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Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

Objective: To elucidate the effects of low-dose arginine vasopressin on cardiopulmonary functions and nitrosative stress using an established model of acute lung injury., Design: Prospective, randomized, controlled laboratory experiment., Setting: Investigational intensive care unit., Subjects: Eighteen chronically instrumented sheep., Interventions: Sheep were randomly assigned to a sham group without injury or treatment, an injury group without treatment (40% total body surface area third-degree burn and 48 breaths of cold cotton smoke), or an injured group treated with arginine vasopressin (0.02 IU·min⁻¹) from 1 hr after injury until the end of the 24-hr study period (each n = 6). All sheep were mechanically ventilated and fluid resuscitated using an established protocol., Measurements and Main Results: There were no differences among groups at baseline. The injury was characterized by a severe deterioration of cardiopulmonary function (left ventricular stroke work indexes and Pao2/Fio2 ratio; p < .01 each vs. sham). Compared with controls, arginine vasopressin infusion improved myocardial function, as suggested by higher stroke volume indexes and left ventricular stroke work indexes (18-24 hrs and 6-24 hrs, respectively; p < .05 each). In addition to an improved gas exchange (higher Pao2/Fio2 ratios from 6 to 24 hrs, p < .01 each), pulmonary edema (bloodless wet-to-dry-weight ratio; p = .018), bronchial obstruction (p = .01), and pulmonary shunt fraction (12-24 hrs; p ≤ .001 each) were attenuated in arginine vasopressin-treated animals compared with controls. These changes occurred along with reduced nitrosative stress, as indicated by lower plasma levels of nitrate/nitrite (12-24 hrs, p < .01 each), as well as lower myocardial and pulmonary tissue concentrations of 3-nitrotyrosine (p = .041 and p = .042 vs. controls, respectively). At 24 hrs, pulmonary 3-nitrotyrosine concentrations were negatively correlated with Pao2/Fio2 ratio (r = -.882; p < .001) and myocardial 3-nitrotyrosine content with stroke volume indexes (r = -.701; p = .004)., Conclusions: Low-dose arginine vasopressin reduced nitrosative stress and improved cardiopulmonary functions in sheep with acute lung injury secondary to combined burn and smoke inhalation injury.

Clinical studies evaluating the use of phenylephrine in septic shock are lacking. The present study was designed as a prospective, crossover pilot study to compare the effects of norepinephrine (NE) and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock. In 15 septic shock patients, NE (0.82 +/- 0.689 microg x kg(-1) x min(-1)) was replaced with phenylephrine (4.39 +/- 5.23 microg x kg(-1) x min(-1)) titrated to maintain MAP between 65 and 75 mmHg. After 8 h of phenylephrine infusion treatment was switched back to NE. Data from right heart catheterization, acid-base balance, thermo-dye dilution catheter, gastric tonometry, and renal function were obtained before, during, and after replacing NE with phenylephrine. Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE with phenylephrine except for a significant decrease in heart rate (phenylephrine, 89 +/- 18 vs. NE, 93 +/- 18 bpm; P < 0.05). However, plasma disappearance rate (phenylephrine, 13.5 +/- 7.1 vs. NE, 16.4 +/- 8.7% x min(-1)) and clearance of indocyanine green (phenylephrine, 330 +/- 197 vs. NE, 380 +/- 227 mL x min(-1) x m(-2)), as well as creatinine clearance (phenylephrine, 81.3 +/- 78.4 vs. NE, 94.3 +/- 93.5 mL x min(-1)) were significantly decreased by phenylephrine infusion (each P < 0.05). In addition, phenylephrine increased arterial lactate concentrations as compared with NE infusion (1.7 +/- 1.0 vs. 1.4 +/- 1.1 mM; P < 0.05). After switching back to NE, all variables returned to values obtained before phenylephrine infusion except creatinine clearance and gastric tonometry values. Our results suggest that for the same MAP, phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction as compared with NE.

Although arginine vasopressin and terlipressin have been identified as useful nonadrenergic agents to increase systemic blood pressure in catchecholamine-resistant septic shock, the impairments in cardiac index (CI) and global oxygen transport may limit their clinical applicability. The present study was designed as a prospective controlled laboratory experiment to investigate the effects of dobutamine as an adjunct to terlipressin infusion on cardiopulmonary hemodynamics and global oxygen transport in healthy and endotoxemic sheep. Nine adult ewes were instrumented for chronic study using an established protocol. After a baseline measurement in the healthy state had been performed, 1 mg terlipressin was given as bolus infusion. Thirty minutes later, dobutamine was continuously infused at incremental doses (2 and 5 microg x kg(1) x min(1), each for 1 h). After 24 h of recovery, a hypotensive-hyperdynamic circulation was induced and maintained by a continuous infusion of Salmonella typhosa endotoxin (10 ng x kg(1) x min(1)). After 16 h of endotoxemia, the six surviving sheep received terlipressin and dobutamine according to the same protocol that was used in healthy sheep. Compared with baseline, terlipressin infusion was associated with a significant increase in MAP that, however, occurred at the expense of a compromised CI, oxygen delivery index (DO(2)I), and mixed venous oxygen saturation (SvO(2), each P < 0.05). Dobutamine infusion was followed by a dose-dependent increase in CI, DO(2)I, and SvO(2) in both health and endotoxemia (each P < 0.05). Although the higher dosage of dobutamine exerted favorable effects, such as a decrease in pulmonary vascular resistance index (P < 0.05), the associated onset of tachycardia (P < 0.05) and arterial hypotension (P < 0.05) may limit its therapeutic use under septic conditions. This study provides evidence that dobutamine in a dosage of 2 microg x kg(1) x min(1) is useful to reverse the terlipressin-linked depressions in CI, DO(2)I and SvO(2) in ovine endotoxemia without obvious side effects.

