Lung edema formation following inhalation injury: role of the bronchial blood flow

We investigated the contribution of the bronchial blood flow to the lung lymph flow (QL) and lung edema formation after inhalation injury in sheep (n = 18). The animals were equally divided into three groups and chronically prepared by implantation of cardiopulmonary catheters and a flow probe on the common bronchial artery. Groups 1 and 2 sheep were insufflated with 48 breaths of cotton smoke while group 3 received only room air. Just before injury, the bronchial artery of group 2 animals was occluded. The occlusion was maintained for the duration of the 24-h study period. At the end of the investigation, samples of lung were taken for determination of blood-free wet weight-to-dry weight ratio (W/D). Inhalation injury induced a sevenfold increase in QL in group 1 (7 +/- 1 to 50 +/- 9 ml/h; P less than 0.05) but only a threefold increase in group 2 (10 +/- 2 to 28 +/- 7 ml/h; P less than 0.05). The mean W/D value of group 1 animals was 23% higher than that of group 2 (5.1 +/- 0.4 vs. 3.9 +/- 0.2; P less than 0.05). Our data suggest that the bronchial circulation contributes to edema formation in the lung that is often seen after the acute lung injury with smoke inhalation.     

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

We determined the effect of reduced bronchialblood flow on lung fluid flux through changes in lung lymph flow, lungwet weight-to-dry weight (wet/dry) ratios, and pulmonary microvascularreflection coefficient (). In the first of two surgical procedures,Merino ewes (n = 21) were surgicallyprepared for chronic study. Five to seven days later, in a secondoperation, the bronchial artery of the injection group(n = 7) was ligated, and 4 ml of 70%ethanol were injected into the bronchial artery to cause sclerosis of the airway circulation. In the ligation group(n = 7), only the bronchial artery wasligated. In the sham group (n = 7),the bronchial artery was surgically exposed but left intact withoutligation or ethanol injection. One day after these operations theanimals received a tracheotomy and 48 breaths of cotton smoke. Thevalue of  was determined at two points: 24 h before the secondsurgical procedure and 24 h after smoke inhalation. Lung lymph flow,blood-gas parameters, and hemodynamic data were measured every 4 hafter injury. At the end of investigation, samples of lung were taken for determination of blood-free wet/dry ratio. In the sham group, inhalation injury induced a gradual increase in pulmonary vascular resistance and lung lymph flow, which was associated with deterioration of oxygenation. Reduction of the bronchial blood flow attenuated thesepathophysiological changes, and the degree of this attenuation wasgreater in the injection group than in the ligation group. The value of was significantly higher after smoke inhalation in the injectiongroup compared with the sham group (0.77 ± 0.04 vs. 0.61 ± 0.03, means ± SE) at 24 h. The mean wet/dry ratio value of theinjection group animals was 30% less than that of the sham group. Ourdata show that the bronchial circulation contributes to edema formationin the lung occurring after acute lung injury with smoke inhalation.

     

Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury

During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO(-)). ONOO(-) exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO(-) decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40% total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injury-related increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO(-), were prevented by INO-4885, providing evidence for the neutralization of ONOO(-) action by the compound. Burn and smoke injury induced a significant drop in arterial Po(2)-to-inspired O(2) fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO(-) decomposition catalyst. In conclusion, the current study suggests that ONOO(-) plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO(-) decomposition catalyst may represent a potential treatment option for this injury.     

