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Objective: To determine if the selective vasopressin type 1a receptor agonist selepressin (FE 202158) is as effective as the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist vasopressor hormone arginine vasopressin when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis., Design: Prospective, randomized, controlled laboratory experiment., Setting: University animal research facility., Subjects: Forty-five chronically instrumented sheep., Interventions: Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure fell by more than 10 mm Hg from baseline level, an additional continuous IV infusion of arginine vasopressin or selepressin was titrated to raise and maintain mean arterial pressure within no less than 10 mm Hg from baseline level. Effects of combination treatment of selepressin with the selective vasopressin V2 receptor agonist desmopressin were similarly investigated., Measurements and Main Results: In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index decreased by ~50%, and ~7 L of fluid were retained over 24 hours; this fluid accumulation was partially reduced by arginine vasopressin and almost completely blocked by selepressin; and combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to arginine vasopressin treatment., Conclusions: Resuscitation with the selective vasopressin type 1a receptor agonist selepressin blocked vascular leak more effectively than the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist arginine vasopressin because of its lack of agonist activity at the vasopressin V2 receptor.

Objective: To test the hypothesis that restoration of antithrombin plasma concentrations attenuates vascular leakage by inhibiting neutrophil activation through syndecan-4 receptor inhibition in an established ovine model of acute lung injury., Design: Randomized controlled laboratory experiment., Setting: University animal research facility., Subjects: Eighteen chronically instrumented sheep., Interventions: Following combined burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn; 4 × 12 breaths of cold cotton smoke), chronically instrumented sheep were randomly assigned to receive an IV infusion of 6 IU/kg/hr recombinant human antithrombin III or normal saline (n = 6 each) during the 48-hour study period. In addition, six sham animals (not injured, continuous infusion of vehicle) were used to obtain reference values for histological and immunohistochemical analyses., Measurements and Main Results: Compared to control animals, recombinant human antithrombin III reduced the number of neutrophils per hour in the pulmonary lymph (p < 0.01 at 24 and 48 hr), alveolar neutrophil infiltration (p = 0.04), and pulmonary myeloperoxidase activity (p = 0.026). Flow cytometric analysis revealed a significant reduction of syndecan-4-positive neutrophils (p = 0.002 vs control at 24 hr). Treatment with recombinant human antithrombin III resulted in a reduction of pulmonary nitrosative stress (p = 0.002), airway obstruction (bronchi: p = 0.001, bronchioli: p = 0.013), parenchymal edema (p = 0.044), and lung bloodless wet-to-dry-weight ratio (p = 0.015). Clinically, recombinant human antithrombin III attenuated the increased pulmonary transvascular fluid flux (12-48 hr: p ≤ 0.001 vs control each) and the deteriorated pulmonary gas exchange (12-48 hr: p < 0.05 vs control each) without increasing the risk of bleeding., Conclusions: The present study provides evidence for the interaction between antithrombin and neutrophils in vivo, its pathophysiological role in vascular leakage, and the therapeutic potential of recombinant human antithrombin III in a large animal model of acute lung injury.

Objective: Acute lung injury secondary to smoke inhalation is a major source of morbidity and mortality in burn patients. We tested the hypothesis that nebulized epinephrine would ameliorate pulmonary dysfunction secondary to acute lung injury by reducing airway hyperemia and edema formation and mediating bronchodilatation in an established, large animal model of inhalation injury., Design: Prospective, controlled, randomized trial., Setting: University research laboratory., Subjects: Twenty-four chronically instrumented, adult, female sheep., Interventions: Following baseline measurements, the animals were allocated to a sham-injured group (n = 5), an injured and saline-treated group (n = 6), or an injured group treated with 4 mg of nebulized epinephrine every 4 hrs (n = 6). Inhalation injury was induced by 48 breaths of cotton smoke. The dose of epinephrine was derived from dose finding experiments (n = 7 sheep)., Measurements and Main Results: The injury induced significant increases in airway blood flows, bronchial wet/dry weight ratio, airway obstruction scores, ventilatory pressures, and lung malondialdehyde content, and contributed to severe pulmonary dysfunction as evidenced by a significant decline in Pao₂/Fio₂ ratio and increase in pulmonary shunt fraction. Nebulization of epinephrine significantly reduced tracheal and main bronchial blood flows, ventilatory pressures, and lung malondialdehyde content. The treatment was further associated with significant improvements of Pao₂/FIO₂ ratio and pulmonary shunting., Conclusions: Nebulization of epinephrine reduces airway blood flow and attenuates pulmonary dysfunction in sheep subjected to severe smoke inhalation injury. Future studies will have to improve the understanding of the underlying pathomechanisms and identify the optimal dosing for the treatment of patients with this injury.

