and CD+FO produced a delayed, sustained hyperemia to the distal gut. CONCLUSIONS: Gastrointestinal blood flow distribution after feeding is dependent on nutrient composition. These findings suggest that omega-3 fatty acids are the components of the enteral IED, Impact (Novartis Corp), which produce the increased blood flow to the terminal ileum and its contiguous gut-associated lymphoid tissue. Our data suggests that an intact enterohepatic bile pathway is needed for the IED blood flow effect.

Animals↗