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R Neal Garrison

Publications and source records attributed to R Neal Garrison.

At least 19 recordsLinked to original sources
PubMed2006

Hypertonic saline resuscitation improves intestinal microcirculation in a rat model of hemorrhagic shock.

BACKGROUND: Conventional resuscitation (CR) from hemorrhagic shock (HS) often restores and maintains hemodynamics but fails to restore intestinal perfusion. Post-CR intestinal ischemia has been implicated in the initiation of a gut-derived exaggerated systemic inflammatory response and in the progressive organ failure following HS. We propose that intestinal ischemia can be prevented with hypertonic saline resuscitation (HTSR). METHODS: Anesthetized male Sprague-Dawley rats (200 to 215 g) were hemorrhaged to 50% of mean arterial pressure (MAP) for 60 minutes and randomly assigned to 1 of the resuscitation groups (n = 7 each): Group I: sham operation and no HS; Group II: HS + CR with the return of the shed blood + 2 volumes of normal saline (NS); Group III: HS + return of the shed blood + hypertonic saline (HTS); (7.5 % NaCl, 4 ml/kg); Group IV: HS + HTS, then return of the shed blood after 60 minutes; Group V: HS + HTS, then 1 volume of NS after 60 minutes. Microvascular diameters of inflow (A1) and proximal and distal premucosal arterioles (A3) in terminal ileum and flow in A1 were measured using in vivo videomicroscopy and optical Doppler velocimetry. Hematocrit, plasma osmolarity, and electrolytes were measured in Groups II and III. RESULTS: HS caused a selective vasoconstriction in A1 arterioles that was not seen in the premucosal arterioles. CR restored and maintained MAP and caused generalized, progressive vasoconstriction at all intestinal arteriolar levels that is associated with hypoperfusion. HTSR failed to restore or maintain MAP or intestinal A1 arteriolar blood flow until the shed blood was returned. However, HTSR prevented the post-resuscitation, premucosal vasoconstriction and produced an insidious selective vasodilation in the A3 arterioles, which was most significant with early blood return (Group III). This selective arteriolar vasoactivity was associated with a significant improvement of endothelial cell function. Plasma hyperosmolality and hypernatremia persisted during the entire 2 hours post-resuscitation with HTS. CONCLUSIONS: Small-volume HTSR can be used as a resuscitation regimen at the trauma scene and for selective clinical conditions where hypotensive resuscitation is indicated. HTSR improves intestinal perfusion by selective vasodilation of the precapillary arterioles even at MAP close to shock levels.

Animals↗
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

Disparity in osmolarity-induced vascular reactivity.

Conventional peritoneal dialysis solutions (PDS) are vasoactive. This study was conducted to identify vasoactive components of PDS and to describe quantitatively such vasoactivity. Anesthetized nonheparinized rats were monitored continuously for hemodynamics while the microvasculature of the jejunum was studied with in vivo intravital microscopy. In separate experiments, vascular reactivity of rat endothelium-intact and -denuded aortic rings (2 mm) was studied ex vivo in a standard tissue bath. In both studies, suffusion of the vessels was performed with filter-sterilized isotonic and hypertonic solutions that contained glucose or mannitol as osmotic agents. PDS served as a control (Delflex 2.25%). Hypertonic glucose and mannitol solutions produced a significant vascular reactivity in aortic rings and instantaneous and sustained vascular relaxation at all levels of the intestinal microvasculature. Similarly, lactate that was dissolved in a low-pH isotonic physiologic salt solution produced significant force generation in aortic rings. Whereas isotonic glucose and mannitol solutions had no vasoactivity in aortic rings, isotonic glucose produced a selective, insidious, and time-dependent vasodilation in the intestinal premucosal arterioles (18 +/- 0.2% of baseline), which was not observed in the larger inflow arterioles (100 mum). This isotonic glucose-mediated vascular relaxation can be attenuated by approximately 50% with combined adenosine A(2a) and A(2b) receptor antagonists and completely abolished by adenosine A(1) receptor inhibition. By using two different experimental techniques, this study demonstrates that hyperosmolality and lactate are the major vasoactive components of clinical peritoneal dialysis solutions. The pattern and the magnitude of such reactivity are dependent on vessel size and on the solutes' metabolic activity. Low pH of conventional PDS is not a vasoactive component by itself but renders lactate vasoactive. Energy-dependent transport of glucose into cells mediates vasodilation of small visceral arterioles by an adenosine receptor-mediated mechanism and constitutes a significant fraction of PDS-mediated vascular reactivity in the visceral microvasculature.

