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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.

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-γ, 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.

Background. Clinical studies show that immuneenhancing 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. © 2002 Elsevier Science (USA)

Introduction. Acetylcholine (Ach) is frequently used to assess endothelium-dependent vasodilation during sepsis. However, the effects of sepsis on constitutive nitric oxide synthase activity (NOS-1 and -3) and other non-NOS effects of Ach are unclear. Methods. Sepsis was induced in rats by inoculation of an implanted sponge with Escherichia coli and Bacteroides fragilis (109 CFU each). Thoracic aortic rings (2 mm) were harvested at 24 h from septic (N = 9) and control (N = 9) rats and were suspended in physiological salt solution (PSS), PSS + l-N6-(1-iminoethyl)lysine (l-NIL: NOS-2 inhibitor, 10 μM), or PSS + l-NG-monomethylarginine (l-NMMA: NOS-1, -2, and -3 inhibitor, 60 μM). Rings were set at 1-g preload and precontracted with phenlyephrine (10−8 M). Relaxation dose–response curves were generated with six doses of Ach (3 × 10−8 to 10−5 M). Results. Sepsis increased the maximal relaxation to Ach under basal conditions. NOS 2 inhibition with l-NIL decreased Ach-induced relaxation in controls (66% vs 84%, P < 0.05, two-way ANOVA) and more so in septic rats (44% vs 93%, P < 0.05). Total NOS inhibition with l-NMMA decreased Ach-induced relaxation to 45% (P < 0.05) in controls and to 30% (P < 0.05) in septic animals. Conclusions. Inhibition of NOS-1, -2, and -3 failed to abolish Ach-induced relaxation, suggesting the presence of other Ach-induced vasodilator mechanisms. NOS-2 inhibition reduced Ach-induced relaxation by 20–25% in the normal thoracic aorta, but by 50% in septic animals. The remaining Ach-induced non-NOS vasodilation (after inhibition of NOS-1 + NOS-2 + NOS-3) was reduced from 45% in normals to 30% in septic animals. Vascular dysregulation in sepsis is a complex event involving increased NOS-2, decreased NOS-1 + NOS-3, and decreased Ach-induced non-NOS vasodilator mechanisms.

Early sepsis leads to renal hypoperfusion, despite a hyperdynamic systemic circulation. It is thought that failure of local control of the renal microcirculation leads to hypoperfusion and organ dysfunction. Of the many mediators implicated in the pathogenesis of microvascular vasoconstriction, arachidonic acid metabolites are thought to be important. Vasoconstriction may be due to excess production of vasoconstrictors or loss of vasodilators. Using the isolated perfused kidney model, we describe a sepsis-induced rise in renal vascular resistance and increased production of key arachidonic acid metabolites, both vasoconstrictors and vasodilators, suggesting excessive production of vasoconstrictors as a cause for microcirculatory hypoperfusion. There is evidence of increased enzymatic production of arachidonic acid metabolites as well as nonenzymatic, free radical, catalyzed conversion of arachidonic acid. Pentoxifylline (a phosphodiesterase inhibitor) and U74389G (an antioxidant) both have a protective effect on the renal microcirculation during sepsis. Both drugs appear to alter the renal microvascular response to sepsis by altering renal arachidonic acid metabolism. This study demonstrates that sepsis leads to increased renal vascular resistance. This response is in part mediated by metabolites produced by metabolism of arachidonic acid within the kidney. The ability of drugs to modulate arachidonic acid metabolism and so alter the renal response to sepsis suggests a possible role for these agents in protecting the renal microcirculation during sepsis.

