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D L Traber

Publications and source records attributed to D L Traber.

At least 19 recordsLinked to original sources
PubMed1998

Effect of cutaneous burn injury and resuscitation on the cerebral circulation in an ovine model.

The aim of our study was to evaluate the effects of a large cutaneous burn injury on the cerebral circulation. Anesthetized sheep (n = 8) were prepared with vascular catheters, a urinary catheter and a Richmond bolt for intracranial pressure monitoring. A scald injury was inflicted on 70 percent of total body surface area with hot water. Resuscitation was started 30 min after scald with Ringer's lactate to restore and maintain baseline oxygen delivery. Resuscitation maintained blood pressure, cardiac output and urine output at normal levels. Brain blood flow was measured with colored microspheres. During resuscitation intracranial pressure rose slowly from 10.6 +/- 1.5 to 17.0 +/- 4.0 mmHg (P < 0.05) and cerebral perfusion pressure was reduced from 86.4 +/- 6.8 to 64.1 +/- 2.8 mmHg (P < 0.05). During early resuscitation cerebrovascular resistance declined to maintain brain blood flow and oxygen delivery at baseline or better. After 6 h, mean cerebrovascular resistance was inappropriately increased during a period of reduced cerebral perfusion pressure which resulted in brain blood flow reductions of half the baseline levels. These data suggest that autoregulation maintains brain blood flow immediately after burn shock and early resuscitation, but the autoregulation may be less effective as burn resuscitation proceeds.

Animals↗
PubMed1998

Altered systemic organ blood flow after combined injury with burn and smoke inhalation.

Systemic organ blood flow was longitudinally determined with fluorescent microspheres after severe thermal injury in unanesthetized sheep. After chronic instrumentation, 20 sheep were subjected to combined injury with 40% body surface area third-degree burn and 48 breaths of cotton smoke insufflation. During the next 72 h of the experimental period, all animals were resuscitated with Ringer's lactate following the Parkland formula. To test the effect of systemic administration of ibuprofen, animals were assigned to the control group (n=11) or the ibuprofen group (n=9). In the ibuprofen group, animals received ibuprofen as a 12 mg/kg bolus injection 1 h after injury and 6 mg/kg/h as a continuous infusion for the next 47 h. After this combined injury, animals exhibited a biphasic hemodynamic alteration, with an initial shock period and a later hyperdynamic period, a phenomenon often seen in severely burned patients. Among multiple organs, the splanchnic organs exhibited more dominant and sustained decreases in regional blood flow, whereas heart and kidney blood flow were maintained at more than 90% of baseline level even in the initial hypovolemic phase. In the postresuscitation period, no organ except the heart showed increased regional blood flow, despite a more than 20% increase in cardiac output. Ibuprofen had effects on early recovery from the initial shock period, and it improved intestinal organ blood flow, suggesting a potential benefit of this drug for severe thermal injury.

Animals↗
PubMed1998

Effect of reduced bronchial circulation on lung fluid flux after smoke inhalation in sheep.

We determined the effect of reduced bronchial blood flow on lung fluid flux through changes in lung lymph flow, lung wet weight-to-dry weight (wet/dry) ratios, and pulmonary microvascular reflection coefficient (sigma). In the first of two surgical procedures, Merino ewes (n = 21) were surgically prepared for chronic study. Five to seven days later, in a second operation, the bronchial artery of the injection group (n = 7) was ligated, and 4 ml of 70% ethanol were injected into the bronchial artery to cause sclerosis of the airway circulation. In the ligation group (n = 7), only the bronchial artery was ligated. In the sham group (n = 7), the bronchial artery was surgically exposed but left intact without ligation or ethanol injection. One day after these operations the animals received a tracheotomy and 48 breaths of cotton smoke. The value of sigma was determined at two points: 24 h before the second surgical procedure and 24 h after smoke inhalation. Lung lymph flow, blood-gas parameters, and hemodynamic data were measured every 4 h after injury. At the end of investigation, samples of lung were taken for determination of blood-free wet/dry ratio. In the sham group, inhalation injury induced a gradual increase in pulmonary vascular resistance and lung lymph flow, which was associated with deterioration of oxygenation. Reduction of the bronchial blood flow attenuated these pathophysiological changes, and the degree of this attenuation was greater in the injection group than in the ligation group. The value of sigma was significantly higher after smoke inhalation in the injection group compared with the sham group (0.77 +/- 0.04 vs. 0.61 +/- 0.03, means +/- SE) at 24 h. The mean wet/dry ratio value of the injection group animals was 30% less than that of the sham group. Our data show that the bronchial circulation contributes to edema formation in the lung occurring after acute lung injury with smoke inhalation.

