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Biomedical subjects

L D Traber

Publications and source records attributed to L D Traber.

At least 55 records · Page 3Linked to original sources
PubMed1996

Changes in regional hemodynamics after nitric oxide inhibition during ovine bacteremia.

We studied the action of nitric oxide synthase (NOS) inhibition on changes in regional blood flow during a continuous infusion of live bacteria. Eighteen ewes were chronically instrumented. After a 7-day recovery period, an infusion of 10(6) colony-forming units/min Pseudomonas aeruginosa was begun. At 24 h, cardiac output increased significantly above baseline in all groups (5.9 +/- 0.4 vs. 8.2 +/- 0.6 l.min 1.m-2), systemic vascular resistance decreased (1,362 +/- 120 vs. 821 +/- 145 dyn.g.cm-5.m-2), and cerebral, cephalic mesenteric, and hindlimb blood flows increased. The animals were then equally and randomly assigned to a bolus of a NOS inhibitor, either 25 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) or 20 mg/kg N omega-monomethyl-L-arginine (L-NMMA), followed by a continuous infusion of 7 mg.kg-1.min-1 L-NMMA or saline. After NOS inhibition, cardiac index decreased [5.6 +/- 0.1 (L-NAME) and 5.5 +/- 0.4 l.min-1.m-2 (L-NMMA)] and remained significantly decreased for 12 h. 1-NAME decreased carotid and mesenteric blood flows to 64% of the preseptic baseline, and they remained below baseline for 20 h. L-NMMA decreased blood flows only to preseptic baseline values. NOS inhibitors may affect blood flows independently of their hemodynamic effects.

Animals↗
PubMed1996

Unilateral smoke inhalation in sheep: effect on left lung lymph flow with right lung injury.

We previously reported that smoke inhalation to the right lung will result in damage to the air-insufflated left lung. In this study we confirm these findings and determine whether this injury is associated with an elevation in lung lymph flow and pulmonary microvascular permeability to protein as indexed by changes in reflection coefficient. Sheep (n = 12) were surgically prepared by placement of a Swan-Ganz catheter and pneumatic occluders on all pulmonary veins and the left pulmonary artery. The left lung lymphatic was selectively cannulated as shown previously (Y. Kikuchi, H. Nakazawa, and D. Traber. Am. J. Physiol. 269 (Regulatory Integrative Comp. Physiol. 38): R943-R947, 1995). All afferent lymphatics from the right lung were severed, and the right pulmonary ligament was sectioned. The caudal end of the lymph node was sectioned to remove systemic lymph contamination. The sheep were studied in the unanesthetized state 7 days later. To ensure that lymph flow was exclusively from the left lung (QLL), right pulmonary microvascular pressure was increased, a procedure that resulted in little or no change in QLL, as was previously shown. The sheep were then anesthetized, and a Carlens tube was positioned to allow separate ventilation of the right and left lung. The right lungs of five sheep and the left lungs of two sheep were insufflated with cotton smoke. Insufflation of the left lung with cotton smoke produced a fourfold increase in QLL that began 4 h after insult. Insufflation of the right lung with smoke led to a doubling of QLL that began 12 h after insult. Changes in QLL were associated with increased microvascular permeability, as indexed by the reflection coefficient. Control sheep (air insufflated into both lungs, n = 5) showed no change in QLL. Injury to the right lung resulted in damage to the left air-insufflated lung, suggesting a hematogenous mediation of the response.

Animals↗
PubMed1996

Effect of severe smoke inhalation injury on systemic microvascular blood flow in sheep.