Acute lung injury is a common complication of gram-negative sepsis. Pulmonary hypertension and increased lung vascular permeability are central features of lung injury following experimental bacteremia. Platelet-activating factor is a prominent proinflammatory mediator during bacterial sepsis. Our previous studies have demonstrated that exogenous administration of platelet-activating factor (PAF) induces pulmonary edema without causing pulmonary hypertension. Interestingly, inhibition of PAF activity during Escherichia coli bacteremia prevents the development of both pulmonary hypertension and pulmonary edema. These data suggest that PAF contributes to pulmonary hypertension during sepsis, but that this is unlikely to be a direct vascular effect of PAF. The goal of the present study was to investigate the mechanism by which acute E. coli bacteremia induces pulmonary injury and to define the role that PAF plays in this injury. We hypothesized that the effects of PAF on pulmonary hypertension during bacteremia are due to the effects of PAF on other vascular mediators. Several studies suggest that PAF induces the expression of endothelin-1 (ET), a potent peptide vasoconstrictor. Further, our previous studies have implicated ET as a central mediator of systemic vasoconstriction during bacteremia. We therefore sought to assess whether ET is modulated by PAF. E. coli has also been demonstrated to increase endothelial production of nitric oxide (NO), which contributes to maintenance of basal vascular tone in the pulmonary circulation. We hypothesized that PAF might increase pulmonary vascular resistance during bacteremia by activating neutrophils, increasing expression of ET, and decreasing the tonic release of NO. Furthermore, we hypothesized that hypoxic vasoconstriction did not contribute to pulmonary vasoconstriction during the first 120 min of E. coli bacteremia.Pulmonary artery pressure (PAP), blood pressure (BP), heart rate (HR), and arterial blood gases (ABG) were measured in anesthetized spontaneously breathing adult male Sprague-Dawley rats. E. coli (10(9) CFU/100 g body wt) was injected at t = 0, and hemodynamic data were obtained at 10-min intervals and ABG data at 30-min intervals for a total of 120 min. Sham animals were treated equally but received normal saline in place of E. coli. In treatment groups, a 2.5 mg/kg dose of WEB 2086, a PAF receptor antagonist, was administered intravenously 15 min prior to the onset of sepsis or sham sepsis. The groups were (1) intravenous E. coli (n = 5); (2) intravenous WEB 2086 pretreatment + intravenous E. coli (n = 5); (3) intravenous WEB 2086 alone (n = 5); and (4) intravenous normal saline (n = 6). Nitric oxide metabolites (NOx) and ET concentrations were assayed from arterial serum samples obtained at the end of the protocol. Lung tissue was harvested for measurement of myeloperoxidase (MPO) activity and pulmonary histology.E. coli bacteremia increased HR, PAP, and respiratory rate early during sepsis (within 20 min), while hypoxemia, hypotension, and hemoconcentration were not manifest until the second hour. Pretreatment with WEB 2086 completely abrogated all of these changes. E. coli bacteremia increased the activity of serum ET, lung MPO, and neutrophil sequestration in the lung parenchyma via a PAF-dependent mechanism. However, the mechanism of increased production of NO appears to be PAF independent.These data support the hypothesis that E. coli bacteremia rapidly induces pulmonary hypertension stimulated by PAF and mediated at least in part by endothelin-1 and neutrophil activation and sequestration in the lung. Microvascular injury with leak is also mediated by PAF during E. coli bacteremia, but the time course of resultant hypoxemia and hemoconcentration is slower than that of pulmonary hypertension. The contribution of hypoxic vasoconstriction in exacerbating pulmonary hypertension in gram-negative sepsis is probably a late

Background. The two-hit theory of multiple organ dysfunction syndrome proposes that an initial insult primes the host for an altered response to subsequent stimuli. We have previously documented enhanced dilator tone in the small intestine after a two-hit insult; however, the effects on vasoconstrictor function are unknown. We postulated that prior hemorrhage and resuscitation followed by bacteremia would alter microvascular responsiveness to α-adrenergic stimulation. Methods. Male Sprague–Dawley rats underwent fixed-volume hemorrhage with resuscitation (H/R) or sham procedure (Sham). At 24 or 72 h, in vivo videomicroscopy of the small intestine was performed (inflow A1 and premucosal A3 arterioles). Constrictor function was assessed by topical application of norepinephrine (NE; 10−8–10−6 M) before and 1 h after intravenous Escherichia coli or saline. Results. Sham, 24 or 72 h H/R, and E. coli alone produced no significant changes in A1 or A3 response to NE. Sequential H/R + E. coli resulted in decreased constrictor response in both A1 (72 h H/R + E. coli—38% from baseline vs Sham — 54%, P < 0.05) and A3 arterioles (−8% vs −51%, P < 0.05) at high doses of NE (10−6 M). Conclusions. Prior H/R primes the intestinal microvasculature for an altered response during a subsequent stress and these effects persist for up to 72 h following H/R. Sequential insults in this two-hit model caused marked hyporesponsiveness to NE. These alterations in control of microvascular tone might contribute to the hemodynamic compromise of sepsis, impair mucosal blood flow, and contribute to the development of MODS.