Objectives: Inhalation injury contributes to the morbidity and mortality of burn victims. In humans and in an ovine model of combined smoke inhalation and burn injury, bronchospasm and acute airway obstruction contribute to progressive pulmonary insufficiency. This study tests the hypothesis that muscarinic receptor antagonist therapy with tiotropium bromide, an M1 and M3 muscarinic receptor antagonist, will decrease the airway constrictive response and acute bronchial obstruction to improve pulmonary function compared to injured animals without treatment., Design: Randomized, prospective study involving 32 sheep., Setting: Large-animal intensive care research laboratory., Interventions: The study consisted of six groups: a sham group (n=4, instrumented noninjured), a control group (n=6, injured and not treated), and tiotropium bromide-treated groups, including both preinjury and postinjury nebulization protocols. Treatments for these groups included nebulization with 36 μg of tiotropium bromide 1 hr before injury (n=6) and postinjury nebulization protocols of 18 μg (n=6), 36 μg (n=6), and 72 μg (n=4) administered 1 hr after injury. All treated groups received an additional 14.4 μg every 4 hrs for the 24-hr study period., Main Results: Pretreatment with tiotropium bromide significantly attenuated the increases in ventilatory pressures, pulmonary dysfunction, and upper airway obstruction that occur after combined smoke inhalation and burn injury. Postinjury treatments with tiotropium bromide were as effective as pretreatment in preventing pulmonary insufficiency, although a trend toward decreased obstruction was present only in all post-treatment conditions. There was no improvement noted in pulmonary function in animals that received a higher dose of tiotropium bromide., Conclusions: This study describes a contribution of acetylcholine to the airway constrictive and lumenal obstructive response after inhalation injury and identifies low-dose nebulization of tiotropium bromide as a potentially efficacious therapy for burn patients with severe inhalation injury.

Objective: To test the hypothesis that hypoproteinemia reduces plasma volume expansion produced by a bolus of crystalloid solution given to awake sheep., Design: Prospective and observational., Setting: Laboratory., Subjects: Five female merino sheep (n = 5) weighing 37 ± 3 kg were anesthetized., Interventions: Each animal was subjected to a 5-day test period: day 1: 50 mL/min 0.9% saline infusion over 20 mins. Days 2-4: daily plasmapheresis and replacement of the shed plasma with 6 L of 0.9% saline were performed in increments., Measurements and Main Results: Fractional plasma volume expansion after rapid infusion of saline on days 1 and 5 was calculated from changes in hemoglobin concentration. There was a significant reduction in total plasma protein concentration after plasmapheresis (p < .05). Colloid osmotic pressures were also significantly lowered (p < .05). A crystalloid infusion of 0.9% saline did not alter any of these values compared with baseline. The hemodynamic measurements did not show significant differences between the experiments. The plasma volume expansion reached approximately 20% at the end of infusion and stayed at 10-15% during the experiments. No difference was found in plasma volume expansion produced by a bolus of 50 mL/min of 0.9% in the hypoproteinemic state when compared with the euproteinemic state (p = .61). No difference in cumulative urinary output was found between the two states., Conclusions: In contrast to our hypothesis, severe acute hypoproteinemia does not reduce plasma volume expansion in response to 50 mL/min 0.9% saline infusion in nonspleenectomized sheep when compared with the resultant plasma volume expansion after a 50 mL/min of 0.9% infusion in the euproteinemic state.

