Biomedical subjects

K G Proctor

Publications and source records attributed to K G Proctor.

At least 19 recordsLinked to original sources

PubMed1996

Acadesine and lipopolysaccharide-evoked pulmonary dysfunction after resuscitation from traumatic shock.

BACKGROUND: We have reported that the purine precursor acadesine (AICAR) improved the microcirculation, repleted adenosine triphosphate, and attenuated local and lung neutrophil infiltration after intestinal reperfusion and that it quickly improved systemic hemodynamics after resuscitation from hemorrhagic shock. This study evaluated the therapeutic potential of AICAR after fluid resuscitated trauma. METHODS: Anesthetized (fentanyl) mongrel pigs were subjected to tissue injury plus hemorrhage and randomized to receive resuscitation fluids comprised of shed blood plus either lactated Ringer's solution (LR) or AICAR (1 or 10 mg/kg bolus + 0.5 mg/kg/min x 30 min). Thereafter either LR or AICAR (1 or 10 mg/kg) was administered at 12-hour intervals for 72 hours. In a smaller series (n = 7) a single bolus (0.5 mg/kg) of the adenosine deaminase inhibitor deoxycoformycin was administered at the time of resuscitation. After 72 hours, and endotoxin challenge (0.5 microgram/kg, lipopolysaccharide [LPS]) was administered. RESULTS: At 1 mg/kg (n = 9), AICAR had no obvious effect versus LR (n = 31). At 10 mg/kg AICAR (n = 11), the fluid required to stabilize hemodynamics after trauma was higher (66 +/- 5 versus 52 +/- 3 ml/kg/hr, p = 0.014), but there were fewer deaths 3 days after trauma versus LR (0 of 11 versus 4 of 31, p = 0.210), fewer deaths within 5 hours after LPS administration (3 of 11 versus 16 of 27, p = 0.074), and a longer survival time after LPS administration (4.5 +/- 0.3 versus 3.9 +/- 0.2 hr, p = 0.054). Deoxycoformycin had similar salutary effects on survival after LPS administration. LPS increased protein permeability of pulmonary capillaries, increased peak inspiratory pressures on constant tidal volume, increased dead space ventilation, and caused progressive arterial desaturation on 0.65 FiO2 (all p < 0.05). This pulmonary dysfunction was associated with a compensatory increase in cardiac output, decrease in systemic vascular resistance, increase in O2 consumption, and rise in plasma cortisol level (all p < 0.05). All these changes were blunted or eliminated with 10 mg/kg AICAR. Hematocrit and systemic pressures were maintained relatively constant after LPS administration with fluid resuscitation, but less was required with AICAR versus LR (40 +/- 8 versus 83 +/- 14 ml/kg/hr, p = 0.023). AICAR caused a concentration-related reduction in CD18 expression on LPS-stimulated neutrophils in vitro, but there was no effect versus LR on circulating leukocyte counts in vivo and no effect of AICAR on LPS-stimulated production of tumor necrosis factor in vitro or in vivo. CONCLUSIONS: 1. AICAR reduced the pulmonary dysfunction associated with posttrauma endotoxemia but had no effect on circulating leukocytes, so its mechanism could be related to an adenosine-mediated improvement in peripheral perfusion or O2 use. 2. AICAR is a generic compound that is safe and apparently efficacious in human beings, so AICAR prophylaxis could be cost-effectively administered to trauma patients.

Adenosine↗

PubMed1996

Actions of acute ethanol intoxication on cardiopulmonary function after an endotoxin challenge.

BACKGROUND: This study examined whether acute ethanol (EtOH) intoxication could alter the systemic inflammatory response evoked by endotoxin (lipopolysaccharide, LPS). METHODS: Anesthetized (fentanyl) and mechanically ventilated mongrel pigs were administered 20% EtOH (3 gm/kg) or its vehicle (VEH) by means of gastric lavage. After 60 minutes of equilibration, blood levels were 110 to 130 mg/dl, and LPS (1 microgram/kg per 30 minutes) was infused intravenously to mimic the type of sepsis that might be encountered after a penetrating abdominal injury. RESULTS: LPS caused initial pulmonary vasoconstriction followed by cardiovascular collapse in 7 of 14 pigs with EtOH versus 0 of 14 pigs with VEH (p = 0.0058); survival time averaged 2.4 +/- 0.5 hours for EtOH versus 4.5 +/- 0.3 hours for VEH (p = 0.002). At 3 to 5 hours after LPS infusion the survivors were acidotic (base excess, -5.1 +/- 1.5 versus 0.4 +/- 1.1 mEq/L; p = 0.007) and vasodilated (systemic vascular resistance, 54% +/- 9% versus 111% +/- 9% baseline; p = 0.005). Systemic arterial pressure and cardiac filling pressures were maintained with fluid resuscitation, but more was required for EtOH versus VEH (80 +/- 11 versus 42 +/- 5 ml/kg/hr; p = 0.0034). A diffuse capillary leak was detected with gamma scintigraphy and regional uptake of technetium 99m albumin. With EtOH versus VEH microvascular permeability was higher in abdomen (p = 0.01) and liver (p = 0.06) but not in lung (p = 0.29). These changes were probably mediated in part by leukosequestration: neutrophil counts were initially reduced more than 80% in both groups, but they then rebounded with VEH (p < 0.05) but not EtOH. The early versus late deaths within the EtOH group were distinguished by higher baseline levels of cortisol (1.4 +/- 0.3 versus 0.9 +/- 0.2 micrograms/dl; p = 0.075) and by a 50% decrease evoked by EtOH (p = 0.0042) versus no change in the late death subgroup. After LPS infusion cortisol peaked sooner and then recovered with VEH (p < 0.05), whereas the peak occurred later and there was no decay with EtOH. In addition, at 60 and 90 minutes after LPS infusion tumor necrosis factor was 119 +/- 27 and 240 +/- 40 pg/ml with VEH versus 62 +/- 15 and 95 +/- 23 pg/ml with EtOH (p = 0.041 and p = 0.0030). CONCLUSIONS: By means of a leukocyte-mediated mechanism in the splanchnic circulation, acute EtOH impaired host defense, which exacerbated LPS-evoked systemic inflammatory response. In context with our earlier experimental study and two large clinical trials, it appears that acute EtOH can have opposite effects on the vulnerability to posttrauma sepsis, depending on the timing of the septic insult and on the immune status at the time of septic challenge.