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

Peritoneal resuscitation.

BACKGROUND: After resuscitation from hemorrhagic shock, intestinal microvessels constrict leading to impaired mucosal blood flow. This occurs despite restoration of central hemodynamics. We review studies on the use of peritoneal dialysis fluid as an adjunct treatment in amelioration of this gut hypoperfusion. METHODS: Using in vivo microscopy of the intestinal microcirculation, the effects of topically applied dextrose-based peritoneal dialysis fluid was measured. In other words, animal experiments, the survival benefits, the morbidity, blood flow distribution, and the postresuscitation inflammatory response to direct peritoneal resuscitation (DPR) were determined. RESULTS: Simulated DPR caused a dramatic vasodilation compared with a progressive vasoconstriction when used during conventional resuscitation (CR) from hemorrhagic shock. It also reversed established vasoconstriction 2 and 4 hours after CR. In CR animals, there was a 40% mortality compared with 100% survival in DPR animals. DPR resulted in a downregulation of the gut-associated proinflammatory response noted after CR and similarly prevented edema formation. CONCLUSION: DPR enhances organ blood flow to organs incited in the pathogenesis of multiple organ failure and improves survival after severe hemorrhage and CR.

Analysis of Variance↗
PubMed2005

Direct energy delivery improves tissue perfusion after resuscitated shock.

BACKGROUND: Conventional resuscitation (CR) from hemorrhagic shock (HS) does not restore intestinal blood flow. Indicators of anaerobic metabolism suggest that cellular energy production also is compromised. We hypothesize that the direct intravenous delivery of lipid-encapsulated high-energy phosphates to cells improves intestinal perfusion during HS and resuscitation (RES). METHODS: MAP (MAP) was monitored in male rats (200 g), terminal ileum microvessel diameters were measured by in vivo videomicroscopy, and blood flow (Doppler velocimetry) was calculated. Cellular energy delivery was accomplished by intravenous infusion during RES of fusogenic unilamellar lipid vesicles that contain adenosine triphosphate (ATP; VitaSol). Our protocol was HS to 50% baseline MAP for 60 minutes, 30 minutes of RES, and continued microscopy observation for 120 minutes. Experimental groups (n=8 each) were HS+CR (group I); HS+CR+ VitaSol (group II); HS+CR+Vehicle, Vehicle is the phospholipid vesicles without magnesium ATP, (group III); HS+ VitaSol (group IV); sham-operated control+VitaSol (group V); and a time-matched sham-operated control (group VI). The survival outcome and total tissue water from wet weight/dry weight ratio as a function of adjunct VitaSol resuscitation were evaluated in separate intact animal experiments. RESULTS: HS caused a selective vasoconstriction of the intestinal inflow arterioles (100 microm), which was not seen in the smaller intestinal premucosal arterioles (7-15 microm). CR, which restored baseline hemodynamics, resulted in an initial restoration of intestinal microvascular diameters at all arteriolar levels. However, this was followed by a progressive vasoconstriction and hypoperfusion in premucosal vessels at 120 minutes after RES (-20.48% +/- 2.95% from baseline diameters). In contrast, VitaSol with CR caused enhanced premucosal dilation (+34.27% +/- 4.62%) and augmented flow (+20.50% +/- 10.70%) above prehemorrhage baseline. Vesicles alone had no effect, and VitaSol alone caused only a modest dilation. CR of moderate HS (40% of baseline MAP for 60 minutes, n=10) caused 20% mortality, whereas adjunct VitaSol resuscitation had a 100% survival and less tissue water content. CONCLUSIONS: Our data confirms that CR causes progressive intestinal hypoperfusion. Cellular resuscitation with direct intravenous energy delivery improves intestinal perfusion after CR and results in improved survival and less tissue edema.