Objective: To investigate ceftazidime in acute lung injury (ALI) and sepsis., Design and Setting: Prospective, randomized, controlled animal study in an investigational ICU at a university hospital., Interventions: Eighteen female Merino sheep were prepared for chronic study and subjected to smoke inhalation and septic challenge according to an established protocol., Measurements and Results: Whereas global hemodynamics and oxygenation remained stable in sham animals (no injury, no treatment), the injury contributed to a hypotensive-hyperdynamic circulation in the control group (smoke inhalation and sepsis, no treatment), as indicated by a significant increase in cardiac index) and heart rate and a drop in mean arterial pressure. Treatment with ceftazidime (smoke inhalation and sepsis, treatment group) stabilized cardiac index and heart rate and attenuated the decrease in mean arterial pressure. The deterioration in PaO2/FiO2 ratio and pulmonary shunt fraction (Qs/Qt) was significantly delayed and blunted by ceftazidime. At 24 h after injury a significant increase in airway obstruction scores of bronchi and bronchioles in both injured groups was observed. Ceftazidime significantly reduced airway obstruction vs. control animals. Whereas plasma nitrate/nitrite levels increased similarly in the two injured groups, lung 3-nitrotyrosine content remained at the baseline level in the ceftazidime group., Conclusions: In ovine lung injury ceftazidime improves global hemodynamics and oxygenation not only by bacterial clearance but also via reduction in toxic nitrogen species such as 3-nitrotyrosine. Therefore ceftazidime appears as a clinically relevant adjunct in the common setting of sepsis-associated lung injury.

Previously, our group developed an ovine model of hyperdynamic sepsis associated with acute lung injury. In this study, we sought to modify this sepsis model by the administration of gentamicin to more closely simulate the symptoms observed in human sepsis in the intensive care unit. In a prospective, controlled, randomized laboratory experiment, 18 female sheep were surgically prepared for chronic study. After a tracheotomy had been performed, the sheep were randomized into sham, control, and gentamicin groups (n = 6 each). Sham animals were surgically prepared for the study but were neither injured nor treated. Control and gentamicin animals received 48 breaths of cotton smoke (<40 degrees C) followed by the instillation (via a bronchoscope) of live Pseudomonas aeruginosa (2-5 x 10(11) colony-forming units) bacteria into the lung. All sheep were mechanically ventilated with 100% O2 for the duration of the 24-h experimental period. Gentamicin (2 mg/kg) was administered at 6, 12, and 18 h after injury. The animals were resuscitated with lactated Ringer's solution to maintain filling pressures and hematocrit on a constant level. Cardiopulmonary variables were stable in sham animals, but in the control group, cardiac index increased significantly after 24 h versus baseline (BL, 5.1 +/- 0.4 L.min(-1).m(-2) vs. 24 h, 7.3 +/- 0.7 L.min(-1).m(-2); P < 0.05); this was associated with a significant drop in mean arterial pressure (BL, 95 +/- 3 mmHg vs. 24 h, 65 +/- 4 mmHg, P < 0.05) and systemic vascular resistance index (BL, 1410 +/- 118 dynes s.cm.m vs. 24 h, 598 +/- 101 dynes s.cm.m, P < 0.05). Treatment with gentamicin stabilized cardiac index (BL, 5.0 +/- 0.4 L.min(-1).m(-2) vs. 24 h, 4.7 +/- 0.4 L.min(-1).m(-2)) and attenuated the decrease in mean arterial pressure (BL, 99 +/- 3 mmHg vs. 24 h, 84 +/- 4 mmHg) and systemic vascular resistance index (BL, 1573 +/- 173 dynes s.cm.m vs. 24 h, 1263 +/- 187 dynes s.cm.m). In addition, the fluid requirement in the gentamicin group was significantly lower than in the control group. Pulmonary function remained stable in sham animals, but the PaO2/FiO2 ratio and shunt fraction deteriorated similarly in the control and the gentamicin groups. Because gentamicin improved hemodynamic variables and reduced the fluid requirement in this ovine model, we believe that this modified sepsis model might provide a clinically relevant and useful new approach for future studies focusing on hemodynamic variables and outcome.

This study was designed as a prospective laboratory experiment to evaluate the effects of the ATP-sensitive potassium-channel inhibitor glibenclamide on hemodynamics and end-organ function in an ovine model of hemorrhagic shock. Twenty-four adult sheep were anesthetized and surgically prepared to measure hemodynamics of the systemic and pulmonary circulation. The anterior surface of the abdominal aorta was exposed at a location 6 cm superior to the iliac bifurcation. After a 60-min period of stabilization, this location was punctured with a 14-G needle. To induce a hemorrhagic hypotension (mean arterial pressure [MAP] less than 50 mmHg) via bleeding, the needle was left in place for 15 s to insure good blood flow. Thereafter, it was removed, and the abdomen closed. The animals were then randomized to receive either glibenclamide (4 mg/kg over 15 min) or an equal volume of the vehicle, started 1 h postinjury. Hemodynamic variables were measured every 30 min. Compared with the control group, MAP and systemic vascular resistance index (SVRI) were significantly higher in the intervention group throughout the entire 6-h study period. Ileal pH and urine output were higher in treated than in control animals (4 h, ileal pH 7.29 +/- 0.31 vs. 7.17 +/- 0.6; 6 h, urine output 36 +/- 9 vs. 7.5 +/- 2 mL; P value less than 0.05 each). Because glibenclamide improved both hemodynamics and organ function, it may be a beneficial component in the acute treatment of hemorrhagic shock.