Animals↗

PubMed1996

Acute ethanol intoxication and endotoxemia after trauma.

To determine actions of acute intoxication on pathophysiologic responses to trauma, anesthetized and ventilated mongrel pigs received a 20% solution of ethanol (EtOH) by an intravenous (IV group; 2 g/kg, n = 8) or an oral (PO group; 3 g/kg, n = 12 x 60 minutes) route of administration, or the lactated Ringer's vehicle (LR group; n = 12). After 60 minutes, all were subjected to soft tissue injury and 30 to 35% hemorrhage, 60-minute shock, and then resuscitation, with shed blood plus supplemental LR. After 3 days, host defense was challenged with Escherichia coli lipopolysaccharide (LPS); (1 microgram/kg x 30-minutes IV). The supplemental resuscitation was identical (50-53 mL/kg/hours), but posttraumatic acidosis was observed in the IV group and the PO group (base deficit = 4.4 +/- 1.3 and 5.5 +/- 0.9 mEq/L) and not in the LR group. After 3 days, the acid-base equilibrium was restored, but a difference in host defense was unmasked by LPS. In the LR group, LPS-evoked pulmonary vasoconstriction was followed by decreased compliance and ventilation-perfusion mismatch, which was associated at 3 to 5 hours with a base deficit, reduced SVO2, and reduced PO2 (-0.5 +/- 0.2 mEq/L, 46 +/- 1%, 127 +/- 1 mm Hg). These changes were blunted in the PO group (2.0 +/- 0.1 mEq/L, 56 +/- 1%, 183 +/- 4 mm Hg) and potentiated in the IV group (-4.3 +/- 0.5 mEq/L, 40 +/- 2%, 60 +/- 2 mm Hg), even though more fluid was required to maintain systemic arterial and cardiac filling pressures following LPS administration in the IV (40 +/- 6 mL/kg/ hours) versus the LR or PO groups (31 +/- 5 or 23 +/- 3). The PO versus LR differences could not be attributed to enteral nutrition because an isocaloric solution of 50% dextrose had no effect versus LR solution. EtOH caused neutropenia following trauma, relative to LR solution, but the IV versus PO differences could not be discriminated on the basis of neutrophil or lymphocytes counts, nor CD18 receptor expression, nor renal or hepatic dysfunction. However, T4 lymphocytes and cortisol, a nonspecific index of inflammation, were higher for at least 24 hours after trauma with IV, relative to PO or LR. Blood EtOH was similar with IV or PO during resuscitation (100-120 mg/dL), but the kinetics were different prior to trauma. With PO, blood EtOH slowly accumulated to a steady state plateau, the level of which was higher with no anesthesia or no trauma. With IV, blood EtOH peaked at 275 mg/dL and then exponentially declined with a rate that was not influenced to a major extent by trauma or by anesthesia. Therefore: 1) EtOH absorption is impaired during trauma (in part because of reduced gut blood flow); 2) acute EtOH intoxication at the time of trauma altered neutrophils, plasma cortisol, and T4 lymphocytes during recovery and host defense to a superimposed LPS challenge. The apparently favorable effect of PO versus IV EtOH on the response to endotoxemia after trauma probably reflects differences in the kinetics of blood EtOH in the interval before reperfusion but a "first pass" effect (metabolism in the gut or liver) might also explain the data.

Animals↗

PubMed1995

Antibiotic pharmacokinetics following fluid resuscitation from traumatic shock.