Animals↗
PubMed1998

Pyridoxalated hemoglobin polyoxyethylene conjugate reverses hyperdynamic circulation in septic sheep.

We investigated the effects of modified hemoglobin on regional blood flow and function of different organs during hyperdynamic sepsis. Fourteen sheep were surgically prepared for the study. After a 5-day recovery period, a continuous infusion of live Pseudomonas aeruginosa bacteria was begun and maintained for 48 h. At 24 h, after a hyperdynamic circulation had developed, the animals were randomly assigned to two groups: 1) a treatment group (n = 7) that received an infusion with 100 mg/kg pyridoxalated hemoglobin polyoxyethylene conjugate (PHP) over 30 min and 2) a control group (n = 7) that received only the vehicle. PHP infusion increased mean arterial pressure from 86 +/- 2.8 to 101.8 +/- 3.5 mmHg (P < 0.05) and systemic vascular resistance index from 769 +/- 42.1 to 1,087 +/- 56.8 dyn . s . m2 . cm-5 (P < 0.05). PHP infusion did not decrease regional blood flow, measured with fluorescent microspheres, below the baseline values in any of the analyzed tissues. None of the investigated blood chemistry variables showed any changes indicative of impaired organ function after PHP infusion. In our model of ovine sepsis we found no side effects after PHP infusion that would limit the use of PHP as a nitric oxide scavenger in sepsis.

Animals↗
PubMed1998

Endogenous nitric oxide and the pulmonary microvasculature in healthy sheep and during systemic inflammation.

Nitric oxide (NO) influences microvascular integrity. NO synthase inhibitors are regarded as therapeutic options, but their impact on the pulmonary microvasculature is not well defined. We studied the microvascular effects of the nonselective NO synthase inhibitor N(omega)-nitro L-arginine methylester (L-NAME) in healthy sheep and during systemic inflammation. Permeability analysis was performed in 30 adult ewes with chronic lung lymph fistulas and pulmonary venous occluders. Experiment 1: 20 sheep received Escherichia coli endotoxin (lipopolysaccharide, 10 ng/kg/min) for 32 h. After 24 h of endotoxemia, 10 sheep were given L-NAME (25 mg/kg), and 10 sheep received NaCl 0.9%. Experiment 2: six sheep were treated with L-NAME (25 mg/kg), and four animals received NaCl 0.9%. Endotoxin induced a phasic pulmonary microvascular response with early transiently increased endothelial permeability at 4 h and late normalization of microvascular integrity to large molecules after 24 h. At that time systemic vasodilation had occurred. L-NAME raised pulmonary artery pressure and pulmonary vascular resistance index without signs of increased permeability in either experiment. NO is involved in vascular tone in healthy sheep and during systemic inflammation, but it does not seem to play a role in the integrity of the pulmonary microvascular barrier function to large molecules.

Animals↗
PubMed1997

Total arteriovenous CO2 removal: simplifying extracorporeal support for respiratory failure.

BACKGROUND: To reduce the complexity, complications, and cost of conventional extracorporeal membrane oxygenation, we have developed a technique of simplified arteriovenous extracorporeal CO2 removal (AVCO2R) with a low-resistance membrane gas exchanger for total CO2 removal to provide lung rest in the setting of severe respiratory failure. METHODS: We initially used AVCO2R in healthy animals to quantify the gas exchange capabilities of the system and establish ventilator management protocols for the subsequent studies of AVCO2R in a large animal model of respiratory failure secondary to a severe smoke inhalation injury. RESULTS: In healthy sheep the maximum spontaneous arteriovenous flow ranged from 1,350 to 1,500 mL/min, whereas CO2 removal plateaued at a blood flow of approximately 1,000 mL/min in which 112 +/- 3 mL/min CO2 was removed, allowing an 84% reduction in the minute ventilation of from 6.9 +/- 0.8 L/min to 1.1 +/- 0.4 L/min (p < 0.01) without triggering hypercapnia. A subsequent reduction in extracorporeal flow at a reduced minute volume led to the development of hypercapnia only if it decreased to less than 500 mL/min. We also applied AVCO2R in mechanically ventilated sheep with a severe smoke inhalation injury and removed 95% (111 +/- 4 mL/min) of the total CO2 production. This allowed the minute ventilation to be reduced by 95% and the peak inspiratory pressures by 52% (both p < 0.05) over 6 hours and produced no adverse hemodynamic effects. The partial pressure of arterial oxygen was maintained above 100 mm Hg at a maximally reduced minute volume. The mean AVCO2R flow was 1,213 +/- 29 mL/min, averaging 27% +/- 1% of the cardiac output. CONCLUSIONS: We conclude that AVCO2R in a simple arteriovenous shunt is a less complicated technique than extracorporeal membrane oxygenation and is capable of total CO2 removal that allows a significant reduction in the minute ventilation and peak airway pressure during severe respiratory failure.