Multiple nonpulmonary organ dysfunction is frequently associated with acute lung injury; however, the mechanisms underlying the pathogenesis of this process are not completely understood. Decreased oxygen delivery to distant organs due to maldistribution of blood flow may be a contributing factor. We examined the effects of acute lung injury induced by smoke inhalation on microvascular blood flow to various organs in sheep. Seven sheep were prepared with arterial, venous, pulmonary artery, and left atrial catheters. After a 5 day recovery period, a tracheostomy was performed, followed by insufflation with 48 breaths of cool cotton smoke. Determination of microvascular blood flow using colored microspheres, standard hemodynamic measures, and blood gas analysis were performed before and at 12 h intervals after smoke inhalation. Animals were resuscitated to maintain left atrial pressure at +/- 2 mmHg of the baseline value and FiO2 was adjusted to maintain Sao2 at > 90%. After 48 h, sheep were killed and an autopsy was performed. Samples of trachea, left ventricle, ileum, colon, spleen, pancreas, and cortex from both kidneys were obtained for determination of microvascular blood flow. Blood flow to the trachea was substantially increased, while blood flow to the kidneys was preserved near baseline levels. Left ventricular blood flow decreased slightly; however, this decline was not statistically significant. Blood flow to ileum, colon, spleen, and pancreas was significantly decreased, particularly at 36 and 48 h after injury. These decreases were independent of changes in cardiac output or systemic oxygen delivery. It is likely that alteration in microvascular blood flow may contribute to the development of nonpulmonary organ dysfunction after acute lung injury.

Animals↗
PubMed1995

Effects of ibuprofen on airway vascular response to cotton smoke injury.

We studied the effects of ibuprofen on bronchial blood flow and myocardial function after inhalation injury. Sheep (n = 12) were chronically instrumented with cardiovascular and pulmonary catheters. After 5 days of recovery period, baseline data were collected and the sheep were divided into two groups. Group S (n = 6) were insufflated with 48 breaths of cotton smoke; while group I (n = 6) were pretreated with ibuprofen (12mg/kg bolus followed by 3 mg/kg/h continuous infusion for 24 h) and challenged with the same dose of smoke. All the animals were studied for 24h. Bronchial blood flow increased significantly in both groups throughout the experimental period; while stroke volume as well as right and left ventricular stroke work indices of both groups were significantly decreased (group I worse than group S) in the second half of the experimental period. These data suggest that vasodilatory prostaglandins do not play a major role in the bronchial vascular response to smoke inhalation injury and myocardial depression seen post injury is worse in animals treated with ibuprofen.

Animals↗
PubMed1995

Smoke inhalation causes a delayed increase in airway blood flow to primarily uninjured lung areas.

OBJECTIVE: Single lung inhalation injury causes tissue damage to the contralateral lung. We therefore examined airway blood flow after smoke inhalation in chronic instrumented sheep to get further information about the underlying pathophysiology. DESIGN/PATIENTS: The right lung and lower trachea of 5 animals were smoke-exposed, while their left lung was air-insufflated using a split ventilation technique. Three animals, where both lungs were only air-insufflated, served as controls. Blood flow to the airway was measured using a labeled microsphere technique. All animals were studied for 24 h following smoke inhalation. Then they were sacrificed and their tissues harvested. RESULTS: The airway blood flow to the smoke-exposed lung was elevated 11-fold immediately after inhalation injury. The bronchial blood flow to the air insufflated lung became significantly elevated 24 h post-smoke, although to a lesser extent. The control animals did not show any changes of bronchial blood flow during the observation time. CONCLUSIONS: Damage to one lung can lead to pathophysiologic changes in the contralateral lung. This response appears to be mediated by hematogenous factors.

Analysis of Variance↗
PubMed1995

Pulmonary blood flow regulation: influence of positive pressure ventilation.

Positive pressure ventilation with PEEP has been reported to reduce hypoxic pulmonary vasoconstriction (HPV) and thus increase venous admixture. This effect was investigated in six chronically instrumented unanesthetized healthy sheep. The change in left pulmonary arterial blood flow (Qlpa, ultrasonic transit time) in response to unilateral lung hypoxia (10 min of N2 alternately to the left (LLH) and right lung (RLH) was evaluated during mechanical ventilation with and without PEEP of 10 cm H2O in comparison to spontaneous breathing. In the spontaneously breathing animal and during mechanical ventilation without PEEP, Qlpa decreased during LLH from 30% to 16% of cardiac index, during RLH it increased to 51%. With 10 cm H2O of PEEP, Qlpa showed an identical reaction to hypoxia both in the left and right lung. It is concluded that mechanical ventilation and PEEP up to 10 cm H2O does not interfere with pulmonary blood flow regulation to hypoxia.