OBJECTIVE: To describe the pharmacokinetic profile of aztreonam and vancomycin hydrochloride in a clinically relevant experimental model of hemorrhagic shock and trauma. METHODS: Ten mongrel pigs (mean +/- SD weight, 26.7 +/- 6.4 kg) were anesthetized with fentanyl citrate and ventilated, and an indwelling catheter was placed in the jugular vein. On day 3, all pigs were subjected to fentanyl administration, ventilation, soft-tissue injury, and an arterial hemorrhage (mean +/- SD, 40% +/- 8%). After a 1-hour shock period, baseline hemodynamics were restored by reinfusing shed blood plus twice the shed volume as lactated Ringer's solution. Aztreonam and vancomycin were infused on day 1, after resuscitation on day 3, and on days 4 and 8. Serial plasma samples were collected for 6 hours after treatment, and differences were compared with analysis of variance. RESULTS: Aztreonam clearance initially decreased with trauma, but subsequently increased by 48% (P < .02) by day 8. Aztreonam steady-state volume decreased by 34% (P = .05, baseline value vs that on day 8). Vancomycin clearance was increased between 25% and 52% (P < .001) on days 3, 4, and 8 compared with the baseline value. Vancomycin steady-state volume initially increased with trauma (P = .009), but it subsequently decreased by 29% (P < .001) on day 8. These data cannot be explained by changes in plasma volume per se because levels of plasma sodium, potassium, chloride, and calcium were within normal reference ranges at all time points. Neither liver nor renal functions were severely impaired because levels of serum urea nitrogen, bilirubin, liver enzymes, creatinine, and plasma proteins were within normal reference ranges. Furthermore, our previous work demonstrated that systemic and splanchnic organ oxygen delivery and demand were near normal immediately after fluid resuscitation and for at least 3 days thereafter; thus, there were probably no major perfusion abnormalities in the liver or kidney. CONCLUSIONS: For at least 5 days after trauma, clearance and steady-state volume of aztreonam and vancomycin are altered. These changes suggest that the interval and magnitude of dosing should be adjusted, relative to the standard recommended dosages of each antibiotic, to maximize their efficacy. Similar studies should be done for other antibiotics.

Animals↗

PubMed1995

Reduced tumor necrosis factor production in endotoxin-spiked whole blood after trauma: experimental results and clinical correlation.

BACKGROUND: The overproduction of tumor necrosis factor-alpha (TNF) plays a key role in virtually every experimental model of septic shock, which has led to the development of several therapies that target TNF and other cytokines in clinical sepsis. However, our previous work showed that plasma TNF was reduced, rather than increased, when a septic challenge was administered 3 days after hemorrhagic shock. In this study we compared whole-blood TNF production ex vivo in human beings and animals after trauma. METHODS: TNF was measured before and after a 4-hour incubation of whole blood with 0 or 5 micrograms/ml Escherichia coli endotoxin (LPS) at 37 degrees C ex vivo. Samples were obtained from trauma patients with (n = 8) and without (n = 14) sepsis and compared with those obtained in healthy volunteers (n = 11). In parallel experiments in a pig model TNF was measured before and after fluid resuscitation from trauma after an ex vivo (0 or 5 micrograms/ml LPS) or an in vivo (5 micrograms/kg LPS, 30 minutes intravenously) challenge. RESULTS: With either an immunoassay or a bioassay in either human beings or pigs before or after trauma, TNF was at or below the threshold of detection, unless the blood sample was spiked with LPS. After spiking, TNF was markedly elevated, but the increment was reduced after trauma. In pigs an LPS challenge in vivo delayed 3 days after trauma evoked an increment in plasma TNF that was blunted compared with that in an uninjured control. This trauma-induced reduction in blood TNF could not be attributed to a simple reduction in the number of monocytes nor to changes in cortisol, nor to increased numbers of neutrophils, whose proteolytic enzymes can impair production or increase the degradation of TNF. Although the plasma concentration of soluble TNF-binding proteins (60 kd) was elevated in nonsepsis (p = 0.0358) and sepsis trauma patients (p = 0.0148), the correlation with TNF production was relatively weak (R2 = 0.260). CONCLUSIONS: There was no evidence of TNF overproduction in whole blood after trauma. If these results could be generalized to other tissues, it would be difficult to justify therapeutic targeting of TNF in exaggerated inflammatory response (or septic complications) after trauma.

Adult↗

PubMed1995

Gastric and extragastric actions of the histamine antagonist ranitidine during posttraumatic sepsis.