Adenosine Triphosphate↗
PubMed2005

Direct peritoneal resuscitation from hemorrhagic shock: effect of time delay in therapy initiation.

BACKGROUND: After conventional resuscitation from hemorrhagic shock, splanchnic microvessels progressively constrict, leading to impairment of blood flow. This occurs despite restoration and maintenance of central hemodynamics. The authors' recent studies have demonstrated that topical and continuous ex vivo exposure of the gut microvasculature to a glucose-based clinical peritoneal dialysis solution (Delflex), as a technique of direct peritoneal resuscitation (DPR), can prevent these postresuscitation events when initiated simultaneously with conventional resuscitation. This study aimed to determine whether DPR applied after conventional resuscitation reverses the established postresuscitation intestinal vasoconstriction and hypoperfusion. METHODS: Male Sprague-Dawley rats were bled to 50% of baseline mean arterial pressure and resuscitated intravenously over 30 minutes with the shed blood returned plus two times the shed blood volume of saline. Initiation of ex vivo, topical DPR was delayed to 2 hours (group 1, n = 8), or to 4 hours (group 2, n = 8), respectively, after conventional resuscitation. Intravital microscopy and Doppler velocimetry were used to measure terminal ileal microvascular diameters of inflow A1 and premucosal A3 (proximal pA3, distal dA3) arterioles and blood flow in the A1 arteriole, respectively. Maximum arteriolar dilation capacity was obtained from the topical application, in the tissue bath, of the endothelium-independent nitric oxide-donor sodium nitroprusside (10M). RESULTS: Hemorrhagic shock caused a selective vasoconstriction of A1 (-24.1% +/- 2.15%) arterioles from baseline, which was not seen in A3 vessels. This caused A1 blood flow to drop by -68.6% of the prehemorrhage value. Conventional resuscitation restored and maintained hemodynamics in all the animals without additional fluid therapy. In contrast, there was a generalized and progressive postresuscitation vasoconstriction of A1 (-21.7%), pA3 (-18.5%), and dA3 (-18.7%) vessels. The average postresuscitation A1 blood flow was -49.5% of the prehemorrhage value, indicating a persistent postresuscitation hypoperfusion. Direct peritoneal resuscitation reversed the postresuscitation vasoconstriction by 40.9% and enhanced A1 blood flow by 112.9% of the respective postresuscitation values. CONCLUSIONS: Delayed DPR reverses the gut postresuscitation vasoconstriction and hypoperfusion regardless of the initiation time. This occurs without adverse effects on hemodynamics. Direct peritoneal resuscitation-mediated enhancement of tissue perfusion results from the local effects from the vasoactive components of the Delflex solution, which are hyperosmolality, lactate buffer anion, and, to a lesser extent, low pH. The molecular mechanism of this vasodilation effect needs further investigation.

Analysis of Variance↗
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↗
PubMed2004

Direct peritoneal resuscitation as adjunct to conventional resuscitation from hemorrhagic shock: a better outcome.

BACKGROUND: Conventional resuscitation (CR) from hemorrhagic shock often culminates in multisystem organ failure and death, commonly attributed to a progressive splanchnic vasoconstriction and hypoperfusion, a gut-derived systemic inflammatory response (SIR), and fluid sequestration. Direct peritoneal resuscitation (DPR) produces a sustained state of tissue hyperperfusion in splanchnic and distant organs. In this study we evaluated the therapeutic potential of DPR on the SIR and fluid sequestration as parameters of treatment outcome. METHODS: Anesthetized nonheparinized rats continuously monitored for hemodynamics were bled to 40% of mean arterial pressure for 60 minutes. Animals were randomized for CR or CR plus DPR under aseptic conditions. Sham nonhemorrhaged rats served as control. Qualitatively, animals were blindly observed for body weight, illness score, or death for 72 hours. Tissues were harvested from survivors, and SIR was measured by interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, and enzyme-linked immunosorbent assay, and fluid sequestration was measured by dry weight/wet weight ratio (DW/WW). RESULTS: Adjunct DPR caused a marked increase (P >.01 by analysis of variance) in the immunoregulator IL-10 in the liver (10,990 +/- 1,470 pg/g) and gut (1815 +/- 640 pg/g), compared to CR rats (6450 +/- 1000 pg/g and 1555 +/- 590, respectively), which is associated with down-regulation of IL-6 and tumor necrosis factor-alpha in liver and gut, from 57 +/- 4 and 20 +/- 3 pg/g, respectively, to 42 +/- 4 and 9 +/- 2 pg/g in DPR-treated animals. CR animals had a lower DW/WW ratio in liver (-36%), spleen (-22%), and lung (-24%) compared to DPR (P <.05), where the DW/WW ratio did not differ from control animals. This fluid sequestration is consistent with a 12% and 5% gain in prehemorrhage body weight at 24 and 72 hours after treatment in the CR animals. Thirty percent of CR animals died within 24 hours, and survivors were squeaking, cold, and pale in eyes and ears and oliguric despite features of fluid overload. In comparison, DPR animals exhibited normal appearance by 24 hours and demonstrated a 100% survival at 72 hours. CONCLUSIONS: This study demonstrates that DPR as adjunct to CR has beneficial effects on the pathophysiology of resuscitated hemorrhagic shock. In addition to restoration of tissue perfusion, DPR has immunomodulation and anti-fluid sequestration effects. These modulations result in improved outcome.