Objective: To compare the effects of a first-line therapy of combined arginine vasopressin, levosimendan, and norepinephrine with arginine vasopressin + norepinephrine or norepinephrine alone in ovine septic shock., Design: Prospective, randomized, controlled laboratory experiment., Setting: University animal research facility., Subjects: Twenty-one chronically instrumented sheep., Interventions: After the onset of fecal peritonitis-induced septic shock (mean arterial pressure <60 mm Hg), sheep were randomly assigned to receive first-line treatment with arginine vasopressin (0.5 mU·kg·min), combined arginine vasopressin (0.5 mU·kg·min) and levosimendan (0.2 μg·kg·min), or normal saline (each n = 7) for 24 hrs. In all groups, open-label norepinephrine was additionally titrated to maintain mean arterial pressure at 70 ± 5 mm Hg, if necessary., Measurements and Main Results: Arginine vasopressin + levosimendan + norepinephrine improved left ventricular contractility (higher stroke work indices at similar or lower preload) and pulmonary function (Pao2/Fio2 ratio) when compared with the other groups (p < .05 each). Both nonadrenergic treatment strategies reduced open-label norepinephrine doses. However, only arginine vasopressin + levosimendan + norepinephrine limited fluid requirements and positive fluid balance vs. both other groups (p < .05 each). In addition, arginine vasopressin + levosimendan + norepinephrine increased mixed venous oxygen saturation as compared with arginine vasopressin + norepinephrine. Histologic tissue analyses and pulmonary hemeoxygenase-1 activity revealed no differences among groups. Notably, arginine vasopressin + levosimendan + norepinephrine therapy reduced pulmonary 3-nitrotyrosine levels (p = .028 vs. control animals) as well as urinary protein/creatinine ratio (p < .05 each) and slightly prolonged survival when compared with both other groups (4 hrs vs. arginine vasopressin + norepinephrine: p = .013; 7 hrs vs. norepinephrine alone: p = .003)., Conclusions: First-line cardiovascular support with combined arginine vasopressin and levosimendan supplemented with norepinephrine improves myocardial, vascular, pulmonary, and renal function as compared with arginine vasopressin + norepinephrine in septic shock.

Objective: Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation., Design: Prospective, randomized, controlled, experimental animals study., Setting: Investigational intensive care unit at university hospital., Subjects: Adult female sheep., Interventions: Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 microg/kg/hr. Sham and control groups received same amount of saline., Measurements and Main Results: Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of injured sheep with neuronal nitric oxide synthase inhibitor attenuated all the observed pulmonary pathophysiology., Conclusions: The results provide definitive evidence that inhibition of neuronal nitric oxide synthase-derived excessive nitric oxide may be a novel and beneficial treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.

Objective: Acute lung injury with subsequent pneumonia and sepsis represents a major cause of morbidity and mortality in thermally injured patients. Production of nitric oxide by the neuronal and inducible nitric oxide synthase may be critically involved in the pathophysiology of the disease process at different time points, and thus specific inhibition at different times may represent an effective treatment regimen., Design: Prospective, controlled, randomized trial., Setting: University research laboratory., Subjects: Eighteen chronically instrumented, adult, female sheep., Interventions: Following baseline measurements, the animals were allocated to either sham-injured, nontreated controls (sham), injured, nontreated controls (control), or injured animals treated with continuous infusion of 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, during the first 12 hrs postinjury and infusion of BBS-2, a specific inducible nitric oxide synthase inhibitor, during the next 12 hrs. Injury was induced by 48 breaths of cotton smoke and subsequent instillation of Pseudomonas aeruginosa into the lungs. All sheep were mechanically ventilated and fluid resuscitated for the entire duration of the 24-hr experiment., Measurements and Main Results: The injury induced severe pulmonary dysfunction, which was associated with increases in lung edema formation, airway obstruction, and vascular endothelial growth factor, 3-nitrotyrosine, and poly(adenosine diphosphate ribose) expression in lung tissue. The treatment reduced the degree of airway obstruction and improved pulmonary gas exchange, whereas the development of lung edema was not affected. The increases in lung tissue vascular endothelial growth factor, 3-nitrotyrosine, and poly(ribose) expression were attenuated by the treatment., Conclusions: The combination of early neuronal nitric oxide synthase and delayed inducible nitric oxide synthase inhibition shows potential benefit in ovine acute lung injury by reducing nitrosative stress in the lung and limiting the degree of airway obstruction.