BACKGROUND: Histamine H2 antagonists (e.g., ranitidine) are generally thought to specifically reduce gastric acid secretion and are commonly used for stress ulcer prophylaxis in critically ill patients because of their efficacy and safety profile. A few reports suggest that ranitidine might also bind to extragastric sites and/or act as an immunomodulator. The potential effects on posttraumatic sepsis are unknown. METHODS: Mongrel pigs (n = 24) were anesthetized with fentanyl, injured by a 10 kg steel bar dropped from a height of 1 m onto the fleshy portion of the posterior thigh, and then 35% of their blood volume was drained through the arterial catheter. All the shed blood plus two times the hemorrhage volume as lactated Ringer's solution was infused after a 1-hour shock period. Either vehicle or ranitidine (1.5 mg/kg) was intravenously administered at the time of resuscitation and every 12 hours thereafter in a blinded fashion. After 72 hours a septic challenge was administered (15 micrograms/kg Escherichia coli lipopolysaccharide [LPS] x 30 min). Serial gastroscopy, gastric pH, hemodynamics, leukocyte counts, cortisol, and tumor necrosis factor were recorded for 180 minutes after LPS. RESULTS: Immediately before LPS all hemodynamic variables were identical between treatments, but gastric pH was slightly higher and stress gastritis was marginally lower with ranitidine. LPS caused profound leukopenia and a hyperdynamic circulatory response (i.e., tachycardia, increased cardiac output, and decreased peripheral vascular resistance at relatively constant blood pressure); these changes were not altered by ranitidine. Gastric pH remained elevated after LPS with ranitidine, but LPS-induced gastritis was not modified. Ranitidine delayed the LPS-induced ventilation-perfusion imbalance and attenuated the peak increase in the proinflammatory cytokine, tumor necrosis factor, without altering its antiinflammatory opponent, cortisol. Similar changes were observed in four additional animals treated with cimetidine. The proportion of circulating neutrophils and lymphocytes was slightly altered 180 minutes after LPS, but there was no obvious effect on T lymphocytes in vivo, and no effect on the LPS-induced increase in neutrophil CD18 expression in vitro was seen. CONCLUSIONS: (1) Ranitidine increased gastric pH, which blunted the stress gastritis caused by trauma but not that caused by LPS; (2) ranitidine delayed the early LPS-evoked pulmonary changes and reduced the tumor necrosis factor spike, which is consistent with a favorable immunomodulatory action that has been reported in patients who are critically ill or are undergoing an elective abdominal surgical procedure; (3) the mechanism is probably related to H2 receptor antagonism rather than to a nonspecific side effect of ranitidine, which suggests that histamine may have a previously unrecognized role in posttraumatic septic responses; and (4) the site of action is probably not in the heart or peripheral resistance vessels, but salutary effects on circulating lymphocytes or neutrophils cannot be excluded.

Acidosis↗

PubMed1995

Actions of prostaglandin E1 on lipopolysaccharide-evoked responses in vivo and in vitro following resuscitated trauma.

Prostaglandins of the E series (PGE1, PGE2) have well-described immunosuppressive (antiinflammatory) as well as vasodilator (pro-inflammatory) actions. The net effect on an acute inflammatory response would depend on the dose, timing, and site of action. Egg phosphatidyl liposomes are novel drug delivery vehicles that can alter the in vivo disposition of PGE1. The purpose of this study was to explore the therapeutic potential of PGE1, with or without liposome encapsulation, on the systemic inflammatory response evoked by endotoxin following trauma. Anesthetized pigs received a soft tissue injury + hemorrhage, and fluid resuscitation after 1 h. In one series, whole blood was incubated with PGE1 (0, 40, or 200 micrograms/mL) and Escherichia coli endotoxin (LPS; 0, 1, 5, or 10 micrograms/mL) in vitro and neutrophil CD18 adherence receptor density was measured with immunomonitoring. In another series, LPS (5 micrograms/kg) was administered 3 days following trauma to animals pretreated with either phosphate-buffered saline (PBS) + PGE1 (62 ng/kg/min x 40 min, 2.5 micrograms/kg total, n = 8), PBS (n = 12), liposomes alone (Lipo, n = 10) or liposome-encapsulated PGE1 (Lipo + PGE, n = 7). This PGE1 dose had minimal effects on blood pressure in baseline conditions. Hemodynamics, cell differential counts, plasma cortisol, and plasma tumor necrosis factor (TNF) were measured for 3 h post-LPS. LPS in vitro caused a dose-related increase in neutrophil CD18 expression that was not altered by < 200 micrograms/mL PGE1 before or after trauma.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1994

Neutrophil CD18 expression and blockade after traumatic shock and endotoxin challenge.

OBJECTIVE: The expression of the leukocyte CD18 adhesion complex on polymorphonuclear leukocytes (PMNs) was measured, and the physiologic effects of blockade of the complex were studied after trauma and sepsis. SUMMARY BACKGROUND DATA: Margination of PMNs occurs early during inflammation and depends, in part, on expression of the CD18 adhesion complex. Blockade of this adherence complex can reduce PMN-mediated damage. This study tests the hypothesis that PMN activation after resuscitated trauma produces an occult endothelial injury that increases the vulnerability to a delayed inflammatory stimulus. METHODS: Anesthetized (fentanyl) mongrel pigs were sham injured or fluid resuscitated from soft tissue injury +35% hemorrhage. Systemic blood was collected at 24-hour intervals from awake animals. The CD18 density on circulating PMNs was determined with flow cytometry using mean channel fluorescence (MCF). The CD18 receptors were blocked with monoclonal antibodies either immediately before trauma or immediately before an endotoxin (lipopolysaccharide [LPS]) challenge that was administered to all groups 3 days after the shock episode. Bronchoscopy was performed before trauma, pre-LPS, and post-LPS, and protein content was measured in bronchoalveolar lavage (BAL). RESULTS: Mean channel fluorescence was reduced on PMNs for 48 hours in animals with trauma versus animals with sham injuries. Anti-CD18 therapy produced higher circulating PMN counts compared with nontreated sham or shock groups. The incremental rise of BAL protein after shock was prevented with anti-CD18; the increment after LPS was attenuated. Anti-CD18 was administered before trauma and reduced the fluids necessary to maintain cardiac filling pressures after LPS. CONCLUSIONS: These data suggest that PMNs are activated after resuscitation from traumatic shock and that these cells produce an endothelial injury that may increase the vulnerability to a septic challenge. The broad implication is that temporarily blocking PMN adhesiveness at the time of trauma might salvage some host tissue and reduce the incidence of septic complications in the post-trauma period.