Animals↗
PubMed2004

Impairment of endothelium-dependent dilation response after resuscitation from hemorrhagic shock involved postreceptor mechanisms.

Resuscitation from hemorrhagic shock is associated with impairment of the endothelium-dependent dilation response, whereas the dilation response induced by the endothelium-independent pathway, which is mediated by nitroprusside, a nitric oxide (NO) donor and a direct activator of guanylate cyclase, remains unaltered. Whether the impairment of the endothelium-dependent dilation response is caused by a specific receptor alteration or generally a defect in signal transduction pathway remains undetermined. Anesthetized rats were monitored for hemodynamics, and the terminal ileum was prepared for intravital videomicroscopy. Hemorrhage was 50% of mean arterial pressure for 60 min followed by resuscitation with the shed blood returned plus 2 volumes of normal saline. Intestinal microvascular reactivity to the endothelium-dependent receptor-dependent agonists acetylcholine or substance P (10(-8) or 10(-6) M), as well as the endothelium-dependent receptor-independent calcium ionophore, was determined at baseline and at 2 h postresuscitation from hemorrhagic shock. Measured vascular diameters for premucosal A3 arterioles (pA3 and dA3) were normalized and expressed as percentage of the maximal dilation capacity, as obtained from the response to the endothelium-independent NO donor sodium nitroprusside (10(-4) M). At 2 h postresuscitation, there was a marked constriction of pA3 (-70.1 +/- 20) and dA3 (-61.5 +/- 11.6) from maximal dilation capacity. Baseline premucosal arteriolar response to substance P (10(-8) M) was 30.68 +/- 4.19% and 34.66 +/- 5.82% for pA3 and dA3 arterioles, respectively. This was significantly reduced to 20.97 +/- 2.41% and 17.94 +/- 3.60% at 2 h postresuscitation. However, no significant difference between baseline and postresuscitation arteriolar responses was observed at the higher dose of substance P (10(-6) M). Postresuscitation premucosal arteriolar response to the endothelium-dependent receptor-independent calcium ionophore (10(-9) to 10(-5) M) is characterized by a marked decrease in sensitivity and an enhanced threshold for calcium ionophore-mediated dilation. The logEC50 was -7.62 +/- 0.39 and -7.75 +/- 0.32 for the pA3 and dA3 at baseline, respectively. This was significantly (P < 0.01) reduced to -5.15 +/- 0.14 and -4.39 +/- 0.71 at 2 h postresuscitation. These data suggest that impairment of the endothelium-dependent dilation response after resuscitation from hemorrhagic shock is not mediated by specific receptor alteration. Cellular mechanisms that participate in or are part of oxygen free radical formation after resuscitation from hemorrhagic shock such as Ca2+ and leukocytes, appear to have a pivotal role in the mechanism of cellular dysfunction.

Animals↗
PubMed2004

Role of neutrophils on shock/resuscitation-mediated intestinal arteriolar derangements.