Animals↗
PubMed1997

Nitric oxide and shock.

Shock can be defined as the failure of the circulatory system to provide necessary cellular nutrients, including oxygen, and to remove metabolic wastes. Although it is now recognized that more than 100 different forms of shock exist, this recognition is more a reflection of the widespread use of the term to describe a variety of disease states. For the purpose of this monograph, we concentrate on various forms of cardiovascular shock, in particular, shock that may be linked to inappropriate vasodilation from overproduction of the endogenous vasodilator, nitric oxide. Some forms of shock have been extensively studied, and convincing evidence exists for the role of nitric oxide. Other disease states have been less well characterized in terms of their association with excess nitric oxide production. Available evidence of a role for nitric oxide is discussed in the hope of stimulating the interest of investigators to explore these areas more thoroughly.

Anaphylaxis↗
PubMed1997

Prolonged hemodynamic stability during arteriovenous carbon dioxide removal for severe respiratory failure.

OBJECTIVE: The effects of prolonged arteriovenous carbon dioxide removal on hemodynamics during severe respiratory failure were evaluated in adult sheep with severe smoke inhalation injury. METHODS: Adult female sheep (n = 6,33.8 +/- 5.2 kg) were subjected to intratracheal cotton severe smoke insufflation to a mean carboxyhemoglobin level of 83% +/- 3%. Twenty-four hours after injury, a low-resistance 2.5 m2 membrane oxygenator was placed in a carotid-to-jugular pumpless arteriovenous shunt at unrestricted flow to allow complete carbon dioxide removal and reductions in ventilator support. Animals remained conscious, and heart rate, cardiac output, mean arterial pressure, and pulmonary arterial pressure were measured at baseline, after injury, and daily during support with the arteriovenous carbon dioxide removal circuit for 7 days. RESULTS: All animals survived the study period. Carbon dioxide removal ranged from 99.7 +/- 13.7 to 152.2 +/- 16.2 ml/min, and five (83%) of the six animals were successfully weaned from the ventilator before day 7. During full support with the arteriovenous carbon dioxide removal circuit, shunt flow ranged from 1.24 +/- 0.06 to 1.43 +/- 0.08 L/min and accounted for 20.1% +/- 1.4% to 25.9% +/- 2.4% of cardiac output. No statistically significant changes in heart rate, cardiac output, mean arterial pressure, or pulmonary artery pressure were demonstrated over the study course despite the extracorporeal shunt flow. CONCLUSIONS: Arteriovenous carbon dioxide removal as a simplified means of extracorporeal gas exchange support is relatively safe without adverse hemodynamic effects or complications.

Animals↗
PubMed1997

Significant reduction in minute ventilation and peak inspiratory pressures with arteriovenous CO2 removal during severe respiratory failure.