Animals↗

PubMed1994

Plasma tumor necrosis factor and post-traumatic hyperdynamic sepsis evoked by endotoxin.

To examine the role of systemic plasma tumor necrosis factor (TNF) in the septic response following trauma, an endotoxin (lipopolysaccharide (LPS)) challenge was administered to anesthetized mongrel pigs 72 h following either hemorrhagic shock/resuscitation or sham shock. For TNF to be considered a mediator, at least two conditions should be satisfied: a TNF increase should precede other manifestations of the septic response and the magnitude of that increase should correlate with the symptoms. Immediately following resuscitation from shock, hemodynamics were stable, but heart rate, cardiac index (CI), and systemic oxygen delivery (DO2) were elevated 20-60%, and systemic vascular resistance (SVR) was decreased 40%, relative to the preshock baseline. After 72 h, the animals were reanesthetized, reinstrumented, and all hemodynamic values were near normal in both groups. At this point, either 1.5 (shock, n = 2; sham, n = 2), 15 (shock, n = 7; sham, n = 6) or 150 (shock, n = 11; sham, n = 4) micrograms/kg of Escherichia coli LPS was administered intravenously over 30 min. Serial hemodynamic data, complete blood counts, and TNF were recorded for 3 h post-LPS. LPS evoked profound leukopenia and pulmonary hypertension within 15 min that was followed by a hyperdynamic septic response (i.e., progressive arterial desaturation, tachypnea, tachycardia, increased CI, and decreased SVR) and rise in plasma TNF at 60-90 min. In the shock group, LPS-evoked TNF changes were less than or equal to those in the sham group, even though mortality was higher after shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Gamma-scintigraphy and early hepatocellular dysfunction during posttraumatic sepsis.

BACKGROUND: To determine whether the hepatic conjugation-detoxification function was altered during sepsis, the metabolism of bilirubin was measured with gamma-scintigraphy. METHODS: Time-activity curves were generated after a radiolabeled bilirubin analog (technetium 99m-mebrofenin, hepatoiminodiacetic acid [HIDA]) was administered to anesthetized (fentanyl) mongrel pigs in the following conditions: control (n = 16); 30 minutes after 5 micrograms/kg intravenous Escherichia coli endotoxin (LPS; n = 6); 30 minutes after trauma (40% arterial hemorrhage plus soft tissue injury, n = 9); 72 hours after sham trauma (n = 6); 72 hours after fluid resuscitated trauma either before (n = 9) or 30 minutes after (n = 10) LPS administration. All were ventilated with 65% O2 and instrumented with pulmonary artery oximetric catheters. RESULTS: After trauma plus LPS, the rate of HIDA uptake was depressed 20% to 30% (p < 0.05), whereas its elimination half-time was increased almost threefold (p < 0.05) relative to before LPS administration. At the corresponding time after trauma alone or LPS alone, uptake was not altered and elimination was prolonged less than twofold (p < 0.05) relative to control. Perfusion differences could not explain these data because cardiac index (CI, ml/min/kg) was reduced to the same extent after trauma alone (62 +/- 10), LPS alone (79 +/- 6), or trauma plus LPS (71 +/- 6) compared with control (102 +/- 5), sham (112 +/- 11), or pre-LPS (120 +/- 10) (p < 0.05, respectively). Levels of serum alanine aminotransferase and creatine kinase were both elevated (p < 0.05) 72 hours after resuscitation, but there were no added increments caused by LPS administration. Levels of other enzymes and plasma bilirubin were not increased by trauma or LPS alone or in combination. Changes in HIDA uptake-excretion within 30 minutes of LPS after resuscitated trauma coincided with neutropenia and pulmonary hypertension and preceded a hyperdynamic inflammatory state characterized by increased CI (194 +/- 19 ml/min/kg, p < 0.05) at 90 +/- 13 minutes, decreased systemic vascular resistance (0.48 +/- 0.04 mm Hg per ml/min/kg, p < 0.05 relative to 1.08 +/- 0.07 for control or 0.88 +/- 0.08 for pre-LPS) at 81 +/- 8 minutes, and increased systemic O2 consumption (6.96 +/- 0.93 vs 4.16 +/- 0.23 ml O2/min/kg, p < 0.05 relative to pre-LPS) at 96 +/- 12 minutes. CONCLUSIONS: (1) A prior episode of resuscitated traumatic shock exhausts hepatic reserve and this occult dysfunction in the conjugation-detoxification system or bilirubin metabolism is unmasked by LPS; (2) hepatic dysfunction could have a role in the pathogenesis of the hyperdynamic circulatory response evoked by LPS because HIDA clearance was reduced before CI increased or systemic vascular resistance decreased; (3) HIDA clearance is a rapid, reliable, and inexpensive estimate of bilirubin metabolism that may have a practical application in patients with septic trauma or others with occult liver dysfunction.

Aniline Compounds↗

PubMed1994

Splanchnic and systemic hemodynamic responses to portal vein endotoxin after resuscitation from hemorrhagic shock.