Introduction. Sepsis results in hyporesponsiveness to α-adrenergic stimulation. This is thought to be mediated by the release of vasoactive compounds from the septic endothelium or by the direct effect of sepsis on vascular smooth muscle (VSM) contractile mechanics and machinery. Previous studies have used lethal models of sepsis or endotoxemia to examine this phenomenon. The present study utilizes a clinically relevant, nonlethal model of soft tissue infection to determine the effects of sepsis on α-adrenergic mechanisms. We hypothesize that subacute sepsis causes impaired α-adrenergic vascular responsiveness by a combination of effects on adrenergic constrictor mechanisms, endogenous dilator tone, and VSM contractile function. Methods. Male Sprague-Dawley rats underwent implantation of a 2 × 2-cm 2 gauze sponge into a subcutaneous pocket created at the base of the tail. Five days after implantation, sepsis (S) was induced by inoculation of the sponge with 10 9 CFU Escherichia coli and Bacteroides fragilis. Controls (C) were inoculated with saline. Thoracic aortic harvest was performed 24 and 48 h after sponge inoculation for organ bath ring studies. Receptor-mediated (phenylephrine) and nonreceptor-mediated (KCl) maximum force of contraction (F max ) was measured. Vessel sensitivity (pD 2 ) to phenylephrine, acetylcholine, and KCl was calculated from dose-response curves. Results. At 24 h, sepsis resulted in a lower F max to phenylephrine (1.15 for C vs 0.5 for S, P < 0.05 by ANOVA), despite an increase in vessel sensitivity (pD 2 ) to α-adrenergic stimulation (6.70 for C vs 6.88 for S, P < 0.05 by ANOVA). F max to KCI was lower in septic animals at 24 h (3.50 for C vs 2.77 for S, P < 0.05 by ANOVA) and sensitivity to acetylcholine (pD 2 ) was markedly increased (6.56 for C vs 7.23 for S, P < 0.05 by ANOVA). At 48 h, the impairment in F max to α-adrenergic stimulation (2.29 for C vs 1.72 for S, P < 0.05 by ANOVA) and KCl (3.5 for C vs 3.08 for S. P < 0.05 vs 24 h C by ANOVA) persisted without any change in sensitivity to phenylephrine or acetylcholine. Conclusions. Subacute sepsis results in an early suppression of maximum contractile force despite an increase in adrenergic receptor sensitivity (pD 2 ). This may be secondary to an elevation in dilator sensitivity combined with a direct effect of sepsis on VSM contractile mechanisms. Later in the septic process, however, α-adrenergic hyporesponsiveness ( ↓ F max ) is primarily due to changes in VSM contractile machinery.

Background. The two-hit theory of multiple organ dysfunction (MOD) proposes that an initial insult, such as hemorrhage (HEM), primes the host for an abnormal response to a second stress such as infection. The immunologic/inflammatory component of this theory has been well examined; however, the effects on vascular responsiveness are poorly understood. We hypothesized that HEM primes the vasculature for an altered response to a second pathophysiologic stress. Methods. Male Sprague-Dawley rats underwent a fixed-volume HEM with resuscitation (H/R) or sham procedure (Sham). At 48 h, animals were given iv E. coli or saline and followed for 1 h. Thoracic aortic rings were then placed in organ baths containing Krebs buffer aerated with 95% O 2 , 5% CO 2 . Cumulative dose-response curves to phenylephrine (PHE) and acetylcholine (ACH) were obtained. Maximum force of contraction (F max ) was measured and pD 2 values (receptor sensitivity) were derived. Results. H/R alone resulted in heightened constrictor tone and blunted dilator tone. E. coli reduced F max in response to PHE by 50% in Sham vs 76% in H/R. Receptor sensitivity (pD 2 ) to PHE was reduced to a greater degree in H/R (3-fold vs 2-fold). These animals also had a more pronounced enhancement of ACH receptor sensitivity (7-fold vs 2-fold). Conclusions. Hemorrhage primes the vasculature for an altered response to a subsequent stress. When infection is added as a second hit, responsiveness to adrenergic agents is diminished and dilator tone is increased. These data may explain the cardiovascular derangements seen clinically in patients who develop MODS after major hemorrhage followed sequentially by infection.