Objective: To assess the time changes and mechanism of pulmonary and peripheral vascular permeability in sheep with acute lung injury and sepsis., Design: Prospective, controlled, randomized trial., Setting: University research laboratory., Subjects: A total of 21 chronically instrumented, adult female sheep., Interventions: Sheep were instrumented with lung and prefemoral lymph fistulas and allocated to either an uninjured control group (n = 5) or sepsis group (n = 5). The sheep in the sepsis group received cotton smoke inhalation injury followed by instillation of Pseudomonas aeruginosa into the lungs. All sheep were mechanically ventilated and fluid resuscitated for the entire duration of the 24-hr experiment. Additional sheep (n = 11) received injury and were killed at different time points for the measurement of vascular endothelial growth factor in lung tissue., Measurements and Main Results: The injury induced a hypotensive-hyperdynamic circulation; increases in pulmonary capillary pressure, net fluid balance, lung and prefemoral lymph flow and protein content, lung water content, abdominal and thoracic fluid and protein content, neutrophil accumulation in the lung, and vascular endothelial growth factor expression in lung tissue; and decreases in PaO2/FiO2 ratio, plasma protein concentration, plasma oncotic pressure, and myocardial contractility., Conclusions: Lung edema formation in this model was the result of marked increases in both pulmonary microvascular permeability and pressure. Pulmonary vascular hyperpermeability peaked 12 hrs postinjury and was related to vascular endothelial growth factor overexpression. Early myocardial failure was a potential contributor to the constant increase in pulmonary capillary pressure. The sepsis-induced increase in peripheral microvascular permeability was associated with significant accumulation of fluid and protein in the third space.

Objective: We hypothesized that nitric oxide derived from the neuronal nitric oxide synthase (NOS) is responsible for much of the injury resulting from skin burn and smoke inhalation. Therefore, we aimed to examine the effects of selective neuronal NOS inhibition on cardiopulmonary functions and cellular injury in sheep with acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury., Design: Prospective, randomized, controlled laboratory experiment., Setting: Investigational intensive care unit., Subjects: A total of 22 chronically instrumented adult ewes., Interventions: Sheep were randomly assigned to either healthy controls (sham), injured controls (40% third-degree flame burn; 48 breaths of cotton smoke), or an injury group treated with the specific neuronal NOS inhibitor 7-nitroindazole (1 mg x kg(-1) x hr(-1)) from 1 hr postinjury to the end of the 48-hr study period. Hypoxic pulmonary vasoconstriction was assessed as decrease in left pulmonary blood flow in response to single-lung hypoxic challenges (100% nitrogen) at baseline, 24 hrs, and 48 hrs., Measurements and Main Results: The combination injury contributed to a approximately 90% loss of hypoxic pulmonary vasoconstriction and was associated with significant pulmonary shunting and death of one animal. The increase in nitrate/nitrite plasma levels in injured controls (12 hrs: 17 +/- 2 vs. 6 +/- 1 microM in sham animals; p < .001) was linked to increases in inducible NOS messenger RNA and 3-nitrotyrosine formation in lung tissue (48 hrs: 22 +/- 1 vs. 0.8 +/- 0.3 nM in sham animals; p < .001). 7-Nitroindazole treatment prevented the injury-associated changes in inducible NOS messenger RNA, nitrate/nitrite, and 3-nitrotyrosine, thereby attenuating the loss of hypoxic pulmonary vasoconstriction and improving gas exchange. In addition, 7-nitroindazole decreased lung tissue concentrations of hemoxygenase-1 and ameliorated myocardial depression, airway obstruction, pulmonary edema, ventilatory pressures, and histopathologic changes seen in injured controls., Conclusions: The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

Objective: To study the effects of a novel, intermittently administered, aerosolized nitric oxide donor, methyl-N-2-dimethylaminoethyl-3-aminoproprionid/nitric oxide (DMDE-NO), on pulmonary hemodynamic responses to sepsis., Design: Prospective, randomized, controlled study in awake sheep., Setting: Investigational intensive care unit of a university medical center., Subjects: Thirteen instrumented merino ewes weighing 36 +/- 0.9 kg underwent a hemodynamic study 1 wk postoperatively., Interventions: On the day of the experiment, the sheep received a tracheotomy and mechanical ventilation was subsequently started. Pseudomonas aeruginosa bacteria were infused intravenously, beginning at time 0 hrs and continuing throughout the 48-hr experiment. The animals were randomly assigned to receive nebulized DMDE-NO 1 mg/kg, dissolved in 8 mL of saline (DMDE-NO group, n = 7), or nebulized saline alone (control group, n = 6) delivered by a nebulizer. The nebulizations started at 2, 6, 20, 24, and 43 hrs after the baseline, each time lasting for 1 hr., Measurements and Main Results: Inhaled aerosolized DMDE-NO reversibly reduced the sepsis-induced increase in pulmonary artery pressure by 13-17% and pulmonary vascular resistance index by 21-31% compared with the values registered before the administration of the drug. Systemic hemodynamics underwent an early hypodynamic phase followed by a gradual increase in cardiac index and a decrease in both mean arterial pressure and systemic vascular resistance index, but with no significant difference between groups. Gas exchange variables and plasma nitrite/nitrate did not differ significantly between groups either., Conclusions: In sheep, inhaled nebulized DMDE-NO reduces sepsis-induced changes in pulmonary hemodynamics with no change in systemic hemodynamics or gas exchange.