BACKGROUND: Hemorrhagic shock and sepsis are usually studied separately or in rodents. This study combined the two insults in a large animal model. METHODS: Anesthetized pigs were bled, held in shock for 1 hour, and then resuscitated with fluid. After 3 days, Escherichia coli endotoxin LPS was infused into the portal vein (150 micrograms/kg x 30 min) to mimic the effect of enteric substances breaching the mucosal barrier. Systemic and splanchnic hemodynamics, circulating leukocytes, and plasma levels of tumor necrosis factor (TNF) were measured in five groups: 40% hemorrhage plus fluid only resuscitation, 40% hemorrhage plus fluid-blood resuscitation, 50% hemorrhage plus fluid-blood resuscitation, sham, or sham plus 5 micrograms/kg LPS priming dose instead of hemorrhage. RESULTS: On day 4 before infusion of LPS, there were no differences between groups in hemodynamics or O2 utilization, but systemic O2 delivery and O2 consumption were each reduced in the hemorrhaged groups because of the hemodilution associated with resuscitation. For 3 hours after infusion of LPS, all animals received aggressive fluid and respiratory support, but arterial blood pressure decreased, and systemic O2 utilization, splanchnic O2 utilization, and arterial lactate level increased; there were no differences between groups. In the 50% group compared with sham, LPS-evoked decreases in cardiac index and stroke index were eliminated, and LPS-evoked tachycardia, pulmonary and systemic vasoconstriction, and increases in hepatic and portal vein lactate levels were blunted. Despite similar leukocyte counts before infusion of LPS and similar leukopenia after LPS infusion, plasma LPS level was higher in the 50% group compared with sham. Furthermore, LPS evoked increases in portal and hepatic vein plasma TNF in the shams, but those changes were reduced in the 50% group. CONCLUSIONS: Most responses to LPS were similar after hemorrhagic shock or a sham operation, which is inconsistent with the concept of "priming." LPS-evoked increases in plasma TNF were blunted after shock, probably because of trauma-induced immune dysfunction. A combined shock plus septic challenge in a large animal model may be valuable for investigating the pathogenic mechanism in human beings.

Analysis of Variance↗

PubMed1993

Resuscitation of hemorrhagic shock with hypertonic saline/dextran or lactated Ringer's supplemented with AICA riboside.

Anesthetized and ventilated swine were bled 23 ml/kg (34% of calculated blood volume) to a mean arterial pressure < 50 mm Hg. After 60 min, a bolus of either 7.5% hypertonic saline/6% dextran 70 (HSD, 4 ml/kg x 5 min) or lactated Ringer's (LR, 32 ml/kg x 5 min) was infused i.v. LR (25-30 ml/kg) was administered to all animals for the next 60 min. Amino imidazole carboxamide riboside (AICAR), which increases endogenous adenosine in ischemic tissues, was added to the initial bolus and the subsequent LR (10 mg/kg bolus + 0.5 mg/kg x 60 min) in half the study population. At 2 hr post-shock, hematocrit, urine output, arterial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, portal venous O2 saturation, and pulmonary arterial O2 saturation were similar in all groups. With HSD vs. LR, cardiac outputs and stroke volumes were each significantly higher, while right atrial pressures and pulmonary vascular resistances were each significantly lower, which is consistent with augmented cardiac contractility with HSD. Furthermore, systemic oxygen consumptions were significantly higher, and intracranial pressures were each significantly lower with HSD. Nevertheless, no variables were far outside the normal range in either group. The addition of AICAR to LR and HSD eliminated the difference in intracranial pressure, systemic oxygen consumption, reduced heart rate by 30-40 beats/min during the first hour of resuscitation, and increased stroke volume by 20-30%.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoimidazole Carboxamide↗

PubMed1992

Extracellular and intracellular actions of adenosine and related compounds in the reperfused rat intestine.

By using pharmacological tools, the biological actions of adenosine (ADO) were manipulated in rat intestine that had been rendered ischemic for 5 or 15 minutes and reperfused for 1 or 24 hours. With 100 microM ADO topically administered for 30 minutes after ischemia and then washed out, intestinal arteriolar blood flow (BF) and tissue ATP were restored to preocclusion levels, and histological damage was minimal after 1 hour of reperfusion. For comparison, with vehicle treatment after ischemia, BF was reduced by 50%, tissue ATP was reduced by 50%, myeloperoxidase levels in the intestine and lung were increased at least twofold, and mucosal villi were shortened and thickened after 1 hour of reperfusion. Furthermore, with vehicle treatment, both baseline BF and reactivity to endothelium-dependent (acetylcholine) and endothelium-independent (2-chloroadenosine) vasodilators were significantly depressed after 24 hours of reperfusion. In contrast, with ADO, baseline BF remained near normal, and vascular reactivity to 2-chloroadenosine and acetylcholine was preserved after 24 hours. The salutary effect of ADO on BF was reduced by simultaneous application of the antagonist 8-phenyltheophylline or the cellular uptake inhibitor dipyridamole. The nonmetabolized agonist 2-chloroadenosine, the purine precursor aminoimidazole carboxamide riboside, or dipyridamole alone all had favorable effects relative to the vehicle, but all were less potent than ADO. The conclusions are as follows: 1) Endogenous ADO modulates the inflammatory response evoked by intestinal reperfusion because aminoimidazole carboxamide riboside or dipyridamole, which increases its availability, generally had favorable effects, whereas 8-phenyltheophylline tended to have opposite effects. 2) Exogenous ADO arrests most of the inflammatory changes associated with reperfusion by mechanisms that include both extracellular (e.g., receptor-mediated vasodilation and granulocyte inhibition) and intracellular (e.g., restoration of ATP) actions. 3) The effectiveness of ADO-related compounds even when administered after ischemia attests to the practicality of salvaging ischemic bowel, at least in some conditions.