Animals↗
PubMed1995

Pentafraction for superior resuscitation of the ovine thermal burn.

OBJECTIVE: To determine if a new hydroxyethyl starch, pentafraction, will cause better capillary retention of fluid in thermally burned and nonburned tissues when compared with some currently used volume expanders. DESIGN: Randomized, controlled, experimental study. SETTING: University research laboratory. SUBJECTS: Twenty-one healthy adult range ewes. INTERVENTIONS: Sheep, surgically prepared for chronic study, were randomly assigned to one of three colloid groups for the resuscitation of thermal injuries: a) ovine fresh-frozen plasma group; b) pentastarch group; and c) pentafraction group. Twenty-one sheep were subjected to a 40% total body surface, third-degree flame burn under anesthesia (1.5% to 2% halothane). When awakened, the sheep received 15 mL/kg of one of the above colloids, and then lactated Ringer's solution (2 mL/hr/kg). All animals survived and were killed at 48 hrs after burn injury. MEASUREMENTS AND MAIN RESULTS: We found that cardiac index decreased and systemic vascular resistance increased in the pentastarch and plasma groups. However, cardiac index increased in the pentafraction group, while systemic vascular resistance increased by only half as much as in the other two groups. Cardiac index in the plasma group decreased significantly for the first 8 hrs, and did not return to the baseline value for 48 hrs. Systemic vascular resistance increased significantly for the first 8 hrs in both the plasma and pentastarch groups. Prefemoral lymph flow was significantly more increased in the pentastarch group, while the lung lymph/plasma oncotic gradient was maintained only by the pentafraction group. CONCLUSIONS: Pentafraction is as good, or even superior, for volume resuscitation in the burn patients, when compared with pentastarch and plasma. This conclusion is made most evident by the attenuated changes in systemic vascular resistance and cardiac index. Pentafraction decreases the fluid flux and potential subsequent edema significantly in burned tissues and effectively maintains the pulmonary microvascular integrity.

Animals↗
PubMed1995

Effect of phenytoin on smoke inhalation injury in sheep.

To determine whether the anti-inflammatory effects of phenytoin might reduce cardiopulmonary dysfunction we studied the effects of phenytoin treatment on acute lung injury induced by smoke inhalation. Twenty-one chronically instrumented sheep were observed for 24 h after smoke inhalation injury. Myocardial contractility was evaluated by left ventricular end-systolic pressure-diameter relationship (LVESPDR) with a pair of ultrasonic transducers and strain-gauge transducer. In the control group (n = 6), uninjured sheep were given a bolus of phenytoin (12.5 mg/kg). Smoke-insufflated sheep were divided into nontreatment (n = 7) and phenytoin (n = 8) groups. Phenytoin alone had no effects in uninjured sheep except an early rise in heart rate and LVESPDR. In the group given smoke without treatment, there was a significant increase in pulmonary artery pressure and pulmonary vascular resistance index and a decrease in cardiac index. Pulmonary vascular changes were attenuated by treatment with phenytoin. Pulmonary transvascular fluid flux was evaluated by using a lung lymph fistula. LVESPDR fell in the smoke group but not in the group given phenytoin. There was a marked increase in lung lymph flow with smoke inhalation but this phenomenon was not affected by phenytoin treatment. In conclusion, phenytoin treatment reduced early hemodynamic depression.

Animals↗
PubMed1995

S-ethylisothiourea, a nonamino acid inhibitor of nitric oxide synthase, reverses septic vasodilation in sheep.

S-ethylisothiourea (3936W92) is a nonamino acid antagonist of nitric oxide synthase. Its selectivity for the inducible form of nitric oxide synthase is twice as high as for the constitutive form of the enzyme. We tested 3936W92 in 20 sheep, which were surgically prepared for chronic study. In all sheep, a hyperdynamic sepsis was induced by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, nine sheep received a continuous infusion of 3936W92 over the next 24 h, whereas the control group (n = 9) received saline instead. Two sheep died within the first 24 h of sepsis. 3936W92 caused a complete reversal of the hyperdynamic circulation, while sheep in the control group remained hyperdynamic. Although the cardiac index decreased significantly during treatment with 3936W92 (7.9 +/- .8 vs. 6.0 +/- .7 l/min/m2), a simultaneous increase in oxygen extraction prevented oxygen consumption from falling.