We investigated changes in cardiac output and organ blood flow induced by medetomidine in sheep and determined changes in cardiac output and organ blood flow after reversal of medetomidine-induced sedation by atipamezole. Eight sheep were chronically instrumented. Medetomidine was infused IV to target plasma levels of 0, 0.8, 1.6, 3.2, 6.4, and 12.8 ng/mL for 25 min each, followed by a 5-min infusion of atipamezole. Hemodynamic values and organ blood flow (using colored microspheres) were measured just before medetomidine infusion (baseline), at the end of each medetomidine infusion step, and 30 min after the administration of atipamezole. Medetomidine (12. 8 ng/mL) decreased cardiac output from 6.3 +/- 1.0 to 3.2 +/- 0.7 L/min (P < 0.0001) and increased systemic vascular resistance from 1310 +/- 207 to 3467 +/- 1299 dynes. s(-1). cm(-5) (P < 0.0001). Blood flow decreased in the cerebral cortex from 1.29 +/- 0.40 to 0. 66 +/- 0.12 mL. g(-1). min(-1) (P < 0.0001), left ventricle from 2. 11 +/- 0.61 to 1.40 +/- 0.40 mL. g(-1). min(-1) (P < 0.0001), kidney from 8.28 +/- 3.17 to 6.07 +/- 2.65 mL. g(-1). min(-1) (P < 0.0001), skin from 0.09 +/- 0.04 to 0.05 +/- 0.02 mL. g(-1). min(-1) (P < 0. 0001), intestine from 0.56 +/- 0.13 to 0.27 +/- 0.07 mL. g(-1). min(-1) (P < 0.0001), and skeletal muscle from 0.28 +/- 0.15 to 0.04 +/- 0.01 mL. g(-1). min(-1) (P < 0.0001). Blood flow in the liver (hepatic artery) increased from 0.05 +/- 0.03 to 0.24 +/- 0.16 mL. g(-1). min(-1) (P < 0.0001). After atipamezole infusion, cardiac output and systemic vascular resistance returned to baseline, but the cerebral cortex, left ventricle, and renal blood flows remained below baseline at 0.89 +/- 0.22, 1.37 +/- 0.50, and 6.25 +/- 2.76 mL. g(-1). min(-1), respectively; skeletal muscle blood flow increased above baseline to 0.44 +/- 0.27 mL. g(-1). min(-1), spleen blood flow decreased below baseline to 1.65 +/- 0.61 mL. g(-1). min(-1) (P < 0.0001), and liver, intestine, and lung blood flows returned to baseline values. In conclusion, medetomidine decreased and redistributed organ blood flow in sheep. Atipamezole reversed the medetomidine-induced hemodynamic changes, but redistributed blood flow from the brain, heart, and kidney to the skeletal muscle.

This prospective, non-randomized, controlled experimental study looks at the effects of N(omega)-monomethyl-L-arginine (L-NMMA) on haemodynamics, oxygen transport and regional blood flow in healthy and septic sheep, and compares these effects with those of noradrenaline (NA; norepinephrine). All sheep were chronically instrumented. Six sheep received L-NMMA (7 mg.kg(-1).h(-1)), six sheep received NA, and seven sheep received the carrier alone (0.9% NaCl). The NA dosage was continuously and individually adjusted to achieve the same increase in blood pressure as observed in matched sheep of the L-NMMA group (non-septic phase). Treatment was discontinued after 3 h. Sepsis was initiated and maintained by a continuous infusion of live Pseudomonas aeruginosa. After 24 h of sepsis, the sheep were again challenged over a treatment period of 3 h with their previously assigned drug (septic phase). During the non-septic phase of the experiment, NA and L-NMMA both caused an increase in mean arterial pressure (MAP) through vasoconstriction. Ater 24 h of sepsis, all sheep developed a hyperdynamic circulatory state. While L-NMMA caused an increase in MAP through intense vasoconstriction, NA caused MAP to increase through a further elevation of the cardiac index. The NA dosage needed was significantly higher in the septic phase compared with the non-septic phase, reflecting a reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unchanged during either treatment in both the non-septic and the septic phases. Nevertheless, urine output increased during NA treatment in both the non-septic and the septic phases, while L-NMMA caused urine output to increase only under septic conditions.

Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), a nitric oxide scavenger, causes systemic and pulmonary vasoconstriction in normal and septic sheep. We studied the effect of L-arginine and the endothelin-1 (ET-1) antagonist bosentan on the PHP response to determine whether the PHP-induced vasoconstriction resulted predominantly from the action of ET-1 or solely from removal of NO. After 24 h of carrier solution (nonseptic sheep), sheep received PHP (20 mg/kg/h; n = 5), PHP plus L-arginine (at 28 h, 100 mg/kg bolus and 500 mg/kg for 1 h) plus bosentan (at 32 h, 10 mg/kg; n = 6), and only L-arginine and bosentan (n = 5). These protocols were repeated after 24 h of Pseudomonas aeruginosa (S, 6x10(6) colony-forming units/kg/h). PHP induced vasoconstriction in septic and nonseptic sheep for the duration of its infusion. In nonseptic sheep, neither L-arginine nor bosentan significantly lowered systemic (SVRI) and pulmonary (PVRI) vascular resistance and did not antagonize the PHP-induced vasoconstriction. During sepsis, SVRI fell and cardiac index (CI) rose. L-arginine and bosentan further decreased SVRI (L-arginine: 34+/-2%*, p<.05; bosentan: 35+/-5%*, p<.05) and PVRI (L-arginine: 28+/-2%*, p<.05; bosentan: 33+/-7%*, p<.05) and increased CI (L-arginine: 29+/-4%*, p<.05; bosentan: 11+/-5%, NS). Both agents antagonized the PHP-induced vasoconstriction lowering SVRI (L-arginine: 29+/-3%*, p<.05; bosentan: 26+/-5%*, p<.05) and PVRI (L-arginine: 27+/-4%*, p<.05; bosentan: 32+/-4%*, p<.05) to levels before PHP administration. Plasma ET-1 levels increased during sepsis (from 9.8+/-.2 to 15.6+/-.7* pg/mL, p<.05) and fell during PHP infusion (to 9.7+/-1.6* pg/mL, p<.05). In nonseptic sheep, ET-1 levels decreased during PHP (from 8.5+/-.6 pg/mL to 5.9+/-.6*, p<.05). Bosentan increased ET-1 levels 2.7 times higher in septic than in nonseptic sheep. We conclude that during sepsis, the NO scavenger PHP unmasks an underlying ET-1 mediated vasoconstriction, and its effect is antagonized by L-arginine and bosentan.