2-Chloroadenosine↗

PubMed1991

Microcirculatory flow changes after initial resuscitation of hemorrhagic shock with 7.5% hypertonic saline/6% dextran 70.

In rabbits, laser Doppler flow probes were placed in the jejunum and on the renal cortex. Pulsed Doppler probes were implanted on the abdominal aorta and superior mesenteric and femoral arteries for measuring blood flow velocity. Cardiac output was measured by thermal dilution. Either 30% or 40% of the calculated blood volume was withdrawn through a carotid catheter. After 30 or 60 minutes, an initial bolus of either lactated Ringer's (LR, 16 ml/kg) or 7.5% hypertonic saline/6% dextran 70 (HSD; 4 ml/kg) IV was followed by unlimited IV LR (administered as rapidly as possible) to restore systemic arterial blood pressure to the prehemorrhage levels. With HSD, arterial pressure corrected more rapidly (p less than 0.05), and the initial hemodilution was greater (p less than 0.05), but there were no differences by two hours. With HSD, cardiac output (90%-100% vs. 130%-160% of control; p less than 0.05), plasma Na+ (139-140 mM vs. 146-148 mM; p less than 0.05) and plasma osmolarity (292-295 mOsm vs. 308-310 mOsm; p less than 0.05) were all significantly higher than the values with LR, but there was no effect on blood flow velocities through the infrarenal aorta, femoral artery, or superior mesenteric artery. Renal cortical perfusion (56% vs. 97% of control; p less than 0.05) and jejunal mucosal perfusion (83% vs. 162% of control; p less than 0.05) were significantly higher with HSD. HSD had no detectable effect on bacterial translocation at 24 hours. Thus: 1) HSD restores blood flow more rapidly to the gut mucosal and kidney microcirculations than initial resuscitation with LR; 2) the mechanism could be associated with a transient hemodilution and persistent increases in plasma Na and osmolarity, which reduce hemorrhage-induced cell swelling and blood viscosity changes; and 3) laser Doppler analysis could aid in the diagnosis of reperfusion injury after shock.

Animals↗

PubMed1991

Activation of brain adenosine receptors evokes vasodilation in skin arterioles.

Metabolically stable adenosine (ADO) agonists were infused into cannulas chronically implanted in the lateral cerebral ventricle intracerebroventricularly (icv) while responses in skin microcirculation of pentobarbital-anesthetized hamsters were observed with intravital microscopy. Cyclohexyladenosine (CHA; A1-receptor selective; 0.0001-1 pmol) and N-ethylcarboxoamidoadenosine (NECA; A2-receptor selective; 0.01-0.05 pmol) were delivered in 10 microliters of bicarbonate-buffered Ringer vehicle. Mean systemic arterial blood pressure, heart rate, skin arteriolar diameter, and red blood cell velocity were continuously monitored. Blood flow was calculated from measurements of arteriolar diameter (20-40 microns) and red blood cell velocity. CHA icv caused dose-related decreases in blood pressure and heart rate, as well as increases in cutaneous perfusion. Comparable amounts of CHA administered intravenously evoked no response. Pretreatment with an A1-selective antagonist xanthine amine congener (XAC, 5 pmol icv or 1 mg/kg iv) had no effect on the depressor response but antagonized the bradycardia. In contrast, a nonselective antagonist 8-phenyltheophylline (8pTHEO, 5 pmol icv or 0.3 mg/kg iv) had no effect on the bradycardia but attenuated the depressor response. By either route, both antagonists prevented the cutaneous microcirculatory responses evoked by icv CHA. NECA icv produced hypotension but no change in the skin, and the depressor response was not altered by icv XAC. These observations provide direct evidence that chemical stimulation of central nervous system (CNS) ADO receptors is linked to a cutaneous vascular response that can be dissociated from other cardiorespiratory depressant actions of CNS ADO.

Adenosine↗

PubMed1991

Direct vasoconstriction evoked by A1-adenosine receptor stimulation in the cutaneous microcirculation.