Animals↗
PubMed1995

Effects of manganese superoxide dismutase on lung fluid balance after smoke inhalation.

There is evidence of increased oxygen free radical activity after smoke inhalation with and without concomitant burn injury. We determined the effects of manganese superoxide dismutase (Mn SOD) on lung fluid balance as measured by lung microvascular permeability coefficient (sigma), filtration coefficient (Kf), and lymph flow. Merino breed ewes (n = 6/group) were surgically prepared. The SOD group (SOD) received Mn SOD (9,000 U/kg) as an intravenous bolus and was insufflated with smoke. The control group (CON) received saline and smoke. sigma and Kf were determined 24 h before and 24 h after smoke injury. Lymph flow, arterial O2-to-inspired O2 fraction ratio, systemic hemodynamics, and pulmonary arterial and capillary pressures were measured. The sigma was significantly (P < 0.05) higher after smoke insufflation in SOD compared with CON (0.71 +/- 0.03 vs. 0.53 +/- 0.05). Kf was significantly lower after smoke insufflation in SOD compared with CON (0.038 +/- 0.010 vs. 0.061 +/- 0.010). Lymph flows were significantly lower during the 24 h after smoke insufflation in SOD compared with CON (33 +/- 7 vs. 55 +/- 8 ml/h at 24 h). Arterial O2-to-inspired O2 fraction ratio was significantly improved at 6 and 12 h after smoke insufflation in SOD compared with CON at the same time points. Mn SOD meliorates the lung microvascular permeability changes associated with smoke inhalation injury.

Administration, Inhalation↗
PubMed1995

Use of nitric oxide synthase inhibitors in animal models of sepsis.

Sepsis, as a general inflammatory process, affects the whole organism, mainly because of the intense vasodilation and reduced perfusion pressures associated with it. The high mortality rates seen with sepsis are correlated with a reduction in mean arterial pressure. Therefore, the restoration of adequate arterial pressures is imperative. Nitric oxide (NO.) is at least partly responsible for the vasodilation. Inhibition of nitric oxide synthase (NOS) is, therefore, a logical approach for the treatment of sepsis. As with any other vasoconstrictive drug, NOS inhibitors are clinically indicated only in hyperdynamic sepsis. In animal models, their administration leads to an immediate restoration of blood pressure, accompanied by improved myocardial, pulmonary, and renal function. An increase in oxygen extraction prevents oxygen consumption from decreasing, despite a marked reduction in cardiac output to normal concentrations. In sepsis, virtually all regional blood flows are increased. In our experiments, no organ systems showed a reduction below preseptic baseline values when NOS inhibitors were administered. Furthermore, NOS inhibition did not cause an increase in lactate concentrations, indicating adequate nutritive organ blood flow. Consequently, NOS inhibitors seem to be beneficial and safe when administered under the right circumstances and in a controlled fashion.

Amino Acid Oxidoreductases↗
PubMed1995

Endotoxin versus bacteremia: a comparison focusing on clinical relevance.