Role of anti-L-selectin antibody in burn and smoke inhalation injury in sheep

We hypothesized that the antibody neutralization of L-selectin would decrease the pulmonary abnormalities characteristic of burn and smoke inhalation injury. Three groups of sheep (n = 18) were prepared and randomized: the LAM-(1-3) group (n = 6) was injected intravenously with 1 mg/kg of leukocyte adhesion molecule (LAM)-(1-3) (mouse monoclonal antibody against L-selectin) 1 h after the injury, the control group (n = 6) was not injured or treated, and the nontreatment group (n = 6) was injured but not treated. All animals were mechanically ventilated during the 48-h experimental period. The ratio of arterial PO2 to inspired O2 fraction decreased in the LAM-(1-3) and nontreatment groups. Lung lymph flow and pulmonary microvascular permeability were elevated after injury. This elevation was significantly reduced when LAM-(1-3) was administered 1 h after injury. Nitrate/nitrite (NO(x)) amounts in plasma and lung lymph increased significantly after the combined injury. These changes were attenuated by posttreatment with LAM-(1-3). These results suggest that the changes in pulmonary transvascular fluid flux result from injury of lung endothelium by polymorphonuclear leukocytes. In conclusion, posttreatment with the antibody for L-selectin improved lung lymph flow and permeability index. L-selectin appears to be principally involved in the increased pulmonary transvascular fluid flux observed with burn/smoke insult. L-selectin may be a useful target in the treatment of acute lung injury after burn and smoke inhalation.     

Pulmonary changes in a mouse model of combined burn and smoke inhalation-induced injury.

The morbidity and mortality of burn victims increase when burn injury is combined with smoke inhalation. The goal of the present study was to develop a murine model of burn and smoke inhalation injury to more precisely reveal the mechanistic aspects of these pathological changes. The burn injury mouse group received a 40% total body surface area third-degree burn alone, the smoke inhalation injury mouse group received two 30-s exposures of cotton smoke alone, and the combined burn and smoke inhalation injury mouse group received both the burn and the smoke inhalation injury. Animal survival was monitored for 120 h. Survival rates in the burn injury group, the smoke inhalation injury group, and the combined injury group were 70%, 60%, and 30%, respectively. Mice that received combined burn and smoke injury developed greater lung damage as evidenced by histological changes (septal thickening and interstitial edema) and higher lung water content. These mice also displayed more severely impaired pulmonary gas exchange [arterial PO2 (PaO2)/inspired O2 fraction (FiO2)<200]. Lung myeloperoxidase activity was significantly higher in burn and smoke-injured animals compared with the other three experimental groups. Plasma NO2-/NO3-, lung inducible nitric oxide synthase (iNOS) activity, and iNOS mRNA increased with injury; however, the burn and smoke injury group exhibited a higher response. Severity of burn and smoke inhalation injury was associated with more pronounced production of nitric oxide and accumulation of activated leukocytes in lung tissue. The murine model of burn and smoke inhalation injury allows us to better understand pathophysiological mechanisms underlying cardiopulmonary morbidity secondary to burn and smoke inhalation injury.     

Role of L-selectin in physiological manifestations after burn and smoke inhalation injury in sheep.

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.     

Effects of allopurinol on smoke inhalation in the ovine model

We hypothesized that the pulmonary damage induced by smoke inhalation is the result of ischemic reperfusion injury. We determined the effect of allopurinol (xanthine oxidase inhibitor) on the pulmonary microvascular fluid flux in an ovine model after inhalation of cotton smoke (n = 13) and compared these data with those from untreated similarly smoke-injured (n = 7), as well as sham- (air, n = 9) smoked, animals and sheep given an equivalent dose of CO (n = 7). Smoke injury resulted in an increased lung lymph flow, lymph-to-plasma protein ratio, lung content of polymorphonuclear cells, and extravascular lung water (gravametric), in addition to histological evidence of tissue (pulmonary) edema and destruction. No significant difference was found in these variables between the sheep that were injured with smoke whether or not they were pretreated with allopurinol. The sham-smoked and CO-insufflated animals showed no significant changes in cardiopulmonary function or morphology. We conclude that there are few data to support a role of ischemic reperfusion injury in the pulmonary damage seen after smoke inhalation.     