Adequate resuscitation from hemorrhagic shock that preserves hemodynamics is associated with a generalized and progressive intestinal arteriolar vasoconstriction and hypoperfusion coupled with impairment of the endothelium-dependent dilation response. This study was performed to investigate the role of neutrophils on the postresuscitation intestinal arteriolar derangements. Experiments were performed in anesthetized rats 24 h after neutrophil depletion. Neutropenia was induced with antineutrophil serum by tail vein injection. Rats injected with rabbit serum lacking anti-rat neutrophil antibody served as controls. Hemorrhagic shock was 50% of mean arterial pressure for 60 min. Resuscitation was with the shed blood returned plus 2 volumes of saline. A nonhemorrhage group served as control. Intravital videomicroscopy of the terminal ileum was used to measure microvascular diameter and centerline red cell velocity. Endothelial function was assessed from the response to the endothelium-dependent dilator acetylcholine (10(-9) to 10(-4) M). Regardless of neutrophil count, hemorrhagic shock caused selective vasoconstriction of inflow A1 arterioles (-21.49 +/- 0.67%) from baseline, which was not seen in the premucosal A3 vessels (pA3, dA3). At 2 h postresuscitation, there was a generalized vasoconstriction from baseline diameter in A1 (-21.26 +/- 2.29%), pA3 (-22.66 +/- 5.02%), and dA3 (-17.62 +/- 4.84%). Neutrophil depletion caused a significant reset of baseline A1 blood flow from 701 +/- 90 nL/s to 978 +/- 90 nL/s and attenuated the postresuscitation hypoperfusion. This occurred independently of the A1 diameter change. Hemorrhagic shock/resuscitation caused impairment of the endothelium-dependent dilation response irrespective of neutrophil count. This study demonstrates that neutrophils do not contribute to the hemorrhagic/resuscitation-mediated intestinal arteriolar derangements, but appear to possess a role in the intestinal arteriolar blood flow regulation under normal and low flow states possibly via a rheologic effect.

Acetylcholine↗
PubMed2004

Practicing surgeons lead in quality care, safety, and cost control.

OBJECTIVE: To report the experiences of 66 surgical specialists from 15 different hospitals who performed 43 CPT-based procedures more than 16,000 times. SUMMARY BACKGROUND DATA: Surgeons are under increasing pressure to demonstrate patient safety data as quantitated by objective and subjective outcomes that meet or exceed the standards of benchmark institutions or databases. METHODS: Data from 66 surgical specialists on 43 CPT-based procedures were accessioned over a 4-year period. The hospitals vary from a small 30-bed hospital to large teaching hospitals. All reported deaths and complications were verified from hospital and office records and compared with benchmarks. RESULTS: Over a 4-year inclusive period (1999-2002), 16,028 elective operations were accessioned. There was a total 1.4% complication rate and 0.05% death rate. A system has been developed for tracking outcomes. A wide range of improvements have been identified. These include the following: 1) improved classification of indications for systemic prophylactic antibiotic use and reduction in the variety of drugs used, 2) shortened length of stay for standard procedures in different surgical specialties, 3) adherence to strict indicators for selected operative procedures, 4) less use of costly diagnostic procedures, 5) decreased use of expensive home health services, 6) decreased use of very expensive drugs, 7) identification of the unnecessary expense of disposable laparoscopic devices, 8) development of a method to compare a one-surgeon hospital with his peers, and 9) development of unique protocols for interaction of anesthesia and surgery. The system also provides a very good basis for confirmation of patient safety and improvement therein. CONCLUSIONS: Since 1998, Quality Surgical Solutions, PLLC, has developed simple physician-authored protocols for delivering high-quality and cost-effective surgery that measure up to benchmark institutions. We have discovered wide areas for improvements in surgery by adherence to simple protocols, minimizing death and complications and clarifying cost issues.

Adult↗
PubMed2004

Peritoneal dialysis solutions contract arteries through endothelium-independent prostanoid pathways.