All phenomena seen under ovine endotoxemia or bacteremia are typically observed in septic humans as well. The lethality (approximately 20%) in both sepsis models underlines the severity of the experimental sepsis in these models. As mentioned above, both models are ideal to objectify the effects of new therapeutic approaches for the treatment of sepsis, because they provide stable conditions. We tested the inhibition of nitric oxide synthase in both models: Nitric oxide is the main mediator of the vasodilation and the hyperdynamic circulation seen in sepsis. Since the restoration of the perfusion pressure is the major therapeutic goal to prevent further tissue damage (Chernow et al. 1990), the blockade of the nitric oxide synthase seems to be a logical approach for the treatment of hyperdynamic sepsis. Therefore, we tested the nitric oxide synthase inhibitor N(W)-nitro-L-arginine methyl ester (L-NAME) in the endotoxemic sheep model as well as in the bacteremic model. L-NAME reversed the hyperdynamic circulation of sepsis (Meyer et al.1992; Dehring et al.1993). The cardiac output was lowered back to baseline, and at the same time, the arterial pressure was elevated to baseline niveau, both resulting in a marked increase in systemic vascular resistance (figure 3). The pulmonary artery pressure showed only a slight increase, but due to the marked reduction in cardiac output the pulmonary vascular resistance increased significantly. The oxygen extraction was elevated to an extent, which prevented the oxygen consumption to fall, although the oxygen delivery dropped significantly because of the lowered cardiac output (figure 4). The intrapulmonary shunt was brought back to baseline (Meyer et al.1994a), allowing an improved pulmonary oxygen uptake. The renal function improved significantly after nitric oxide synthase inhibition in endotoxemia as well as in bacteremia (Hinder et al.1994; Lingnau et al.1994). Not only was the creatinine clearance elevated, but the urine output also increased, lowering the positive fluid balance. Another inhibitor of nitric oxide synthase N(W)-Mono-Methyl-L-Arginine (L-NMMA) was recently tested in these models as well. This drug is now already in clinical trials. The fact that the effects of these nitric oxide synthase inhibitors in septic humans are similar to the effects in the described experimental sepsis models proves the clinical relevance of the endotoxemic and the bacterimic sheep model.

Animals↗
PubMed1994

Gut failure and translocation following burn and sepsis.

Sepsis with multisystem organ failure is a major cause of morbidity and mortality in burns. We studied the anatomic, physiologic, and metabolic changes of gut mucosa as a normal barrier against sepsis and systemic inflammatory response after burn and sepsis in the chronic porcine model. Flow probes were placed on the mesenteric and hepatic arteries and portal vein. Catheters were placed in the pulmonary artery (Swan-Ganz), aorta, superior mesenteric, and hepatic veins. After 5 days, baseline data were collected and studied after a 40%, third degree burn. They were resuscitated with Ringer's lactate solution (Parkland formula). Eighteen hours later, Escherichia coli endotoxin (100 micrograms/kg) was administered. All animals were sacrificed after 30 hr. The data were compared to a group of sham animals. Following thermal injury the cardiovascular status was stable. Endotoxin administration decreased systemic vascular resistance index and mean arterial pressure, but increased cardiac index. Mesenteric blood flow, vascular resistance, and oxygen consumption showed a transient fall after endotoxin infusion with 20, 23, and 40% reduction, respectively. These changes were associated with a rise in plasma levels of conjugated dienes. The intestinal ornithine decarboxylase activity was elevated at the end of the experiment, evidence of gut repair. Gut bacteria translocated into mesenteric lymph nodes, spleen, and burn wounds in 50% of the animals. We concluded that bacterial translocation into mesenteric lymph nodes, spleen, and wound is due to gut mucosal failure after burn trauma and sepsis. These pathophysiologic changes may be the result of mesenteric ischemia and reperfusion injury.

Animals↗
PubMed1994

Effects of nitric oxide synthesis inhibition in hyperdynamic endotoxemia.