The effects of a monoclonal antibody against L-selectin [leukocyte adhesion molecule (LAM)1-3] on microvascular fluid flux were determined in conscious sheep subjected to a combined injury of 40% third-degree burn and smoke inhalation. This combined injury induced a rapid increase in systemic prefemoral lymph flow (sQlymph) from the burned area and a delayed-onset increase in lung lymph flow. The initial increase in sQlymph was associated with an elevation of the lymph-to-plasma oncotic pressure ratio; consequently, it leads to a predominant increase in the systemic soft tissue permeability index (sPI). In an untreated control group, the increased sPI was sustained beyond 24 h after injury. Pretreatment with LAM1-3 resulted in earlier recovery from the increased sPI, although the initial responses in sQlymph and sPI were identical to those in the nontreatment group. The delayed-onset lung permeability changes were significantly attenuated by pretreatment with LAM1-3. These findings indicate that both leukocyte-dependent and -independent mechanisms are involved in the pathogenesis that occurs after combined injury with burn and smoke inhalation.

Objectives: To investigate the effects of S-ethylisothiourea (S-EITU) on hemodynamics, oxygen transport, and regional blood flow in healthy and septic sheep., Design: Prospective, randomized, controlled experimental study with repeated measures., Setting: Investigational intensive care unit at a university medical center., Subjects: Eleven healthy, female adult sheep of the Merino breed, divided into a control group (n = 5) and into a group treated with S-EITU (n = 6)., Interventions: All sheep were chronically instrumented. After a 5-day recovery period, they were randomly assigned to either control or S-EITU groups. While control sheep received only saline, S-EITU was administered in increasing doses of 1, 3, and 9 mg/kg/hr over 1 hr each (nonseptic phase). After 2 days of recovery, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 106 colony-forming units/min) was started in all sheep and maintained for the remainder of the experiment. After 24 hrs of sepsis, the sheep again received their assigned treatment (septic phase). In both the nonseptic and septic phases, the sheep received colored microspheres through a left atrial catheter to allow analysis of regional blood flows. All animals were autopsied at the end of the experiments, and organ probes were removed for blood flow analyses., Measurements and Main Results: The administration of S-EITU caused a dose-dependent vasoconstriction in the nonseptic phase. After 24 hrs of Pseudomonas infusion, all sheep developed a hyperdynamic circulatory state, with increased cardiac indices and reduced arterial pressures and systemic vascular resistances. Oxygen extraction decreased significantly, preventing an increase in oxygen consumption, despite an increased oxygen delivery. The hyperdynamic circulation was dose dependently reversed by S-EITU, causing an increase in arterial pressure by peripheral vasoconstriction. Sheep in the control group showed a continuation of the hyperdynamic circulation. The effects of S-EITU on hemodynamics and regional blood flows were comparable under septic and nonseptic conditions., Conclusions: With the inducible form of nitric oxide synthase expressed under septic, but not under nonseptic conditions, S-EITU was expected to have vasoconstrictive properties only in the septic phase. It produced a comparable vasoconstriction during the nonseptic phase of the experiment. Thus, either S-EITU does not selectively block the inducible nitric oxide synthase in sheep, or other vasodilators besides nitric oxide play an important role in septic vasodilation.

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.

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.

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.

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.

Objectives: Inhaled nitric oxide has been shown to be a selective pulmonary vasodilator, leading to reduced pulmonary arterial pressure and improved ventilation/perfusion ratio in the acute respiratory distress syndrome. This local pulmonary vasodilation theoretically can be achieved by the airway application of a short-acting vasodilator, such as prostacyclin. We hypothesized that nebulized prostacyclin has the same properties for selective pulmonary vasodilation as inhaled nitric oxide., Design: Prospective, experimental study in sheep., Setting: Investigational intensive care unit in a university hospital., Subjects: Six adult ewes of the Merino breed., Interventions: Sheep (n = 6) were surgically prepared for chronic study. After 5 days of recovery, the sheep had tracheostomies performed under anesthesia. Intubation with a modified Robert-Shaw tube allowed side-separated ventilation. The entire left lung was ventilated with pure nitrogen, whereas the right lung was ventilated with pure oxygen. Nitric oxide and prostacyclin were added in different concentrations to the nitrogen, with which the left lung was ventilated., Measurements and Main Results: The blood flows to the left and right lungs were measured with ultrasonic flow probes on the common and left pulmonary artery. Measurements were taken after each compound had been administered for 10 mins at a predefined dose. Both inhaled nitric oxide and nebulized prostacyclin caused effective, selective, dose-dependent pulmonary vasodilation. Inhaled nitric oxide was able to abolish hypoxic pulmonary vasoconstriction when insufflated into the animals at a concentration of 50 ppm of nitrogen, but 100 ppm of nitric oxide had no further effect. Prostacyclin, at a dosage of 10 micrograms/min, showed maximum pulmonary vasodilation, which could not be further increased by doubling the dosage. However, prostacyclin produced less dilation than high doses of nitric oxide, and its maximum pulmonary vasodilation was comparable with that effect obtained under ventilation with 20 ppm of nitric oxide., Conclusions: Both drugs selectively dilated the pulmonary vasculature in ventilated alveoli. Prostacyclin nebulization is an excellent tool to reduce pulmonary hypertension and to improve the ventilation/perfusion ratio. Prostacyclin nebulization can be used without the highly sophisticated technical equipment that is needed for controlled nitric oxide inhalation, and may therefore become a new, noninvasive therapeutic approach for treatment of adult respiratory distress syndrome in hospitals that cannot provide nitric oxide inhalation.