Objective: Atrial natriuretic peptide is regarded as an important regulator of pulmonary vasomotor tone and permeability. This study investigated the role of atrial natriuretic peptide in sepsis-associated pulmonary pathophysiology., Design: Prospective experimental investigation., Setting: Laboratory at a university hospital., Subjects: Twelve awake, chronically instrumented sheep., Interventions: The sheep were instrumented with lung lymph fistulas and received a continuous infusion with live Pseudomonas aeruginosa for 48 hrs. After 40 hrs, the atrial natriuretic peptide-receptor antagonist HS-142-1 was continuously infused in the HS-124-1 group (3 mg/kg/hr, n = 6) for 8 hrs, whereas the control group received the carrier (n = 6)., Measurements and Main Results: Lung lymph flow was markedly elevated in response to sepsis after 40 hrs in both groups. Atrial natriuretic peptide-receptor blockade further increased lymph flows by 41 +/- 17% (41 hrs) up to 64 +/- 20% (44 hrs, p < .05) in the presence of normal permeability to protein. Although mean pulmonary artery pressure increased (p < .05 vs. 40 hrs), capillary pressure remained unaffected. Despite identical fluid balances in both groups, cardiovascular filling variables significantly increased in the HS-142-1 group. This was associated with increasing cardiac index and mean arterial pressure (p < .05 vs. 40 hrs). In the control group, all variables remained constant between 41 and 48 hrs., Conclusion: Blockade of atrial natriuretic peptide receptors increases pulmonary transvascular fluid flux independent of changes in permeability to protein in chronic ovine sepsis. Atrial natriuretic peptide may therefore play a protective role for the alveolar-capillary barrier during sepsis.

Objective: The interaction between coagulation and inflammation has become one of the major topics in critical care medicine. In the present study, we investigated the effect of posttreatment of sepsis with recombinant human antithrombin., Design: Experimental laboratory in a university hospital., Setting: University laboratory., Subjects: Female merino ewes (n = 16)., Interventions: After 1 wk of recovery from the surgical preparation, a tracheotomy was performed followed by insufflation of 48 breaths of cotton smoke (<40 degrees C). Afterward, a stock solution of live (5 x 10(11) colony-forming units) was instilled in the both lung lobes through a bronchoscope. All sheep were mechanically ventilated employing 100% oxygen. An infusion of recombinant human antithrombin (100 units x kg(-1) x 24 hrs(-1), intravenously; n = 6) or saline (n = 6) was started 1 hr after injury. Sham control animals (n = 4) were surgically prepared but not insufflated with smoke and bacteria. Lung histologic changes were evaluated by a scoring system., Measurements and Main Results: The infusion of recombinant human antithrombin maintained the baseline antithrombin activity throughout the study; in the saline-treated group, antithrombin activity decreased significantly. The lung wet/dry weight ratio and the histology score (combined scores for congestion, edema, inflammation, and hemorrhage) were significantly increased by the insult, but recombinant human antithrombin attenuated these responses. More than 30% of both bronchi and bronchioles were obstructed by cast formation after smoke inhalation and pneumonia. The cast was composed of epithelial cells, neutrophils, mucus, and fibrin. The obstruction was significantly improved by recombinant human antithrombin infusion. Arterial pressure and urine output were also attenuated in recombinant human antithrombin-treated animals. The increases in plasma nitrate/nitrite concentrations and pulmonary shunt fraction after the injury were not attenuated by recombinant human antithrombin., Conclusion: Posttreatment by recombinant human antithrombin was effective in treating acute lung injury after smoke inhalation and pneumonia in sheep. We hypothesize that the decrease in antithrombin activity during sepsis might induce severe airway obstruction and that supplementation with antithrombin inhibits this decrease.