Conventional peritoneal dialysis solution (PDS) relaxes visceral and parietal peritoneal arterioles (microvessels) by unclear mechanisms. The present study was originally designed to investigate the mechanisms of PDS-mediated vascular reactivity. Surprisingly, our preliminary data indicated that PDS induces contraction in large vessels such as the aorta. That result contrasts with the relaxation observed in the microvasculature. We therefore extended the study to (1) determine the effect of PDS on the superior mesenteric artery (SMA), (2) confirm the PDS-induced contraction in the aorta, and (3) determine if a prostanoid and nitric oxide are involved in the observed PDS-induced vessel response. Rat SMA rings with intact endothelium and aortic rings with and without endothelium were prepared and placed in baths filled with a non vasoactive physiologic salt solution (PSS), or with PSS plus mefenamic acid (MFA, a cyclo-oxygenase inhibitor), or PSS plus NG-monomethyl-L-arginine (L-NMMA, an inhibitor of nitric oxide synthase) under a force transducer. We recorded changes in tension throughout the protocols. After equilibration, the baths were filled with a conventional glucose-based PDS (Delflex 2.5%: Fresenius Medical Care, Bad Homburg, Germany) with and without MFA or L-NMMA for 30 minutes. The rings were then washed, contracted with phenylephrine, and relaxed with acetylcholine to verify the presence or absence of endothelium. In both SMA and aorta, PDS induced contraction. That contraction was suppressed by MFA [SMA: 0.57 g vs. 0.13 g (+/- 0.035 g); aorta: 0.88 g vs. 0.27 g (+/- 0.035 g); p < 0.05 by analysis of variance (ANOVA)]. Aortic contraction induced by PDS was not altered by L-NMMA. Conventional PDS induces contraction in large vessels, in contrast to its action of relaxation in microvessels. Vascular reactivity in large vessels involves the production of a constrictor prostanoid in the vascular smooth muscle. Peritoneal dialysis solutions do not induce NO in aortic endothelium. Peritoneal dialysis solution-induced, prostanoid-mediated contraction of smooth muscle may contribute to a worsening of hypertension and the premature uterine contractions observed in the rare cohort of pregnant uremic patients on peritoneal dialysis.

Animals↗
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

Sepsis alters vessel contraction by adrenoceptor-induced nitric oxide and prostanoid.

BACKGROUND: Alpha-adrenergic agents contract vascular smooth muscle (VSM) and stimulate endothelial release of secondary factors which modulate VSM contraction. Our study examined constrictor prostanoid (cPN) and nitric oxide (NO) as secondary factors which could alter alpha-1 adrenoceptor-mediated contraction during sepsis. METHODS: Sepsis was induced in rats by inoculation of an implanted sponge with Escherichia coli and Bacteroides fragilis. Aortic rings at 24 h from septic (n = 21) and control (n = 21) rats were suspended in physiological salt solution (PSS) with or without blockers to NO (N(G)-monomethylarginine), cPN (mefenamic acid, MFA), or thromboxane A2 (SQ29548). Contraction dose-response curves were generated to determine maximal contraction force (F(max)) and pD2 (sensitivity) to phenylephrine in each experimental group. RESULTS: Sepsis increased F(max) to phenylephrine (PHE) (1.18 vs 0.90 g, SEM 0.0703). COX inhibition reduced the F(max) in control (0.63 vs 0.90 g, SEM 0.0675) but not in septic animals (1.19 vs 1.18 g, SEM 0.0433). TXA2 receptor inhibition did not alter F(max) in control (1.017 vs 0.973 g, SEM 0.0959) or septic animals (1.28 vs 1.12 g, SEM 0.0823). NOS inhibition enhanced the F(max) in both nonseptic (2.03 vs 0.83 g, SEM 0.0523) and septic rats (1.96 vs 1.15 g, SEM 0.0526), but did less so in the septic animals. CONCLUSIONS: PHE-induced F(max) is determined by a balance between PHE-stimulated VSM alpha-adrenoceptor activity, and PHE-stimulated endothelial release of cPN and NO. Sepsis enhances total PHE-induced F(max) by increasing VSM alpha-adrenoceptor activity and reducing PHE-stimulated endothelial release of dilator NO. Sepsis abolishes the PHE-stimulated endothelial release of cPN. PHE-stimulated cPN is not thromboxane A2, but could be a nonprostanoid dilator in the lipoxygenase (HETE) or cytochrome P450 (EET) pathways.

Animals↗
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.

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