Objectives: To investigate the effects of Nomega-mono-methyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on hemodynamics, oxygen transport, and regional blood flow in an ovine model of hyperdynamic sepsis and to compare these effects with the responses to norepinephrine., Design: Prospective, nonrandomized, controlled experimental study with repeated measures., Setting: Investigational intensive care unit at a university medical center., Subjects: Twenty-five female, healthy, adult sheep of the Merino breed, divided into three groups: nine control sheep; eight sheep treated with L-NMMA; and eight sheep treated with norepinephrine., Interventions: All sheep were chronically instrumented. After a 5-day recovery period, a continuous infusion of live Pseudomonas aeruginosa (2.5 x 10(6) colony-forming units/min) was started and maintained for the remainder of the experiment. After 24 hrs of sepsis, eight sheep received L-NMMA (7 mg/kg/hr), eight sheep received norepinephrine, and nine sheep received the vehicle alone (0.9% saline). The norepinephrine dosage was continuously and individually adjusted to achieve the same increase in blood pressure as was observed in a matched sheep of the L-NMMA group., Measurements and Main Results: After 24 hrs of sepsis, all sheep developed a hyperdynamic circulatory state with increased cardiac indices and reduced arterial pressures, and systemic vascular resistances. L-NMMA reversed the hyperdynamic circulation, causing an increase in arterial pressure by peripheral vasoconstriction. Norepinephrine led to an increase in blood pressure by augmenting cardiac indices, leaving the systemic vascular resistance unaffected. The norepinephrine dose needed to keep the blood pressure high had to be continuously increased, reflecting the reduced vascular responsiveness to catecholamines during sepsis. Renal blood flow remained unaffected by all treatment forms. Norepinephrine and L-NMMA led to a dramatic increase in urine production. Blocking the nitric oxide synthase with L-NMMA did not interfere with the host's pulmonary ability to clear bacteria, nor did treatment with norepinephrine., Conclusions: Blocking nitric oxide synthase had a marked vasoconstrictive effect. Both norepinephrine and L-NMMA increased arterial pressure without reducing renal blood flow, leading to an improved renal function.

Sepsis is characterized by myocardial depression and systemic vasodilation, both of which are most likely mediated by nitric oxide. Propofol inhibits nitric oxide synthase and may therefore be beneficial in sepsis. On the other hand, renal blood flow, known to be only minimally affected by propofol in healthy subjects, may be drastically reduced in septic individuals, because the renal microvasculature is known to be very sensitive to nitric oxide. In this study, the effects of propofol in healthy and in septic sheep, and in combination with fentanyl, were analyzed and compared with nonanesthetized septic sheep. In healthy sheep, propofol caused only minor hemodynamic changes. In septic sheep, however, hemodynamics deteriorated. Renal blood flow was reduced to 60% +/- 10% of the preseptic baseline and to 39% +/- 4% of the septic value. This reduction was selective, since the cardiac output decreased significantly less. These adverse effects of propofol on hemodynamics and renal blood flow were reduced when propofol was combined with fentanyl.

Objective: To test whether renal excretory function decreases after nitric oxide synthase inhibition during experimental hyperdynamic sepsis., Design: Prospective, randomized, controlled animal trial., Setting: Research laboratory at a large university medical center., Subjects: Chronically instrumented Merino breed ewes (n = 18)., Interventions: Continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) for the experimental period of 32 hrs. One group received a bolus of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (25 mg/kg), after 24 hrs, and the remaining sheep were given the carrier, sodium chloride 0.9%., Measurements and Main Results: The sheep developed a hyperdynamic cardiovascular response characterized by a decrease in systemic vascular resistance index (p < .05), and an increased cardiac index (p < .05) by 24 hrs. The sheep retained fluid, with creatinine clearance decreasing in the presence of chronically increased atrial natriuretic peptide. After the administration of N omega-nitro-L-arginine methyl ester, systemic vascular resistance index and cardiac index returned to baseline values, fluid balance normalized, and glomerular filtration rate increased (p < .05), while the control animals continued to retain fluid and their creatinine clearance continued to decrease. The concentrations of atrial natriuretic peptide did not differ significantly between groups after N omega-nitro-L-arginine methyl ester administration., Conclusions: In this ovine model of experimental hyperdynamic sepsis, renal excretory function decreases in the presence of chronically increased concentrations of atrial natriuretic peptide. Administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester, reverses the vasodilatory state, thereby improving fluid balance and glomerular filtration.

We studied the mechanisms responsible for the changes in lung lymph flow (QL) in chronic sepsis induced by the continuous infusion of endotoxin [lipopolysaccharide (LPS), 10 ng.kg-1.min-1]. Sheep (n = 11) were studied in the unanesthetized state 7 days after preparation, and cardiopulmonary variables were measured. In the control group (n = 5) given lactated Ringer solution, no significant changes were observed in any measured variables. In the LPS group (n = 6), QL increased from 11.7 +/- 3.8 to 54.0 +/- 15.0 (SE) ml/h 24 h after LPS infusion had begun. This elevation in QL was associated with little or no change (P > 0.05) in reflection coefficient (0.80 +/- 0.03 to 0.87 +/- 0.05) or pulmonary microvascular pressure (14.3 +/- 0.4 to 16.7 +/- 1.2 mmHg). The filtration coefficient, however, was significantly elevated (0.018 +/- 0.006 to 0.083 +/- 0.024 ml.min-1.mmHg-1). In association with changes in QL that occur as a result of LPS administration, there was a significant increase in cardiac index (6.1 +/- 0.5 to 10.2 +/- 0.3 l.min-1.m-2) and a reduction in mean arterial pressure (90.2 +/- 4.4 to 73.7 +/- 7.3 mmHg) and systemic vascular resistance index (1,229 +/- 134 to 583 +/- 62 dyn.s.cm-5.m2), findings similar to those noted in septic humans.

Objective: To evaluate the hypothesis that heparin administration increases cardiac output and improves oxygenation in experimental hyperdynamic sepsis in sheep., Design: Prospective trial., Setting: Laboratory at a large university-affiliated medical center., Subjects: A total of 14 sheep weighing 28 to 44 kg., Interventions: All 14 chronically instrumented sheep received a continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) over 24 hrs. Seven sheep received a fixed bolus of beef lung heparin (5000 units) every 4 hrs intravenously. The other seven sheep served as controls., Measurements and Main Results: The heparinized animals showed a triphasic cardiovascular response. Cardiac index increased (p < .05), and systemic vascular resistance index decreased (p < .05) at 2 hrs after the start of the endotoxin infusion (early phase, 0 to 2 hrs). Both variables returned to approximately baseline levels at 4 hrs (second period, 2 to 4 hrs). A hyperdynamic state (in terms of an increased cardiac index), a decreased systemic vascular resistance index, and a decreased mean arterial pressure (MAP) (p < .05 for all) was observed in the third phase (8 to 24 hrs). In the control group, cardiac index, systemic vascular resistance index, and MAP showed no changes in the first period, but a slight decrease in cardiac index and a slight increase in systemic vascular resistance index in the second period. The onset of the hyperdynamic state was less pronounced in the control group and cardiac index was lower (p < .05); likewise, systemic vascular resistance index was increased (p < .05) when compared with heparinized animals. Both groups developed pulmonary hypertension during the endotoxin infusion. The gas exchange in the heparin group was significantly impaired in the first and second periods, but returned to baseline levels in the hyperdynamic phase, whereas the oxygenation of the nonheparinized animals showed only minor changes in the first and second phases, but deteriorated significantly during the third phase of endotoxemia., Conclusions: In this experimental model of hyperdynamic sepsis, heparin significantly influenced the cardiopulmonary performance. Heparin preserved gas exchange and increased cardiac output but lowered systemic vascular resistance and MAP in the hyperdynamic state.