Objective: Patients with acute lung injury after smoke inhalation often develop pneumonia subsequently complicated by sepsis. This often is a fatal complication. The aim of this study was to develop a standardized and reproducible model of hyperdynamic sepsis after smoke inhalation in sheep., Design: Prospective, experimental study in sheep., Settings: Experimental laboratory in a university hospital., Subjects: Twenty-one female Merino ewes., Intervention: Animals were anesthetized and surgically prepared for this chronic study. After a week of recovery, baseline data were collected. After tracheostomy was performed, sheep were connected to a volume-controlled ventilator. Acute lung injury was produced by insufflating the lungs with 48 breaths of cotton smoke. During halothane anesthesia, live bacteria suspended in a 30-mL saline solution containing 2-5 x 10(11) colony-forming units were instilled through a bronchoscope into the right lower and middle lung lobes (10 mL each) and left lower lung lobe (10 mL; n = 10). Eleven sheep were given smoke but not bacteria. After injury and the bacterial challenge, the animals were ventilated mechanically with 100% oxygen. The animals were monitored for 48 hrs. was detected in blood cultures after 14-48 hrs., Measurements and Main Results: The sheep developed a hyperkinetic cardiovascular response concomitant with a decrease in Pao similar to severe sepsis in human patients who meet the criteria for acute respiratory distress syndrome (PaO2 /FIO2 <200). These changes were more severe than in animals exposed to smoke inhalation alone. Mean arterial pressures at 48 hrs in the smoke-alone and the smoke + sepsis group were 85.5 +/- 5.2 and 68.1 +/- 7.6 mm Hg, respectively (mean +/- se, p<.05)., Conclusion: This animal model closely resembles hyperdynamic sepsis in humans and may be of great value for studies of sepsis with smoke inhalation.

Objectives: To determine whether treatment with manganese superoxide dismutase (MnSOD), given intravenously after inhalation injury has been established, improves oxygenation and lung fluid balance., Design: Randomized, controlled intervention trial., Setting: University research laboratory., Subjects: Twenty-four chronically instrumented awake ewes with lung lymph fistulas., Interventions: After smoke inhalation with 48 breaths of cotton smoke, the animals were assigned randomly to a control group (n = 6) or a treatment group, receiving 1000 units of MnSOD/kg (n = 6), 3000 units of MnSOD/kg (n = 6), or 9000 units of MnSOD/kg (n = 6) intravenously 1 hr after smoke inhalation., Measurements and Main Results: Different from the other three groups, in the group that received 3000 units of MnSOD, cardiac output and Pao2/Fio2 ratio did not significantly decrease throughout the experimental period. Apart from higher oxygen consumption in the group receiving 3000 units of MnSOD 24 hrs after smoke inhalation (263 +/- 44 mL/min vs. 182 +/- 36 mL/min; p < 0.05), no significant differences between treatment groups and control group were observed., Conclusions: Treatment with MnSOD given after smoke inhalation seems to be less effective then pretreatment with MnSOD, which was reported in previous studies to reduce the degree of inhalation injury.