To determine whether the vasoconstriction evoked by A1-adenosine receptor stimulation in the skin circulation caused the release of other substances or whether A1 stimulation modulated the vasoconstriction evoked by other compounds, a potent A1-selective, synthetic agonist, cyclohexyladenosine (CHA), was topically applied simultaneously with several different vasoconstrictor agonists or antagonists. CHA was chosen instead of adenosine because the parent compound is metabolized quickly and also does not discriminate between A1 or A2 receptors. Blood flow was calculated from measurements of arteriolar diameter (40-60 microns) and red blood cell velocity using intravital videomicroscopy. Responses were recorded only in a steady state. The dose-related vasoconstriction evoked by CHA (ED50, 2.07 +/- 0.80 nM; half-minimal response, 93 +/- 1%) was not attenuated by antagonists to norepinephrine (phentolamine [11 microM] or prazosin [10 microM]), serotonin (methysergide [11 microM]), angiotensin II (saralasin [0.11 microM]), thromboxane (SK&F 88046 [13 microM]), or leukotrienes (SK&F 102922 [2.1 microM]). The vasoconstriction evoked by 2 nM CHA was attenuated by a subthreshold concentration (1 nM) of norepinephrine, whereas the vasoconstriction evoked by 0.1-1 microM norepinephrine was attenuated by a threshold concentration (1 nM) of CHA. Higher concentrations (10-100 nM) of CHA had no additional inhibitory effect. In contrast, CHA had no effect on the vasoconstrictions evoked by angiotensin II (10 nM or 1 microM) or serotonin (100 or 500 nM). Therefore, it is unlikely that A1-receptor stimulation causes the release of norepinephrine, serotonin, angiotensin, thromboxane, or leukotrienes in the skin microcirculation. Because norepinephrine attenuated the vasoconstriction evoked by CHA while CHA attenuated that evoked by norepinephrine, there appears to be a negative interaction between alpha-adrenergic and A1-adenosinergic receptors.

Adenosine↗

PubMed1991

Potentiation of leukotriene B4-mediated inflammatory response by the adenosine antagonist, 8-phenyl theophylline.

Previous in vitro studies have shown that adenosine (ADO)-induced inhibition of granulocyte function is near maximal at the sub-micromolar concentrations that would be anticipated in normal tissues. If this mechanism is operative in vivo, then antagonizing ADO receptors should potentiate granulocyte-mediated inflammatory responses. To unmask the putative inhibition, the antagonist, 8-phenyl theophylline (8pTHEO), was continuously suffused over the hamster cheek pouch microcirculation, which was observed with intravital bright field and fluorescence microscopy. As an index of inflammation, macromolecular permeability was measured by determining extravasation of fluorescein isothiocyanate-labelled dextran (MW 150,000). In addition, tissue specimens were fixed and stained with hematoxylin and eosin for histological quantification of intravascular and extravascular granulocytes. The tissue was challenged with a 10-40 min topical application of leukotriene B4 (LTB4, 1.1-4nM) or histamine (0.5 or 10 microM) with and without 8pTHEO, at a concentration (8 microM) that attenuated vasodilation evoked by exogenous ADO. These two inflammatory stimuli were chosen because LTB4 evokes a granulocyte-dependent response in the cheek pouch, while histamine evokes a granulocyte-independent response. 8pTHEO potentiated the dose-related increase caused by LTB4 but had no effect on permeability in baseline conditions or on the response evoked by histamine. In baseline conditions, there were fewer than 500 intravascular granulocytes/mm2 microvessel surface area and fewer than 3000 extravascular granulocytes/cm2 tissue surface area. After LTB4 challenge, there was a 3-4 fold increase in the numbers of extra- and intra-vascular granulocytes compared to baseline, but no dose-related relationship could be detected over the concentration range 1.1-4 nM. With 8pTHEO + 1.1 nM LTB4, the granulocyte accumulation was similar to that with LTB4 alone, but there were significantly more intravascular and extravascular granulocytes in the 8pTHEO after 2.5-4 nM LTB4. In context with previous studies, these results suggest that endogenous ADO exerts a tonic inhibitory influence on granulocytes during LTB4 stimulation and this action can be unmasked with methylxanthines.

Animals↗

PubMed1991

Beneficial actions of exogenous hyaluronic acid on wound healing.

To determine the effect of exogenous hyaluronic acid (HA) on healing of experimental wounds, responses in the hamster cheek pouch were measured after a hole was cut through the tissue with a biopsy punch. Fluorescence-labeled dextran was administered intravenously as a macromolecular tracer and the microcirculation was observed in vivo with a fluorescence microscope connected to a high-resolution television system. In one group a gelatin sponge soaked in 1.5 ml 16 mg/dl HA in water was applied topically at the time of injury and on postinjury days 1, 3, 5, and 7. The control group received the sponge soaked in the aqueous vehicle. Every 2 days after injury, the microcirculation was observed or histologic specimens were harvested. Wound size decreased almost twice as fast with HA compared with its vehicle (p less than 0.05). Healing was defined as time for total wound closure with at least one microvessel bridging the site of injury and required 16 or more days with vehicle but averaged less than 9 days with HA. Early during healing the repair site was surrounded by widespread extravasation of the fluorescent tracer, an index of inflammation; this area was reduced by two thirds 2 to 4 days after injury with HA compared with its vehicle (p less than 0.05). The density of perfused microvessels was twofold higher with HA 2 to 4 days after injury (p less than 0.05). However, microvessel density was similar in both groups by 6 days after injury and remained similar for at least 45 days after injury, which suggests that HA evoked no unusual angiogenic response. Histologic examination of fixed, stained specimens showed increases in intravascular leukocytes after injury and treatment-related differences in the distribution of intravascular leukocytes in 20 to 40 microns and 40 to 80 microns diameter microvessels 1 to 2 days after injury. Otherwise, leukocyte infiltration during healing was similar in both groups. The mechanism for the beneficial action of HA on healing is unknown. However, several in vitro studies suggest that HA is part of a feedback loop that promotes cell proliferation and migration in actively growing tissues. Alternatively, the role of HA in water homeostasis could favor tissue hydration, which has a well-known beneficial effect on healing.

Animals↗