The hemodynamic and lung lymph changes following near-drowning (ND) were studied in sheep. Experimental ND was by transtracheal aspiration of 10 ml/kg body weight of either seawater (SW) or freshwater (FW). Extravascular lung water and lung lymph protein flux were significantly increased, but cardiac index was depressed in both groups following ND. Systemic and pulmonary vascular resistances were markedly elevated with FW compared to only a slight rise with SW. Lung lymph oncotic pressure decreased with SW ND from baseline of 9.7 +/- 0.4 to 6.8 +/- 0.63 mm Hg (P < 0.05). In contrast, FW ND increased lung lymph oncotic pressure from 12.8 +/- 0.9 to 16.6 +/- 1.3 mm Hg (P < 0.05). These data suggest that the changes in lung lymph and hemodynamic response to SW and FW ND differ in sheep. The changes are immediate and profound with SW, but slower in onset and less severe with FW. FW ND is associated with hemolysis, which is absent in SW ND.

Septic shock is characterized by an increase in cardiac output and a fall in systemic vascular resistance index and mean arterial pressure. Endotoxin alters the smooth muscle function of blood vessels, probably by means of an increased production of the potent vasodilator nitric oxide (NO). The present study was accomplished to determine how the inhibition of NO synthesis influences cardiovascular performance in an ovine model of hyperdynamic endotoxemia. Endotoxemia was induced in five range ewes (41 +/- 2 kg) by continuous infusion of Escherichia coli endotoxin (LPS, 10 ng.kg-1.min-1) over the entire study period. After 24 h of LPS infusion, cardiac output increased from 5.2 +/- 0.3 to 7.9 +/- 0.6 (SE) 1/min (P less than 0.05) and mean arterial pressure and systemic vascular resistance index fell from 92 +/- 5 to 79 +/- 6 mmHg (P = 0.08) and from 1,473 +/- 173 to 824 +/- 108 dyn.s.cm-5.m2 (P less than 0.05), respectively. The pulmonary shunt fraction increased from 0.23 +/- 0.03 to 0.32 +/- 0.03 (P less than 0.05). The intravenous administration of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (25 mg/kg) 24 h after the start of the LPS infusion changed these values to approximately baseline levels over the subsequent 4 h. Although N omega-nitro-L-arginine methyl ester increased pulmonary arterial pressure and pulmonary vascular resistance (P less than 0.05), right and left ventricular stroke volume index showed no significant changes. It is concluded that NO has a major function in cardiovascular performance in endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Background and Methods: There is a marked decrease of the right ventricular ejection fraction after the administration of a bolus of endotoxin to sheep. This hemodynamic response may be the result of thromboxane-mediated pulmonary hypertension. Right ventricular function was studied in an ovine model after the administration of endotoxin (1 microgram/kg Escherichia coli) with and without pretreatment with OKY-046, a selective thromboxane synthetase inhibitor., Results: OKY-046 attenuated the endotoxin-induced increase in pulmonary arterial pressure and prevented the early decreases in right ventricular ejection fraction and cardiac output. However, thromboxane synthetase inhibition failed to prevent endotoxin-induced hypoxemia. The marked increase in plasma thromboxane concentrations, which is usually seen after the administration of endotoxin, was prevented by pretreating the animals with OKY-046. On the other hand, increased plasma prostacyclin concentrations were observed in sheep treated with the thromboxane synthetase inhibitor., Conclusion: This series of experiments shows that the early endotoxin-induced decrease in right ventricular ejection fraction can be alleviated by the application of OKY-046.

The early pulmonary hypertension seen with endotoxin (lipopolysaccharide) has been reported as resulting from the release of thromboxane A2. We studied the cardiopulmonary response to endotoxin in sheep with and without treatment with a thromboxane synthetase inhibitor, OKY-046. The animals were implanted with instruments for crystallographic dimension analysis of the left ventricle and measurement of left ventricular, aortic, left atrial, and pulmonary arterial pressures and cardiac index. Thirteen sheep received 1.0 micrograms/kg of Escherichia coli endotoxin with (n = 6) and without (n = 7) OKY-046 (10 mg/kg bolus, then 10 micrograms/kg/min). OKY-046 prevented the increase in pulmonary arterial pressure and decrease in cardiac index usually seen during the early phase of endotoxemia. Between 8 and 12 hours after the administration of endotoxin, cardiac index increased from 6.4 +/- 0.8 to 8.4 +/- 0.8 L/min/m2. Concomitantly, the end-systolic pressure/diameter relationship (a sensitive myocardial contractility index) significantly decreased from 14.7 +/- 0.6 to 7.7 +/- 0.7 mm Hg/mm. Another index of the left ventricular contractility, the maximum rate of pressure rise was also reduced. OKY-046 prevented decreases in end-systolic pressure/diameter relationship and maximum rate of pressure rise.