Objective: Tumor necrosis factor (TNF)-alpha administration in large amounts can induce a state of shock similar to that observed in patients suffering from septic shock. Small doses of TNF-alpha induce only mild, transient hemodynamic alterations and can confer protection against subsequent inflammatory stimuli. The objective of this study was to determine whether this protective mechanism could be attributed to activity of the anti-inflammatory cytokine interleukin (IL)-10., Design: Prospective, randomized, controlled study., Setting: Investigative intensive care unit at a medical university., Subjects: Female BALB-c mice, 10-12 wks of age (approximately 20 g)., Interventions: All mice were subjected to intraperitoneal (ip) injection of lipopolysaccharide (LPS; Escherichia coli 0111:B4, 125 microg). Mice were randomly assigned to the following groups: TNF-alpha pretreated (100 microg ip 24 hrs before LPS); control (TNF vehicle alone 24 hrs before LPS); TNF/anti-IL-10 pretreated (TNF pretreatment as above and a neutralizing anti-IL-10 antibody); TNF/anti-IL-10 control (TNF pretreatment as above and an isotype-matched control antibody with no IL-10 activity); IL-10 (100 microg ip 1 hr before LPS); and IL-10 control (IL-10 vehicle 1 hr before LPS)., Measurements and Main Results: Mice were observed for a 48-hr period after endotoxin administration. Mortality in each group was recorded. Separate groups of mice were pretreated with TNF (or vehicle) and killed at 0, 2, or 4 hrs after LPS injection for collection of serum and peritoneal lavage samples that were used to assay IL-10 concentrations. A small dose of TNF-alpha attenuated mortality in mice that were subsequently injected with a highly lethal dose of endotoxin and observed for 48 hrs. Peritoneal lavage fluid concentrations of IL-10 were consistently higher in TNF-pretreated mice after endotoxin administration. The TNF-alpha protective effect was reversed by administration of a neutralizing antibody directed against murine IL-10., Conclusions: These findings indicate that administration of a low dose of TNF-alpha can induce cross-tolerance to endotoxin by induction of endogenous anti-inflammatory mechanisms.

Objective: To test the hypothesis that the hypocalcemia and hypoparathyroidism that follow severe burn injury are related to up-regulation of the parathyroid gland calcium-sensing receptor (CaR), which may reduce the set-point for suppression of circulating parathyroid hormone by blood calcium., Design: A controlled but unblinded study., Setting: An investigational intensive care unit., Subjects: Female range ewes., Intervention: Sheep were subjected to a 40% total body surface area burn under anesthesia (n = 9) or sham burn receiving anesthesia and fluid resuscitation only (n = 8) and were killed 48 hrs postburn., Measurements and Results: Blood ionized calcium, magnesium, and creatinine, and urinary calcium, magnesium, and creatinine were monitored for 48 hrs. After the sheep were killed, parathyroids (burn group, n = 3; sham group, n = 4) and kidneys (n = 4, each group) were harvested, snap frozen in liquid nitrogen, and analyzed for CaR messenger ribonucleic acid (mRNA) by Northern blot, and were analyzed for CaR cell-surface staining by immunocytochemistry with a polyclonal CaR-specific antiserum (parathyroids only). Bumed sheep were hypocalcemic and hypomagnesemic compared with sham-burned control sheep. CaR mRNA was increased by 50% (p < 0.005, analysis of variance) with a corresponding increase in the intensity of CaR immunoreactivity associated with the cell surface in parathyroids obtained from burned (n = 3) compared with sham-burned (n = 2) sheep. These findings are consistent with up-regulation of the parathyroid CaR and a related decrease in set-point for calcium suppression of parathyroid hormone secretion that may contribute to the previously reported postburn hypoparathyroidism and hypocalcemia.

Objective: Tumor necrosis factor (TNF)-alpha administration in large amounts can induce a state of shock similar to that seen during severe sepsis. The objective of this study was to determine whether small doses of TNF-alpha might decrease the disposition for the development of shock induced by a subsequent infusion of endotoxin and to determine whether the mechanism of this protective effect of TNF-alpha pretreatment could be associated with up-regulation of the anti-inflammatory cytokine interleukin (IL)-10., Design: Prospective, randomized, experimental study., Setting: Investigative intensive care unit at an academic medical center., Subjects: A total of 14 female Yorkshire pigs, weighing 20-25 kg., Interventions: We studied two groups of animals-pigs treated with 500 ng/kg recombinant porcine TNF-alpha (n = 7) and pigs given diluent alone (n = 7). At 24 hrs after treatment, both groups of pigs were subjected to a 24-hr continuous infusion of lipopolysaccharide (LPS) at a rate of 80 ng/kg/min., Measurements and Main Results: The mortality rate was determined in both groups. Hemodynamic indices, oxygen transport variables, total and differential white cell counts, and serum concentrations of TNF and IL-10 were determined at frequent intervals before and after TNF-alpha administration and during the LPS infusion. Additionally, peripheral blood mononuclear cells were collected for determination of messenger ribonucleic acid expression of IL-10 by reverse transcription-polymerase chain reaction. The administration of TNF-alpha at the dose used in this study did not have any profound effect. No pig treated with TNF-alpha died in response to the LPS infusion. In contrast, three of seven control pigs died during the LPS infusion. Lipopolysaccharide-induced arterial hypotension and arterial hypoxemia were attenuated in the TNF-alpha-treated group. Both groups had significant increases in serum concentrations of TNF-alpha in response to LPS, with no significant difference in peak serum TNF-alpha between groups. Neither serum concentrations of IL-10 nor expression of IL-10 messenger ribonucleic acid in circulating mononuclear cells differed between groups., Conclusions: The administration of TNF-alpha attenuated the severity of hyperdynamic shock induced by a subsequent infusion of endotoxin. This effect could not be associated with increased expression or elaboration of the anti-inflammatory cytokine IL-10.