Glucose-induced absorptive hyperemia of the intestine has been well demonstrated through microsphere blood flow experiments. We have previously demonstrated that glucose, when applied topically to rat ileal epithelium, restores microvascular vessel diameters and blood flow following Escherichia coli bacteremia or hemorrhage/resuscitation. However, the mechanisms of this hyperemia are not completely understood. We hypothesize that nitric oxide is a mediator of the microvascular response to glucose exposure on the rat intestinal epithelium. Methods: Male Sprague-Dawley rats, 200-225 g, were monitored for hemodynamic stability with mean arterial blood pressure and heart rate. A 2-cm segment of the terminal ileum with intact neurovascular supply was exposed for intravital videomicroscopy. Intestinal arteriolar diameters (A1D, inflow; and A3D, premucosal arterioles) and microvascular blood flow (A1Q) were measured following topical application of isoosmotic glucose or saline, with or without L-NAME (LN, 100 mM), a competitive inhibitor of nitric oxide synthase. Statistical analysis was performed by ANOVA followed by Tukey-Kramer honestly significant difference test. Results: All data are expressed as mean percentage changes from baseline standard error of the mean. Hemodynamic variables did not change during the experimental procedure and there were no significant differences among group baselines. Addition of isotonic glucose to the bath solution caused a significant increase in A3D that persisted throughout the experiment (at 30 min, 19.2 ± 4.2 vs -3.9 ± 4.5, P < 0.05). This vasodilation was blocked by topical administration of LN (3.1 ± 2.9, P < 0.05). AID remained at baseline levels (saline and glucose) or constricted (LN) in all groups. Topical LN also attenuated A1Q in both the saline and glucose groups. Conclusions: These data demonstrate that glucose-induced intestinal hyperemia is primarily characterized by premucosal A3 arteriole dilation in this model and that nitric oxide is a mediator of glucose-induced intestinal hyperemia. These findings suggest that either (1) glucose directly causes endothelial nitric oxide production or (2) epithelial cells transduce a vasodilatory signal through vascular endothelial-derived nitric oxide during postprandial intestinal hyperemia.

Background: Multiple system organ failure (MOF) remains a major source of morbidity and mortality in trauma patients. Despite restoration of central hemodynamics, intestinal hypoperfusion can persist. Mucosal ischemia and barrier breakdown are factors in the genesis of MOF. Heparan sulfate is a gycosaminoglycan similar to heparin, but with minimal anticoagulant properties. As an adjunct to resuscitation, it improves immunologic function and restores mucosal oxygenation and function. We hypothesized that resuscitation with heparan following hemorrhage wound prevents intestinal hypoperfusion. Materials and methods:In vivovideomicroscopy was used to study small intestine microcirculation in rats. Animals were hemorrhaged to 50% of baseline mean arterial pressure (MAP) and maintained there. Resuscitation was initiated when the return of 10% shed blood was required to keep MAP at 50%. Animals received either heparan (7 mg/kg/1 ml saline) or saline (1 ml) followed by the remaining shed blood and an equal volume of saline. MAP, cardiac output (CO), A1 arteriole diameters, and flow were determined. Results: Resuscitation of the saline control group resulted in normal MAP with elevation of CO to 25–40% above baseline. The heparan group had return of MAP but only a moderate increase in CO (7–15%). Saline resuscitation led to progressive deterioration in A1 diameters and flow. The addition of heparan prevented delayed A1 constriction and significantly improved perfusion. Conclusions: Heparan prior to resuscitation improved intestinal perfusion, despite a relative reduction in CO. Improvement in nutrient blood flow may protect the mucosal barrier, reducing the incidence of MOF, and suggests that heparan may be useful in resuscitation of trauma patients.

We studied the effect of intraoperative duplex scanning on the incidence of residual and recurrent stenosis and stroke after carotid endarterectomy (CEA). We retrospectively analyzed 98 veteran patients undergoing 106 consecutive CEAs between July 1990 and June 1994. Follow-up duplex scans were available for 86 cases (81%, mean follow-up 20 months). There were no perioperative deaths. Intraoperative duplex scans were obtained in 39 (45%) of 86 CEAs. The incidence of residual stenosis was lower in the patients scanned at the time of surgery (O of 39) than in those who underwent CEA without intraoperative scan (7 of 47, P0.04). One patient who did not receive intraoperative duplex scanning underwent redo CEA for symptomatic residual stenosis due to an intimal flap of the carotid artery. Operative management was changed in 9 of 39 cases because of abnormal intraoperative duplex scans, with no postoperative strokes or residual/recurrent stenosis. The incidence of recurrent stenosis was not different in the two groups (2 of 39 vs 2 of 47, ns). There was no difference in stroke rate. There were three strokes, one perioperative and two postoperative (mean 3.5 months, range 0.5 to 9). Two of the three patients did not undergo an intraoperative duplex scan, but none had developed restenosis50% over a mean of 21 months of follow-up. Intraoperative duplex scanning significantly reduced the incidence of residual stenosis, but did not affect the incidence of recurrent stenosis or stroke following CEA.