Gabexate mesilate (GM), a proteolytic enzyme inhibitor, was given to 31 chronically instrumented sheep either as a pretreatment or treatment to determine its effects on the cardiopulmonary response to endotoxin (ET). Twelve sheep received GM prior to endotoxin (0.75 microgram/kg), 10 after ET and 9 received GM without ET. A typical biphasic response was noted; phase I showed increased lymph flow (QL), reduced lymph to plasma protein ratio (L/P) and increased pulmonary artery pressure (PAP). Phase II occurred two hours after ET; the lymph flow remained elevated and the L/P ratio rose slightly above control. Both phases demonstrated an elevation in total peripheral vascular resistance (TPR) and hematocrit but a reduction in cardiac output (CO). In phase II, QL was reduced 35% with pretreatment; the L/P ratio did not rise as much and the PAP was unchanged. There was also a 35% reduction in lymph flow; no change in the lymph to plasma protein ratio but there was an elevation in pulmonary microvascular pressure. Pretreatment with GM diminished the fall in CO and the rise in TPR seen with endotoxin. The values were unaffected by treatment alone.

During a 3-year period (1984 through 1987), 40 patients with smoke inhalation, cutaneous burns, or a combination of both injuries were studied. Injuries were assigned to the three categories on the basis of bronchoscopic findings and clinical history. Eleven patients had simultaneously sustained a common smoke-inhalation injury without burns while trapped in a burning ship; twelve patients had massive cutaneous burns over 50% of the total body surface area (TBSA); and seventeen patients had cutaneous burns over more than 30% of the TBSA and inhalation injury. Colloid oncotic pressure was maintained with salt-poor albumin infusion. Central venous pressure, arterial saturation, inspired oxygen, arterial pressure, and urine output were continuously monitored. Extravascular lung water (EVLW) and cardiac output were measured by the double indicator (thermal dye dilution) technique. EVLW remained normal throughout the study period in the group of patients with burns alone. In the first 24 hours after injury, EVLW increased in both groups with smoke injury and remained elevated for more than 48 hours after injury in patients with smoke injury only. The group with both smoke-inhalation and burn injuries showed an early increase in EVLW, which returned to normal by 28 hours after injury and which remained normal until 5 days after injury. The EVLW level then increased again until the end of the study period. In this study, lung edema formation is attributed to the toxic effect of smoke inhalation.

Burned sheep, which were infected with Pseudomonas aeruginosa and received intravenous fluid administration, were compared to similarly infected animals allowed free access to oral fluid. In both instances cardiopulmonary variables were measured for three days following inoculation. Both groups demonstrated an elevation in heart rate and hematocrit and a fall in PaO2 and leukocyte count. The animals that received fluid resuscitation demonstrated basically the same cardiovascular response to sepsis as animals that resuscitated themselves. We conclude that the hypodynamic response to sepsis is not secondary to an inadequate fluid intake.

The presence of myocardial depression is difficult to assess in most animal models of septic shock caused by hypovolemia. We studied endotoxemia in fluid-resuscitated conscious sheep. They underwent chronic instrumentation with pulmonary artery, arterial, and left atrial catheters. After 1 week of recovery, 1.5 micrograms/kg of endotoxin (LPS) was administered intravenously over a period of 30 min. One group of nine sheep stayed on baseline fluids (2 ml/kg/h of Ringer's lactate), while a second group (n = 6) was resuscitated with 7 ml/kg/h Ringer's lactate solution over the 24-h study period. Both groups were compared with controls. Eight hours after LPS, left ventricular stroke work index was depressed in both groups. In the group resuscitated with 7 ml/kg Ringer's lactate this depression associated with a normal left atrial pressure and a constant peripheral resistance indicated a shift in the Starling work curve downward and to the right evidencing myocardial depression.

Prostaglandins released during inflammatory reactions cause increases in microvascular hydrostatic pressure, a primary cause of edema. Ibuprofen, a nonsteroidal, anti-inflammatory agent that reduces prostaglandin synthesis via inhibition of cyclooxygenase, was used to investigate the possible role of prostaglandins in the cardiopulmonary responses during sepsis. Sheep, surgically prepared for cardiopulmonary studies and collection of lung lymph, were given 0.75 micrograms/kg per 30 min of E. coli endotoxin iv. Ibuprofen (14 mg/kg) was given 15 min before and 1 h 45 min after the administration of endotoxin. We had previously noted a triphasic character to the hypovolemia encountered in endotoxin sepsis. The initial phase occurs during the first hour after endotoxin administration; it is characterized by decreases in PaO2, neutrophil count, and lymph-to-plasma (L/P) protein concentration ratios and by increases in mean arterial pressure, body temperature, hematocrit, lymph flow, and total plasma protein concentration. In the second phase these variables return toward their baseline values. In Phase 3 the same changes are observed an in Phase 1 except for a decrease in total plasma protein concentration and an increase in L/P ratios. Ibuprofen administration results in a statistically significant reduction in magnitude of Phase 1 changes, without notable effect on Phase 2 or Phase 3 values. These observations support the hypothesis that prostaglandins released during inflammatory reactions contribute to the extravascular fluid movement. Ibuprofen appears to lessen the severity of microvascular hydrostatic pressure-induced edema and the hypovolemia that occurs in the early stages of endotoxin.

The antiprotease aprotinin (Trasylol) (20,000 KIU bolus/kg followed by 10,000 KIU/(kg x h) for 8 h) was administered to sheep which were then given a continuous dose of endotoxin (24 ng/(kg x h) for 24 h). Their cardiopulmonary response was compared to a group of sheep which received endotoxin alone as well as a sham group which received neither endotoxin nor aprotinin. The response to endotoxin was characterized by an increased lung lymph flow and cardiac output. This response was blocked by the administration of aprotinin. In the endotoxin group there was a fall in prekallikrein levels. The action of aprotinin suggests that the cardiopulmonary response to endotoxin may be mediated by the formation of bradykinin.