OBJECTIVES: To quantify CO2 removal using an extracorporeal low-resistance membrane gas exchanger placed in an arteriovenous shunt and evaluate its effects on the reduction of ventilatory volumes and airway pressures during severe respiratory failure induced by smoke inhalation injury. DESIGN: Prospective study. SETTING: Research laboratory. SUBJECTS: Adult female sheep (n = 5). INTERVENTIONS: Animals were instrumented with femoral and pulmonary arterial catheters and underwent an LD50 cotton smoke inhalation injury via a tracheostomy under halothane anesthesia. Twenty-four hours after smoke inhalation injury, the animals were reanesthetized and systemically heparinized for cannulation of the left carotid and common jugular vein to construct a simple arteriovenous shunt. A membrane gas exchanger was interposed within the arteriovenous shunt, and blood flow produced by the arteriovenous pressure gradient was unrestricted at the time of complete recovery from anesthesia. CO2 removal by the gas exchanger was measured as the product of the sweep gas flow (FIO2 of 1.0 at 2.5 to 3.0 L/min) and the exhaust CO2 content measured with an inline capnometer. CO2 removed by the animal's lungs was determined by the expired gas CO2 content in a Douglas bag. We made stepwise, 20% reductions in ventilator support hourly. We first reduced the tidal volume to achieve a peak inspiratory pressure of < 30 cm H2O, and then we reduced the respiratory rate while maintaining normocapnia. PaO2 was maintained by adjusting the FIO2 and the level of positive end-expiratory pressure. MEASUREMENTS AND MAIN RESULTS: Mean blood flow through the arteriovenous shunt ranged from 1154 +/- 82 mL/min (25% cardiac output) to 1277 +/- 38 mL/min (29% cardiac output) over the 6-hr study period. The pressure gradient across the gas exchanger was always < 10 mm Hg. Maximum arteriovenous CO2 removal was 102.0 +/- 9.5 mL/min (96% of total CO2 production), allowing minute ventilation to be reduced from 10.3 +/- 1.4 L/min (baseline) to 0.5 +/- 0.0 L/min at 6 hrs of arteriovenous CO2 removal while maintaining normocapnia. Similarly, peak inspiratory pressure decreased from 40.8 +/- 2.1 to 19.7 +/- 7.5 cm H2O. PaO2 was maintained at > 100 torr (> 13.3 kPa) at maximally reduced ventilator support. Mean arterial pressure and cardiac output did not change significantly as a result of arteriovenous shunting. CONCLUSIONS: Extracorporeal CO2 removal using a low-resistance gas exchanger in a simple arteriovenous shunt allows significant reduction in minute ventilation and peak inspiratory pressure without hypercapnia or the complex circuitry and monitoring required for conventional extracorporeal membrane oxygenation. Arteriovenous CO2 removal can be applied as an easy and cost-effective treatment to minimize ventilator-induced barotrauma and volutrauma during severe respiratory failure.

Acute Disease↗
PubMed1997

The atrial natriuretic peptide receptor antagonist HS 142-1 improves cardiovascular filling and mean arterial pressure in a hyperdynamic ovine model of sepsis.

OBJECTIVE: To test whether systemic vascular resistance and mean arterial pressure increase during the administration of the atrial natriuretic peptide antagonist, HS 142-1, in ovine experimental hyperdynamic sepsis. DESIGN: Prospective trial. SETTING: Research laboratory at a large university medical center. SUBJECTS: Chronically instrumented Merino breed ewes (n = 14). INTERVENTIONS: Continuous infusion of Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) for the experimental period of 48 hrs. One group (HS 142-1) received a continuous infusion of HS 142-1 (3 mg/kg/hr) from 40 to 48 hrs; the remaining sheep ("control") were given the vehicle sodium chloride 0.9%. MEASUREMENTS AND MAIN RESULTS: All sheep developed a hyperdynamic cardiovascular response by 40 hrs that was characterized by low values of systemic vascular resistance index (p < .05) and mean arterial pressure (p < .05), and an increased cardiac index (p < .05). HS 142-1 increased cardiac filling pressures (p < .05) without apparent effects on fluid balance, and was associated with a significantly (p < .05) higher mean arterial pressure than was found in the control group at 44 and 48 hrs. HS 142-1 did not change systemic vascular resistance index. At 44 and 48 hrs, cardiac index values were found to have significantly (p < .05) increased in the animals receiving HS 142-1, when these data were compared with cardiac output values at 40 hrs. CONCLUSION: HS 142-1 increases cardiac filling pressures and maintains mean arterial pressure in hyperdynamic sepsis without reversal of sepsis-induced vasodilation.

Animals↗
PubMed1997

Oxalated pyridoxalated hemoglobin polyoxyethylene conjugate normalizes the hyperdynamic circulation in septic sheep.