Platelet-activating factor (PAF) and bacteremia both cause small intestinal (SI) hypoperfusion which may contribute to mucosal injury, and PAF has been postulated to mediate impaired SI microvascular blood flow during sepsis. Our previous studies demonstrate that sepsis-induced SI hypoperfusion is associated with both arteriolar and venular constriction, but the microvascular mechanisms by which PAF impairs SI blood flow are not well defined. Microcirculation studies in other tissues indicate that PAF is an arteriolar dilator, but this effect in the SI would not explain PAF-mediated hypoperfusion. We studied the effects of PAF on SI microvessels to characterize the microvascular mechanisms which mediate PAF-induced hypoperfusion. We also determined the role of PAF as a mediator of microvascular effects in the intestine during bacteremia by PAF receptor antagonism. Animals received either 10(9) live Escherichia coli IV or PAF applied topically to the SI (30, 80, and 300 nM). Arteriolar and venular diameters and red blood cell velocity (A1, V1) were measured with intravital microscopy and velocimetry. Both PAF and sepsis resulted in impaired SI blood flow (maximum decrease in blood flow -37 and 65%, respectively), but sepsis was associated with both arteriolar and venular constriction (20 and 30% diameter reduction each), whereas PAF produced only venular constriction (50% diameter reduction). Inhibition of PAF action prevented the microvascular alterations of bacteremia (blood flow unchanged, P < 0.05; venular diameter unchanged, P < 0.05), suggesting that PAF is an important mediator of these responses.

Infusion of Escherichia coli bacteria to cause high cardiac output bacteremia produces a differential microvascular response with constriction of large arterioles and dilation of small arterioles in skeletal muscle of rats. An important component to host-defense mechanisms during bacteremia is activation of the complement system. One part of this study explored the possibility that microvascular responses to bacteremia could be mediated by activation of the alternative complement cascade to alter skeletal muscle blood flow during sepsis. Complement activation by iv zymosan into unanesthetized (decerebrate) Sprague-Dawley rats caused constriction of large arterioles and dilation of small arterioles in cremaster muscle, while cardiac output stayed normal or was elevated. These microvascular responses mimic those during bacteremia, suggesting that components of the complement system reediate skeletal muscle microcirculatory responses to live E. coli sepsis. The vasodilation response of small arterioles in skeletal muscle during bacteremia is endothelium-dependent and is mediated at least partially by endothelial-derived relaxing factor (EDRF). Complement activation gives products which interact with endothelial cells. Thus, a second part of this study explored the role of EDRF in the vasodilation of skeletal muscle small ar terioles during activation of the alternate complement pathway. Blockade of EDRF action by hydroquinone totally abolished small arteriole dilation and large arteriole constriction responses to complement activation by zymosan infusion.

Intestinal blood flow has been shown to be impaired after resuscitated hemorrhagic shock. Enteral feeding has been proposed as an adjunct for preserving mucosal integrity and decreasing translocation-related morbidities during stress. The purpose of this study was to determine if an ileal mucosal suffusion with an isotonic glucose or glutamine solution begun after resuscitation would prevent development of this blood flow impairment. The distal ileum of anesthetized Sprague-Dawley rats was prepared for in vivo videomicroscopy. Animals were bled to 50% of baseline blood pressure for 60 min and then resuscitated with their shed blood and an equal volume of lactated Ringer's. After resuscitation was complete, the mucosa was suffused with isotonic glucose, glutamine, or saline (control). Resuscitation restored cardiac output and mean arterial pressure to baseline in all groups; however, first-order arteriolar blood flow remained 50% below baseline in the saline group. Glucose-treated animals demonstrated a 34% increase over baseline in first-order arteriolar blood flow 120 min after resuscitation due to submucosal and previllus arteriolar dilation. This effect became evident 30 min after initiating the suffusion, suggesting an effect mediated via locally generated vasodilators. Glutamine suffusion attenuated the flow impairment by dilation of previllus arterioles but to a lesser degree than that observed in glucose-treated animals. These data demonstrate that mucosal suffusion with an isotonic glucose solution overrides the residual effects of hemorrhagic shock on the intestinal microcirculation and suggest a mechanism for preserving mucosal integrity with the addition of glutamine to standard enteral formulations.