Respiratory failure after smoke inhalation injury is usually preceded by a 12-48 h interval with only minor clinical symptoms. Since pulmonary lesions show a patchy distribution, it has been postulated that vasoconstriction in more severely damaged areas induces a shift of pulmonary blood flow to less severely damaged areas, minimizing venous admixture. This hypothesis was tested in a sheep model in which only one lung was exposed to smoke. Six chronically instrumented (arterial, central venous, pulmonary artery thermodilution, and left atrial catheters; ultrasonic transit time flow probe around the left pulmonary artery) range ewes were intubated with a modified Carlens tube under halothane anesthesia. Smoke from smoldering cotton was insufflated into the left lung until a carboxyhemoglobin level of 50% was achieved. After the smoking procedure, the animals were awakened, extubated, and studied for 24 h. During this time, the pulmonary vascular resistance of the left lungs increased fourfold while the pulmonary vascular resistance of both lungs only doubled. Left pulmonary artery blood flow decreased progressively to 37% of control at 24 h, while cardiac output decreased by only 25%. PaO2 decreased from 107 +/- 12 to 77 +/- 15 mmHg at 24 h. Mean pulmonary arterial pressure rose from 18 to 23 mmHg. Heart rate, mean arterial pressure, left atrial pressure, and PaCO2 showed no statistically significant changes. The results indicate that the response of the pulmonary vasculature to smoke inhalation injury is a two-phase phenomenon. In the first phase, vasoconstriction occurs to counterbalance injury-induced ventilation-perfusion mismatching.(ABSTRACT TRUNCATED AT 250 WORDS)

We document the hemodynamic deterioration in two patients given very rapid intravenous infusions of 25% albumin. We developed an animal model to further elucidate the mechanism involved. Seven sheep were instrumented for the measurement of cardiac index (CI), pulmonary artery pressure (PAP), mean arterial pressure (MAP), left atrial pressure (LAP) and given 0.5 g/kg of Hyland brand 25% albumin over 5 min. Systemic vascular resistance index (SVRI), pulmonary vascular resistance index and left and right ventricular stroke work index were calculated. Equal volumes of normal saline were given to the same sheep as controls. Albumin significantly (p less than 0.05) increased MAP, PAP, LAP and SVRI, while CI decreased over the 3-10-min interval. Ibuprofen (14 mg/kg) intravenously administered 15 min prior to albumin, blunted all the above responses. This implicates a prostanoid as the possible mediator of these changes.

Burn wound sepsis was studied for four days in awake, unanesthetized sheep. Each of the animals was given a 40% third-degree burn, and the wound was infected with Pseudomonas aeruginosa. According to their cardiopulmonary response, the animals were divided into three groups: hyperdynamic, normodynamic, and hypodynamic. The hyperdynamic group had an increased cardiac index and a decreased total peripheral resistance index. The hypodynamic group was characterized by the following: decreased cardiac index, increased total peripheral resistance index, increased hematocrit, decreased PaO2, increased pulmonary vascular resistance index, and decreased neutrophils (P less than or equal to 0.05). The hypodynamic group was inoculated with more P aeruginosa, had more positive cultures for P aeruginosa, and had a greater mortality rate than the other two groups. It is suggested that the hypodynamic group was hypovolemic as a result of a fluid shift from the vascular compartment, that this fluid shift may be important in preventing the animals from responding to sepsis with an elevated cardiac index, and that the derivation of the cardiovascular response to sepsis is related to the severity of the initial septic insult.

Sheep which have been previously prepared for cardiopulmonary studies and collection of lung lymph were given 0.75 micrograms/kg of E coli endotoxin iv. This induced sepsis produced a triphasic response. Phase 1 occurs during the first hour after endotoxin administration and is characterized by a decreased cardiac output, lymph to plasma protein ratio, neutrophil count, and an increased hematocrit, total plasma protein concentration, lymph flow, and pulmonary artery pressure. During phase 2 these variables tend to return toward their baseline values. Phase 3 begins 2.5 hr after the administration of endotoxin and shows many of the same changes that were observed in phase 1. Also during the late phase, the plasma protein concentration and lymphocyte count were reduced and the lymph to plasa protein ratio was increased. It is concluded that (1) An early fall in cardiac output occurs as a consequence of hypovolemia. The decreased volume is the result of fluid movement from the vascular compartment to the interstitial space consequent to a microvascular pressure increase. Since the changes occur coincidentally with a drop in neutrophil count, these cells may bear some causal relationship to the response. (2) The late fall in cardiac output in phase 3, also the result of a diminished vascular volume, occurs secondarily to extravasular fluid movement as a consequence of both an elevated microvascular pressure and an increased permeability to protein. The latter may be causally related to a fall in lymphocytes.

An ovine anti-neutrophil antibody has been produced by immunizing rabbits with purified sheep neutrophils. Serial intraarterial infusions of anti-neutrophil antibody in awake instrumented sheep produced selective and profound neutropenia. Intravascular infusion of endotoxin (Escherichia coli, 1.5 micrograms/kg/30 min) resulted in significant and equivalent increases in pulmonary artery pressure, peripheral vascular resistance, and protein-rich pulmonary lymph flow in an endotoxin group (n = 9) and a depletion + endotoxin group (n = 4). Changes in cardiopulmonary parameters were most pronounced 2 to 8 hr after endotoxin administration in both groups. Cardiac index (CI) showed a precipitous and transient fall in both experimental groups at 0.5 to 1 hr after endotoxin infusion; however, by 8 hr CI rose significantly in the endotoxin group, while it remained unchanged in the depletion + endotoxin group. A significant rise in the peripheral neutrophil count was associated with the increase in CI in the endotoxin group. Plasma and pulmonary lymph levels of thromboxane-B2 were unchanged during the depletion period with a significant increase 1 hr after endotoxin infusion. In this study questions arise regarding the exclusive role of circulating neutrophils in the microvascular permeability changes seen in sepsis-mediated adult respiratory distress syndrome.

Peptidoglycans (PG) and lipopolysaccharides (LPS) are cell wall constituents of bacteria. The relative contents vary significantly between gram-negative and gram-positive strains. Since both strains take part in clinical septicemia, we compared hemodynamic and permeability properties in a sheep model with chronic instrumentation and lung lymph drainage. The cardiovascular reaction patterns of PG and LPS were comparable at very different dose levels, with LPS being 10,000-fold more potent. Continuous infusion produced an increase in lung permeability (only with LPS) and cardiac output, as well as fever, to mimic the hyperdynamic situation in early septicemia.