OBJECTIVE: Excessive production of nitric oxide significantly contributes to the hyperdynamic state associated with sepsis. The ability of hemoglobin to scavenge nitric oxide may therefore be beneficial in the treatment of sepsis. In this study, we determined the effects of different doses of the modified human pyridoxalated hemoglobin polyoxyethylene conjugate in an ovine model of hyperdynamic sepsis. DESIGN: Prospective, experimental study. SETTING: Large animal research laboratory at a university medical center. INTERVENTIONS: Sheep (n = 23) were surgically prepared for chronic study. After a 5-day recovery period, all animals received a continuous infusion of live Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) for the next 48 hrs. After 24 hrs of sepsis, the animals were divided into four groups: a) six sheep were used as controls and received a bolus of 200-mL vehicle; b) three sheep received a bolus of 50 mg/kg hemoglobin; c) six sheep received 100 mg/kg of hemoglobin; d) six sheep received 200 mg/kg of hemoglobin. MEASUREMENTS AND MAIN RESULTS: All animals that survived the first 24 hrs of sepsis (n = 21) developed a hyperdynamic circulation. All three doses of hemoglobin reversed this hyperdynamic state by increasing mean arterial pressure and systemic vascular resistance while decreasing cardiac index. Pulmonary arterial pressure increased after hemoglobin infusion. Increased pulmonary arterial pressure did not affect arterial oxygen saturation nor result in the development of pulmonary edema. Infusion of hemoglobin also caused a 30-fold increase in endothelin-1 plasma concentrations and significantly decreased nitrate and nitrite plasma concentrations. CONCLUSIONS: The infusion of low doses of pyridoxalated hemoglobin polyoxyethylene conjugate in septic sheep reverses the hyperdynamic circulatory state. An increase in pulmonary arterial pressure was the only observed hemodynamic side effect; changes in the structure or function of other organ systems, or their biochemical correlates were not investigated in this study. In addition to a possible nitric oxide scavenging effect, pyridoxalated hemoglobin polyoxyethylene may affect the nitric oxide synthase and endothelin systems.

Animals↗
PubMed1997

Pyridoxalated hemoglobin polyoxyethylene conjugate does not restore hypoxic pulmonary vasoconstriction in ovine sepsis.

OBJECTIVES: Hypoxic pulmonary vasoconstriction, a protective mechanism, minimizes perfusion of underventilated lung areas to reduce ventilation-perfusion mismatching. We studied the effects of sepsis on hypoxic pulmonary vasoconstriction and attempted to determine whether hypoxic pulmonary vasoconstriction is influenced by pyridoxalated hemoglobin polyoxyethylene conjugate, a nitric oxide scavenger. DESIGN: Prospective, randomized, controlled experimental study with repeated measures. SETTING: Investigational intensive care unit at a university medical center. SUBJECTS: Nineteen female merino sheep, divided into three groups: group 1, controls (n = 5); group 2, sheep with sepsis (n = 6); and group 3, septic sheep treated with pyridoxalated hemoglobin polyoxyethylene conjugate (n = 8). INTERVENTIONS: All sheep were instrumented for chronic study. An ultrasonic flow probe was placed around the left pulmonary artery. After a 5-day recovery, a tracheostomy was performed and a double-lumen endotracheal tube was placed. Animals in groups 2 and 3 received a 48-hr infusion of live Pseudomonas aeruginosa (6 x 10(4) colony-forming units/kg/hr). After 24 hrs, sheep in group 3 received pyridoxalated hemoglobin polyoxyethylene conjugate (20 mg/kg/hr) for 16 hrs; sheep in groups 1 and 2 received only the vehicle. Hypoxic pulmonary vasoconstriction was repeatedly tested by unilateral hypoxia of the left lung with 100% nitrogen. Hypoxic pulmonary vasoconstriction was assessed as the change in left pulmonary blood flow. MEASUREMENTS AND MAIN RESULTS: In the animals in group 1, left pulmonary blood flow decreased by 62 +/- 8 (SEM)% during left lung hypoxia and remained stable during repeated hypoxic challenges throughout the study period. After 24 hrs of sepsis, left pulmonary blood flow decreased from 56 +/- 10% to 26 +/- 2% (group 2) and from 50 +/- 8% to 23 +/- 6% (group 3). In the sheep in group 2, there was no adaptation over time. Pulmonary shunt fraction increased. Pyridoxalated hemoglobin polyoxyethylene conjugate had no effect on hypoxic pulmonary vasoconstriction or pulmonary shunt. The animals receiving the bacterial infusion developed a hyperdynamic circulatory state with hypotension, decreased systemic vascular resistance, and increased cardiac output. Pyridoxalated hemoglobin polyoxyethylene conjugate increased mean arterial pressure and systemic vascular resistance but did not influence cardiac index. Pulmonary arterial pressure was increased during sepsis and increased even further after pyridoxalated hemoglobin polyoxyethylene conjugate administration. Oxygenation and oxygen delivery and uptake were not affected by pyridoxalated hemoglobin polyoxyethylene conjugate. CONCLUSIONS: Hypoxic pulmonary vasoconstriction is blunted during sepsis and there is no adaptation over time. It is not influenced by pyridoxalated hemoglobin polyoxyethylene conjugate. Pyridoxalated hemoglobin polyoxyethylene conjugate reversed hypotension and, with the exception of an increase in pulmonary arterial pressure, had no adverse effects on hemodynamics or oxygenation.