Objectives: To develop a predictable, dose-dependent, clinically relevant model of severe respiratory failure associated with a 40% total body surface area, full-thickness (third-degree) cutaneous flame burn and smoke inhalation injury in adult sheep., Design: Model development., Setting: Research laboratory., Subjects: Adult female sheep (n = 22)., Interventions: Animals were divided into three groups, determined by the number of smoke breaths administered (24, 36, 48) for a graded inhalation injury. The smoke was insufflated into a tracheostomy with a modified bee smoker at airway temperatures <40 degrees C. All animals concurrently received a 40% total body surface area (third-degree) cutaneous flame burn to the body (flanks). After injury, the animals were placed on volume-controlled ventilation to achieve PaO2 >60 mm Hg and PaCO2 <40 mm Hg. Arterial blood gases and ventilator settings were monitored every 6 hrs postinjury for up to 7 days., Measurements and Main Results: All animals survived the induction of injury. In the 24 smoke breath/40% total body surface area burn (24/40) group, PaO2/F(IO2) never decreased below 300, and peak inspiratory pressure was consistently <14 cm H2O with normal arterial blood gases throughout the observation period. With 36 smoke breaths/40% total body surface area burn (36/40) (n = 7), all animals had PaO2/F(IO2) of <200 and peak inspiratory pressure of 26 cm H2O within 40-48 hrs, as 30% died during the study period. With 48 smoke breaths/40% total body surface area burn (48/40) (n = 12), all animals developed respiratory distress syndrome (RDS) in 24-30 hrs, but none survived the experimental period., Conclusions: Development of RDS by smoke and cutaneous flame bum injury depends on smoke inhalation dose. A combination of 36 breaths of smoke and a 40% total body surface area (third-degree) cutaneous flame burn injury can induce severe RDS (PaO2/F(IO2) <200) within 40-48 hrs to allow evaluation of various treatment modalities of RDS.

Objective: Resuscitation of large burn injuries must quickly restore and maintain cardiovascular function and fluid balance while minimizing secondary edema-related damage. We tested the hypothesis that two 4-mL x kg(-1) doses of hypertonic saline dextran (HSD; 7.5% NaCl/6% dextran-70) can produce prolonged reduction in fluid requirements after burn injury., Design: Prospective, pseudo randomized, double-blind study., Setting: Animal research laboratory., Subjects: Female adult Merino sheep (n = 12)., Interventions: Sheep were given a 40% total body surface area full-thickness flame burn under halothane anesthesia. One hour after the burn, the conscious animals received an initial dose of 4 mL x kg(-1) HSD (n = 6) or normal saline (NS; NaCl 0.9%) (n = 6) intravenously during 30 mins. This was followed by lactated Ringer's solution, infused to a target urine output of 1 mL x kg(-1) x hr(-1) throughout the 24-hr study. A second 4-mL x kg(-1) dose of HSD or NS was started at 12 hrs, and infused during 5 hrs., Measurements and Main Results: Hourly urine output measurements were used to guide the infusion rate of the lactated Ringer's. The initial infusion of HSD 1 hr after the burn injury promptly restored cardiac index, promoted diuresis, and reduced fluid requirements compared with the NS controls (73% reduction for HSD relative to NS at 8 hrs). Subsequent rebound fluid accumulation resulted in similar net fluid balances in both groups within 12 hrs after the burn. The second dose of HSD, given at 12 hrs, was without effect on hemodynamics and fluid balance., Conclusions: We conclude a considerable initial, but not sustained fluid-sparing effect of early HSD, and no effect of a late, slowly infused HSD dose in this two-dose regimen.

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.

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.

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.

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.

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: 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.