Effect of 100% O2 on passage of uncharged dextrans from blood to lung lymph

Since charge as well as size may influence the passage of plasma proteins from blood to lung lymph, we used uncharged dextrans as tracers to study the effects of hyperoxic lung injury on the molecular sieving properties of the pulmonary microcirculation in unanesthetized sheep. Polydisperse [3H]dextran was infused intravenously into five sheep before and after the animals breathed 100% O2 until lymph flow increased threefold (66-84 h). Lymph-to-plasma concentration ratios (L/P) were determined for [3H]dextran fractions of graded molecular sizes (1.6-8.4 nm effective radius) from samples obtained during the infusions. Before hyperoxia the blood-lymph barrier was highly restrictive to transport of [3H]dextrans above 5.0 nm in radius; steady-state L/P for these molecules averaged 0.03 or less. After the sheep breathed 100% O2, [3H]dextrans as large as 8.4 nm radius appeared in the lymph. Posthyperoxia, the L/P were significantly increased relative to prehyperoxia base-line values for every [3H]dextran fraction larger than 2.0 nm radius (P less than 0.05). In contrast, neither the L/P for albumin or total protein changed significantly. At autopsy, electron microscopy showed widespread damage to the endothelium of the alveolar capillaries with infrequent gaps between endothelial cells. In two control sheep, inhalation of compressed air for 96 h had no effect on lymph flow or L/P for the [3H]dextrans. We conclude that O2 poisoning reduced the selective sieving of uncharged dextrans across the blood-lymph barrier of the lungs and allowed larger dextrans to enter the lymph. These larger molecules may have leaked from the pulmonary microcirculation via disruptions in the continuity of the endothelial lining.     

gamma-Tocopherol nebulization by a lipid aerosolization device improves pulmonary function in sheep with burn and smoke inhalation injury

Fire accident victims who sustain both thermal injury to skin and smoke inhalation have gross evidence of systemic and pulmonary oxidant damage and acute lung injury. We hypothesized that gamma-tocopherol (gT), a reactive O(2) and N(2) scavenger, when delivered into the airway, would attenuate lung injury induced by burn and smoke inhalation. Acute lung injury was induced in chronically prepared, anesthetized sheep by 40% total burn surface area, third-degree skin burn and smoke insufflation (48 breaths of cotton smoke, <40 degrees C). The study groups were: (1) Sham (not injured, flaxseed oil (FO)-nebulized, n=6); (2) SA-neb (injured, saline-nebulized, n=6); (3) FO-neb (injured, FO-nebulized, n=6); and (4) gT+FO-neb (injured, gT and FO-nebulized, n=6). Nebulization was started 1 h postinjury, and 24 ml of FO with or without gT (51 mg/ml) was delivered into airways over 47 h using our newly developed lipid aerosolization device (droplet size: 2.5-5 microm). The burn- and smoke inhalation-induced pathological changes seen in the saline group were attenuated by FO nebulization; gT addition further improved pulmonary function. Pulmonary gT delivery along with a FO source may be a novel effective treatment strategy in management of patients with acute lung injury.     

Role of sulfidopeptide leukotrienes in synthetic smoke inhalation injury in sheep

Acute lung injury with smoke inhalation results in significant morbidity and mortality. Previously we have shown that synthetic smoke composed of carbon and acrolein, a common component of smoke, causes delayed-onset noncardiogenic pulmonary edema. To study the possible role of the vasoactive and edemagenic sulfidopeptide leukotrienes (SPLT) in smoke inhalation injury, we measured pulmonary hemodynamics, lung lymph flow, and SPLT and leukotriene (LT) B4 in lung lymph before and after 10 min of synthetic acrolein smoke exposure. After smoke exposure there was a significant rise in pulmonary vascular resistance caused by a rise in pulmonary arterial pressure, a fall in cardiac output, and no change in pulmonary capillary wedge pressure. This was accompanied by an increase in total systemic vascular resistance (P less than 0.05), lung lymph flow (P less than 0.05), and extravascular lung water-to-lung dry weight ratio (P less than 0.05). Both SPLT and LTB4 clearance rose significantly (P less than 0.05), but there was a 10-fold increase in SPLT over LTB4 clearance. In sheep pretreated with FPL55712, a SPLT antagonist, the early rise in pulmonary vascular resistance was attenuated, and the rise in systemic vascular resistance was blocked. This was associated with an attenuated and delayed fall in cardiac output. FPL55712 had no effect on lung lymph flow or extravascular lung water-to-dry weight ratio. SPLT, and especially LTD4, may have a role in increased pulmonary and systemic vascular resistance after smoke inhalation injury but does not appear to affect vascular permeability.     