OBJECTIVE: To investigate the effects of N omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, on hemodynamics, gas exchange and oxygen transport in an ovine model of hyperdynamic sepsis. DESIGN: Prospective, nonrandomized, controlled study, with repeated measurements. SETTING: University research laboratory. SUBJECTS: Twenty healthy adult sheep (weighing 20 to 45 kg) were divided into two groups of 12 treated sheep and eight control sheep and studied. INTERVENTIONS: Twenty awake, chronically instrumented sheep received a continuous infusion of endotoxin (10 ng/kg/min) over 48 hrs. Twenty-four hours after the start of the endotoxin infusion, 12 sheep (treatment group) received a bolus of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (25 mg/kg), while the other eight animals (control group) received the carrier (0.9% NaCl). MEASUREMENTS AND MAIN RESULTS: Twenty-four hours after the start of the endotoxin infusion, both groups exhibited a hyperdynamic state with increased cardiac indices, decreased systemic vascular resistance indices, impaired oxygenation, and increased pulmonary shunt fractions. In both groups, oxygen delivery was significantly increased, while oxygen consumption remained virtually unchanged, resulting in a decreased oxygen extraction ratio. In the control group, the significant alterations in systemic hemodynamics, lung function and oxygen transport persisted for the remainder of the study. Administration of N omega-nitro-L-arginine methyl ester normalized cardiac index and systemic vascular resistance index, increased mean arterial blood pressure, and decreased heart rate. Although oxygen delivery significantly decreased after administration of N omega-nitro-L-arginine methyl ester, oxygen consumption did not change, resulting in a normalization of oxygen extraction ratio. Despite a significant reduction of pulmonary shunt fraction, oxygenation did not improve. Pulmonary arterial pressure and pulmonary vascular resistance index showed a peak 2 hrs after administration of the nitric oxide synthesis inhibitor and then tended to decrease. In contrast, the effects of N omega-nitro-L-arginine methyl ester on the systemic circulation persisted for the remainder of the study. CONCLUSIONS: The data support the assumption that augmented nitric oxide production is a major cause of the hemodynamic alterations seen in hyperdynamic endotoxemia. Administration of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester normalized the endotoxin-induced hyperdynamic state, but did not impair oxygen consumption, indicating adequate tissue perfusion of metabolically active organs. Inhibition of nitric oxide synthesis may be a therapeutic option in the treatment of hyperdynamic septic patients when conventional therapy fails to maintain a minimum of cardiovascular performance.

Animals↗
PubMed1994

The sequence of injury determines the degree of lung damage in both inhalation and thermal injuries.

The lung damage resulting from smoke inhalation is an important determinant of morbidity and mortality in thermally injured patients. We hypothesized that the degree of pulmonary microvascular damage seen with smoke inhalation could be affected by whether the smoke insult preceded or followed thermal injury. Fifteen chronically instrumented sheep were divided into two groups: seven were given a 40% 3rd-degree flame burn and then insufflated with smoke (smoke after burn group); eight were insufflated with smoke and then given thermal injury (smoke before burn group). Lung lymph flow and wet/dry weight ratio were significantly higher in smoke before burn group animals. We conclude that lung damage is minimized when thermal injury precedes smoke inhalation injury.

Animals↗
PubMed1994

Left ventricular dysfunction and acute lung injury induced by continuous administration of endotoxin in sheep.

Sixteen sheep were surgically prepared for chronic study. Seven days later, Escherichia coli endotoxin (10 ng/kg/min, lipopolysaccharide (LPS) group, n = 10) or an equivalent amount of 0.9% NaCl (Control group n = 6) was administered. Between 1 and 8 h post-LPS, there was a hypodynamic state with low cardiac index (CI, LPS 5.0 +/- 0.2; sham 6.3 +/- 0.4 liters/min/m2 at 4 h). During this period, the left ventricular end-systolic pressure-diameter relationship (ESPDR), a sensitive index of myocardial contractility, was also lower (LPS 10.4 +/- 1.2; sham 17.2 +/- 0.8 mmHg/mm). Mean pulmonary arterial pressure (PAP) and pulmonary vascular resistance index (PVRI) were remarkably increased 1 h after the administration of LPS (PAP:LPS 37.5 +/- 1.9; sham 21.8 +/- 0.9 mmHg, PVRI: LPS 600 +/- 58; sham 158 +/- 23 dynes x s x cm-5 x m2). The early changes in cardiopulmonary function occurred concomitantly with an elevation in tumor necrosis factor (LPS 1221 +/- 520; sham 0 +/- 0 pg/ml) and thromboxane B2 (LPS 1382 +/- 266; baseline 82 +/- 20 pg/ml) in arterial blood. Following this first phase, the sheep presented a persistent hyperdynamic state characterized by a significant increase in CI. The ESPDR continued to fall. By 24 h post-LPS the CI was 10.1 +/- 0.5 liters/min/m2 (sham, 6.3 +/- 0.3) but the ESPDR had fallen to 8.2 +/- 2.3 mmHg/mm (sham 16.0 +/- 3.0). The pulmonary hypertension was maintained for the duration of the LPS infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