Animals↗
PubMed1997

Cerebral blood flow during experimental endotoxemia in volunteers.

OBJECTIVE: To measure cerebral blood flow, cerebral metabolic rate for oxygen, cerebral oxygen delivery, and cerebral vascular resistance during experimental endotoxemia in volunteers. DESIGN: Experimental, prospective study. SETTING: University general clinical research center. SUBJECTS: Healthy volunteers (six male, four female, 30.1 +/- 1.9 yrs of age). INTERVENTIONS: Volunteers had radial, pulmonary arterial, and jugular venous bulb catheters inserted. All volunteers received a bolus of Escherichia coli endotoxin (4 ng/kg). Cerebral blood flow was measured, using the Kety-Schmidt technique. MEASUREMENTS AND MAIN RESULTS: Cerebral and systemic hemodynamics and oxygenation variables were measured at baseline and hourly for 5 hrs after endotoxin administration. A systemic hyperdynamic response characterized by an increase in body temperature (97.9 +/- 0.02, 100.2 +/- 0.02, and 99.7 +/- 0.02 degrees F [36.6 +/- 0.01, 37.9 +/- 0.1, and 37.6 +/- 0.1 degrees C] at baseline, 3, and 5 hrs, respectively), cardiac index (3.7 +/- 0.2, 6.2 +/- 0.2, and 5.7 +/- 0.2 L/min/m2 at baseline, 3, and 5 hrs), and heart rate (70 +/- 2.6, 96 +/- 2.6, and 93 +/- 2.9 beats/min at baseline, 3, and 5 hrs), and a decrease in mean arterial pressure (99.3 +/- 2.2, 84.4 +/- 2.8, and 84 +/- 3.4 mm Hg at baseline, 3, and 5 hrs) and systemic vascular resistance (1498 +/- 53, 788 +/- 37, 849 +/- 36 dyne.sec/cm5.m2 at baseline, 3, and 5 hrs) followed the endotoxin bolus. Cerebral blood flow (65.4 +/- 4.3, 57.7 +/- 3.1, and 58.6 +/- 3.0 mL/100 g/min at baseline, 3, and 5 hrs), cerebral oxygen delivery (11.6 +/- 0.7, 9.8 +/- 0.6, and 9.5 +/- 0.6 mL/100 g/min at baseline, 3, and 5 hrs), cerebral metabolic rate for oxygen (3.8 +/- 0.4, 3.3 +/- 0.3, and 3.0 +/- 0.3 mL/100 g/min at baseline, 3, and 5 hrs), and cerebral vascular resistance (1.4 +/- 0.2, 1.4 +/- 0.2, and 1.3 +/- 0.2 mm Hg/mL/100 g/min at baseline, 3, and 5 hrs) were unchanged throughout the 5-hr study period. Signs of cerebral dysfunction were not apparent, although the volunteers appeared drowsy during the latter part of the study. CONCLUSION: A dose of endotoxin sufficient to induce systemic vasodilation in healthy subjects does not influence cerebral blood flow or the cerebral metabolic rate for oxygen.

Adult↗
PubMed1997

Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies.

Septic shock is a physiological derangement of the cardiovascular system characterized by pathological vasodilation. Recent studies have established a role for nitric oxide, previously known as endothelium-derived relaxing factor, in the vascular dysfunction of sepsis. This finding suggests that inhibition of nitric oxide synthase (NOS), the enzyme responsible for nitric oxide production, could be a target for therapeutic intervention. Animal studies have provided conflicting results, demonstrating both beneficial and detrimental effects. We provide here an overview of the preclinical studies of NOS inhibitors and an update of the clinical studies. The low toxicity and marked antihypotensive activity of NOS inhibitors in humans highlight some of the drawbacks of certain animal models and provide important insights into the experimental study of septic shock.