Mechanical alteration of blood flow in smoked and unsmoked lung areas after inhalation injury.

The degree of pulmonary perfusion may have an important role in the pathogenesis of inhalation injury. We studied this in sheep that had only one lung exposed to smoke. The right lung and upper airway of 12 chronically instrumented sheep were insufflated with cotton smoke. In six animals, the left pulmonary artery was occluded between 4 and 10 h after smoke insufflation. All animals were studied for 24 h and then killed, and lung tissue was harvested. The smoked as well as the air-insufflated lung of all animals showed an increase in wet-to-dry weight ratio and tissue conjugated dienes (products of lipid peroxidation). Neither the intermittent blood flow increase to the smoked lung nor the simultaneous blood flow reduction with a concomitant polymorphonuclear neutrophil entrapment in the air-insufflated lung significantly affected the histopathological outcome of the respective lung. We conclude that tissue damage after inhalation injury cannot be diminished by increasing the flow to smoked areas. Ischemia-reperfusion injury does not have a major role in the lung damage seen with inhalation injury.     

Vitamin E attenuates acute lung injury in sheep with burn and smoke inhalation injury

Abstract

Introduction: A decrease in α-tocopherol (vitamin E) plasma levels in burn patients is typically associated with increased mortality. We hypothesized that vitamin E supplementation (α-tocopherol) would attenuate acute lung injury induced by burn and smoke inhalation injury.

Materials and Methods: Under deep anesthesia, sheep (33 ± 5 kg) were subjected to a flame burn (40% total body surface area, third degree) and inhalation injury (48 breaths of cotton smoke, < 40°C). Half of the injured group received α-tocopherol (1000 IU vitamin E) orally, 24 h prior to injury. The sham group was neither injured nor given vitamin E. All three groups (n = 5 per group) were resuscitated with Ringer's lactate solution (4 ml/kg/%burn/24 h), and placed on a ventilator (PEEP = 5 cmH₂O; tidal volume = 15 ml/kg) for 48 h.

Results: Plasma α-tocopherol per lipids doubled in the vitamin E treated sheep. Vitamin E treatment prior to injury largely prevented the increase in pulmonary permeability index and moderated the increase in lung lymph flow (52.6 ± 6.2 ml/min, compared with 27.3 ± 6.0 ml/min, respectively), increased the PaO₂/FiO₂ ratio, ameliorated both peak and pause airway pressure increases, and decreased plasma conjugated dienes and nitrotyrosine.

Conclusions: Pretreatment with vitamin E ameliorated the acute lung injury caused by burn and smoke inhalation exposure.     

Administration of a synthetic antiprotease reduces smoke-induced lung injury.

Our previous studies suggest that a neutrophil-mediated inflammatory injury causes a major fraction of the pulmonary edema that occurs after smoke inhalation. Because activated neutrophils extrude cytotoxic proteases, the current study was conducted to evaluate the role of proteases in the pulmonary microvascular injury. Twelve sheep, instrumented for collection of lung lymph, were insufflated with cotton smoke. The sheep were treated 30 min after smoke inhalation with either gabexate mesilate (an inhibitor of serine proteases) or vehicle. Smoke inhalation resulted in an increased protease activity in the lung interstitium, as evidenced by decreases in both antiprotease activity and immunoreactive alpha 2-macroglobulin. Intravenous infusion of gabexate mesilate prevented the decrease in antiprotease activity. The protease inhibitor significantly attenuated the smoke-induced increase in transvascular fluid and protein flux, with untreated animals exhibiting 460% increases in flux compared with 180% in the inhibitor treated sheep. The protease inhibitor also eliminated the functional degradation in gas exchange that was observed in the untreated sheep. These studies strongly suggest that an increase in pulmonary proteolytic enzyme activity is responsible for a significant fraction of the degradation in microvascular integrity and gas exchange that is associated with smoke inhalation injury.     

Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model

Nitric oxide (NO) has been shown to play a major role in acute lung injury (ALI) after smoke inhalation. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that mimics human sepsis and pneumonia. We hypothesized that the inhibition of neuronal NO synthase (nNOS) might be beneficial in treating ALI associated with this model. Female sheep (n = 26) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke (40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa [5 x 10(11) colony forming units (CFU)] into each sheep's lung. All sheep were mechanically ventilated using 100% O2. Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, NG-monomethyl-l-arginine (l-NMMA), a nonspecific NOS inhibitor, or aminoguanidine (AG), an inducible NOS inhibitor, was started 1 h after insult. The administration of 7-NI improved pulmonary gas exchange (PaO2/FiO2; where PaO2 is arterial PO2 and FiO2 is fractional inspired oxygen concentration) and pulmonary shunt fraction and attenuated the increase in lung wet-to-dry weight ratio seen in the nontreated sheep. Histologically, 7-NI prevented airway obstruction. The increase in airway blood flow after injury in the nontreated group was significantly inhibited by 7-NI. The increase in plasma concentration of nitrate and nitrite (NOx) was inhibited by 7-NI as well. Posttreatment with l-NMMA improved the pulmonary gas exchange, but AG did not. The results of the present study show that nNOS may be involved in the pathogenesis of ALI after smoke inhalation injury followed by bacterial instillation in the airway.     

Oleic acid lung injury in sheep

Intravenous infusion of oleic acid into experimental animals causes acute lung injury resulting in pulmonary edema. We investigated the mechanism of oleic acid lung injury in sheep. In experiments with anesthetized and unanesthetized sheep with lung lymph fistulas, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and lymph and plasma protein concentrations. We injured the lungs with intravenous infusions of oleic acid at doses ranging from 0.015 to 0.120 ml/kg. We found that oleic acid caused reproducible dose-related increases in pulmonary arterial pressure and pulmonary vascular resistance, arterial hypoxemia, and increased protein-rich lung lymph flow and extravascular lung water. The lung fluid balance changes were characteristic of increased permeability pulmonary edema. Infusion of the esterified fat triolein had no hemodynamic or lung fluid balance effects. Depletion of leukocytes with a nitrogen mustard or platelets with an antiplatelet serum had no effect on oleic acid lung injury. Treatment of sheep before injury with methylprednisolone 30 mg/kg or ibuprofen 12.5-15.0 mg/kg also had no effects. Unlike other well-characterized sheep lung injuries, injury caused by oleic acid does not require participation of leukocytes.     

Selective permeability changes in the lungs and airways of sheep after toxic smoke inhalation

The effect of toxic smoke inhalation on selective microvascular sieving of macro-molecules and lymph protein flux was assessed in adult sheep to determine whether the time course of microvascular dysfunction differs between the lung and trachea. Protein flux across the lung increased sixfold 48 h after inhalation of the products of incomplete cotton combustion, whereas tracheal protein flux increased fivefold 8 h after exposure and returned to near base line 48 h after exposure. The lung and trachea selectively retained some sieving to three different protein macromolecules with molecular radii of 36, 54, and 123 A. In the lungs the sieving selectivity for these macromolecules was least 48 h after injury, and in the trachea molecular selectivity was least 8 h after injury. These data suggest that the time course of microvascular injury differs for the trachea and the lung; microvascular changes are detected earlier in the trachea than in the lung. The inhalation injury described thus permits the characterization of the time course of airway and lung microvascular changes.     

Distribution of extravascular lung water after acute smoke inhalation

Anesthetized dogs with thoracotomy were injected with Evans blue dye and were exposed acutely (5 min) to wood smoke inhalation. Thin slices from freeze-dried samples were photographed and assessed for periarterial and perivenous cuff area and for blue coloration with a score of 0 to 5. Bloodless extravascular lung water (EVLW) was also measured. The smoke-exposed animals were compared with controls and with animals exposed to alloxan or to high-pressure-induced pulmonary edema. EVLW at 2 h after smoke (6.46 +/- 0.80) was above control value (4.30 +/- 0.63) but not different from the alloxan (6.13 +/- 0.70) or high-pressure (6.88 +/- 1.30) groups. Despite the similarity in EVLW in the edematous lungs, there were marked differences in the intensity of blue color and size of cuffing around arteries and veins: the smoke, alloxan, and high-pressure groups had blue color scores of 1.0 +/- 0.1, 2.9 +/- 0.3, and 0.3 +/- 0.1, respectively. These scores indicated a large increase in microvascular permeability to proteins in the alloxan group, a moderate increase in the smoke group, and minimal change in the high-pressure group. The perivascular cuff area was largest in the alloxan group and moderate in the smoke and high-pressure groups. The cuff area was higher for arteries than for veins in all groups except the 0.5-h smoke group. We conclude that smoke inhalation causes a moderate increase in permeability and EVLW compared with alloxan. The extravascular lung water accumulates preferentially around the arteries, but the size of the perivascular cuff is not similar for all causes of pulmonary edema.     