I hope that I have neither bored you nor spoken of things that anyone could question or take as offensive. My simple intent was to relate what I truly believe. The discipline of surgery is indeed a noble profession. The portion of this profession that we identify as academic surgery represents a most prestigious and advantageous vocation. It places us in a position to aid our fellow man in a time of true need and vulnerability, to satisfy our intellectual curiosity, and to be good stewards of our time and talents. But, most of all, it gives us each and every day a sense of purpose, accomplishment, and fulfillment. I believe the Association for Academic Surgery represents a concept that helps each of us attain these goals. It has for me. During this past year, it has been both an honor and an enjoyment to be your President. For that I am most grateful. Thank you.

We examined the effect of fixed-volume hemorrhage (10 ml/kg) on microvascular diameters and blood flow in the small intestine of the rat using in vivo videomicroscopic techniques. We found that hemorrhage in the absence of a potent cyclooxygenase inhibitor results in a transient decrease in intestinal blood flow and a preferential redistribution of intramural blood flow toward the mucosa because of a localized vasodilator response of the premucosal microvessels. In the presence of the selective cyclooxygenase inhibitor, mefenamic acid, the decrease in intestinal blood flow was more substantial and prolonged, and the localized vasodilator response of the premucosal microvasculature was abolished. Our results suggest that vasodilator prostaglandins contribute to the compensatory response of the intestine to hemorrhage and are responsible for the shunting of blood toward the mucosa during hemorrhagic hypotension.

After determining that hepatic blood flow remains impaired after resuscitation from hemorrhagic shock, we used the angiotensin II receptor antagonist saralasin and pentoxifylline to investigate their respective effects on hepatic blood flow responses after resuscitation from hemorrhagic shock. Rats were bled to 50% of baseline blood pressure for 60 min and resuscitated with shed blood and an equal volume of lactated Ringer's solution. Saralasin [10 μg/kg per min ( n = 6)], pentoxifylline [25 mg/kg bolus and 12.5 mg/kg per hr ( n = 7)], or saline ( n = 11) were started with the onset of resuscitation. Total hepatic blood flow measured by ultrasonic transit time flow meter, effective nutrient hepatic blood flow measured by galactose clearance, mean arterial pressure, and cardiac output were recorded at 15-min intervals for 2 hr after resuscitation. Hemorrhage decreased cardiac output 57% below baseline and decreased total hepatic blood flow 64% below baseline. Resuscitation restored cardiac output to baseline levels in all three groups. Despite restoration of cardiac output, total hepatic and effective hepatic blood flow remained significantly below baseline in the saline control and saralasin groups but was restored to baseline levels in the pentoxifylline group. These data indicate that angiotensin II does not contribute significantly to the hepatic blood flow impairment after resuscitation from hemorrhagic shock. Improvement in flow with pentoxifylline implies that hemorrhage and resuscitation impair hepatic microvascular hemorrheology and that addition of pentoxifylline to standard resuscitation corrects the impairment.

The high divorce rate and significant stress experienced by families of academic surgeons stimulated the Committee on Issues of the Association of Academic Surgery to choose medical family stress as the topic for the 1987 Committee presentation at the annual meeting. The Committee hoped to provide insight into the cause of this stress and new strategies for coping with this pervasive problem. Forty-three percent of the 505 surgeons who entered the Association from 1981 through 1984 and 38% of their spouses responded to a questionnaire covering issues of time management, response to stress, child rearing, financial security, and spouse career. A panel consisting of Shirley P. Levine, M.D., Hiram C. Polk, Jr., M.D., and Lane A. Gerber, Ph.D., after discussing the questionnaire results, recommended realistic goal setting, specific prioritization of activities, recognition of the considerable contributions of the spouse, and insight into personal limitations as mechanisms for improving family function.