Animals↗
PubMed1997

Inhalation injury increases the anastomotic bronchial blood flow in the pouch model of the left ovine lung.

Pulmonary parenchymal damage often occurs after airway injury. Bronchial venous drainage empties into the pulmonary microvasculature. We developed an in vivo model to study the bronchopulmonary portal system after smoke inhalation injury. Eight ewes were instrumented with hydraulic occluders on the left pulmonary artery (LPA), the left pulmonary vein, and the bronchoesophageal artery (BEA); a catheter in the LPA; and Swan-Ganz and femoral artery catheters. The vasculature between the occluders was defined as pouch. At stable mean arterial and right pulmonary arterial pressures, LPA occlusion reduced the left pulmonary artery pressure (LPAP) from 17 +/- 1 mmHg to 8 +/- 1 mmHg (p < .05). After left pulmonary vein occlusion, LPAP rose to 28 +/- 4 mmHg (p < .05 vs. baseline), indicating that systemic blood had entered the pouch. Opening the pouch to atmospheric pressure revealed an anastomotic bronchial blood flow (anastomotic Qbr) of .76 +/- .11% of cardiac output (CO). BEA occlusion reduced the anastomotic Qbr to .32 +/- .06% of CO (p < .05). Smoke inhalation injury resulted in a further increase in the maximal LPAP to 38 +/- 5 mmHg (p < .05 vs. right pulmonary artery pressure). The anastomotic Qbr rose to 1.29 +/- .13% of CO (p < .05) and was reduced to .40 +/- .09% of CO (p < .05) by BEA occlusion. Inhalation injury increased the anastomotic Qbr mainly due to BEA vasodilatation. Because the BEA supplies the injured airway, it may deliver deleterious material to the lung parenchyma.

Anastomosis, Surgical↗
PubMed1997

Effects of alpha-trinositol on systemic inflammation and renal function in ovine bacterial sepsis.

Neuronally secreted peptides are important mediators of hemodynamic changes in the systemic inflammatory response. The inositol derivative D-myo-inositol[1,2,6]triphosphate (alpha-trinositol) has been demonstrated to be a specific nonpeptide antagonist of vasoconstriction induced by neuropeptide Y. We induced sepsis by a 48 h continuous infusion of Pseudomonas aeruginosa (10(6) colony-forming unit/min intravenously [i.v.]) in 12 chronically instrumented, conscious sheep. After 24 h, the animals were randomized to receive either alpha-trinositol (i.v. bolus of 2 mg/kg, followed by a continuous infusion of 3.5 mg/kg/h) or the saline carrier. alpha-Trinositol increased the heart rate (108 +/- 4 to 152 +/- 9 beats per minute) and reduced the stroke volume index (65 +/- 5 to 49 +/- 2 mL/beat/m2) but did not change cardiac index. Left ventricular stroke work decreased significantly (80 +/- 9 to 58 +/- 7 g.m/m2). All blood flows except the infrarenal aortic flow were increased after 24 h, but treatment decreased only the flow to the hind limb region. Urine output and fractional sodium excretion significantly increased without osmotic diuretic effects after alpha-trinositol. In treated animals, we found significantly lower leukocyte counts in all organ tissues. We conclude that alpha-trinositol modulates the cardiac performance and the local inflammatory response in tissues, and improves the fluid balance in septic sheep.

Animals↗
PubMed1997

Glucose kinetics in interstitial fluid can be predicted by compartmental modeling.

The purposes of this study were to define in sheep a compartmental model for glucose kinetics in the basal condition and to test the hypothesis that interstitial fluid obtained by sampling thoracic duct lymph (TDL) represents one or more peripheral compartments of the glucose model. A bolus of [6,6-(2)H]glucose was injected in nine animals, followed by frequent sampling of blood and TDL. Linear kinetic modeling has been applied to plasma data, indicating that a three-compartment model adequately describes glucose kinetics. Both catenary and mammillary models were identified, and their predictions for the tracer behavior in nonaccessible pools were evaluated. In all experiments, regardless of the model structure, predictions in the compartment most rapidly exchanging with blood (pool 2) well matched the measured tracer-to-tracee ratio in TDL. Furthermore, modeling analysis showed that 90-95% of the tracer in TDL comes from this pool. This supported the physiological identification of a peripheral pool of glucose kinetics as extracellular fluid represented by TDL measurements.

Animals↗