A murine model of sepsis following smoke inhalation injury

Acute lung injury (ALI) by smoke inhalation with subsequent pneumonia and sepsis represents a major cause of morbidity and mortality in burn patients. The aim of the present study was to develop a murine model of ALI and sepsis to enhance the knowledge of mechanistic aspects and pathophysiological changes in patients with these injuries. In deeply anesthetized female C57BL/6 mice, injury was induced by four sets of cotton smoke using an inhalation chamber. Afterward, live Pseudomonas aeruginosa (3.2 × 10⁷ colony-forming units) was administered intranasally. The indicated dose of bacteria was determined based on the results of a dose-response study (n = 47). The following study groups were monitored for survival over 96 h: (1) sham injury group, (2) only smoke inhalation group, (3) only bacteria group, and (4) smoke inhalation plus bacteria group. Each group included 10 mice. The survival rates were 100%, 90%, 30%, and 10%, respectively. The double hit injury was associated with excessive releases of pro-inflammatory cytokines in the plasma, and enhanced neutrophil accumulation, increased lipid peroxidation, and excessive formation of reactive nitrogen species in the lung. In mice receiving only smoke inhalation injury, no systemic cytokine release and increased lung tissue lipid peroxidation were observed. However, smoke alone significantly increased neutrophil accumulation and formation of reactive nitrogen species in lung tissue. In conclusion, bacterial pneumonia is predominantly responsible for mortality and morbidity in this novel murine model of smoke inhalation and pulmonary sepsis. Reactive oxygen and nitrogen species mediate the severity of lung injury.     

Acute effects of combined burn and smoke inhalation injury on carboxyhemoglobin formation, tissue oxygenation, and cardiac performance

The objective of this study was to determine the relationship between carboxyhemoglobin (COHb) formation, global oxygen transport, and cardiac performance in the acute phase of combined burn and smoke inhalation injury. Following a third degree burn of 20% of the total body surface area, adult sheep were subjected to cotton smoke (4x12 breaths) according to an established protocol. Compared with baseline (BL), the burn injury led to an immediate and sustained COHb-independent depression in myocardial contractility. Despite a progressive increase in COHb formation, up to a maximum of 78+/-3% (P < 0.001 vs BL), smoke inhalation did not further impair these hemodynamic changes. This study demonstrated that in the early stage of combined burn and smoke inhalation injury, the depression in cardiac function is basically triggered by the burn injury, whereas COHb generation secondary to cotton smoke exposure primarily contributes to pulmonary shunting.     

Alterations in regional ventilation, perfusion, and shunt after smoke inhalation measured by PET.

Regional changes in ventilation and perfusion occurring in the early hours after smoke inhalation injury were evaluated through the use of positron emission tomography. Five lambs were imaged before and 1, 2, and 4 h after receiving 100 breaths of cotton smoke. Utilizing a recently developed model of (13)N tracer kinetics (3), we evaluated changes in ventilation, perfusion, shunt, and regional gas content in nondependent, middle, and dependent lung zones. The data demonstrated a progressive development of regional shunt in dependent (dorsal) regions in which perfusion remained the highest throughout the study. These findings, together with decreasing regional ventilation and fractional gas content in the dependent regions, correlated with decreasing arterial Pa(O(2)) values over the course of the study. A negative correlation between regional shunt fraction and regional gas content in dependent and middle regions suggests that shunt was caused by progressive alveolar derecruitment or flooding.