Basic Science Aspects
AEROSOLIZED TISSUE PLASMINOGEN INHIBITOR IMPROVES PULMONARY FUNCTION IN SHEEP WITH BURN AND SMOKE INHALATION
Enkhbaatar, Perenlei*; Murakami, Kazunori*; Cox, Robert*†; Westphal, Martin*; Morita, Naoki*; Brantley, Kimberly†; Burke, Ann†; Hawkins, Hal*†; Schmalstieg, Frank*; Traber, Lillian*†; Herndon, David*†; Traber, Daniel*
*Departments of Anesthesiology, Pathology, and Surgery, University of Texas Medical Branch, and †Shriners Hospital for Children, Galveston, Texas 77555
Received 29 Jan 2004;
accepted in final form 29 Mar 2004
first review completed 18 Feb 2004;
Address reprint requests to Dr. Daniel L. Traber, Department of Anesthesiology, University of Texas Medical Branch, 610 Texas Avenue, Galveston, TX 77555-0833. E-mail: firstname.lastname@example.org.
Acute respiratory distress syndrome is a major complication in patients with thermal injury. The obstruction of the airway by cast material, composed in part of fibrin, contributes to deterioration of pulmonary gas exchange. We tested the effect of aerosol administration of tissue plasminogen activator, which lyses fibrin clots, on acute lung injury in sheep that had undergone combined burn/smoke inhalation injury. Anesthetized sheep were given a 40% total body surface, third degree burn and were insufflated with cotton smoke. Tissue plasminogen activator (TPA) was nebulized every 4 h at 1 or 2 mg for each nebulization, beginning 4 h after injury. Injured but untreated control sheep developed multiple symptoms of acute respiratory distress syndrome: decreased pulmonary gas exchange, increased pulmonary edema, and extensive airway obstruction. These control animals also showed increased pulmonary transvascular fluid flux and increased airway pressures. These variables were all stable in sham animals. Nebulization of saline or 1 mg of TPA only slightly improved measures of pulmonary function. Treatment of injured sheep with 2 mg of TPA attenuated all the pulmonary abnormalities noted above. The results provide evidence that clearance of airway obstructive cast material is crucial in managing acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.
Thermal injury often results in multiple organ dysfunction (including lung injury), with subsequent development of acute respiratory distress syndrome. The pathophysiology of acute lung injury induced by combined burn and smoke inhalation injury has been described in a previous study conducted by our group (1, 2).
To maintain normal function in other organs, it is crucial to maintain adequate pulmonary function, including gas exchange. There are several factors that negatively affect pulmonary gas exchange in patients with thermal injury. One of the major factors that progressively worsen pulmonary gas exchange is airway obstruction. In a previous study, we have shown that there was obstruction with a mean reduction in cross-sectional area of about 29% in bronchi, 11% in bronchioles, and 1.2% in respiratory bronchioles in sheep 48 h after combined burn and smoke inhalation injury (3). Obstructive cast material occludes the lumen of the airway, resulting in hypoventilation or focal loss of ventilation. The blood vessels in the underventilated areas fail to constrict normally, causing a perfusion/ventilation mismatch (4). This transfer of blood from a ventilated area to nonventilated part results in poor oxygenation of arterial blood, which leads to hypoxemic changes in organs. In addition, obstruction of part of the bronchial tree results in hyperventilation of the nonoccluded parts, increasing airway pressure when volume-controlled mechanical ventilation is given (5). The overstretching of the alveoli by high pressure results in mechanical trauma or volutrauma of nonobstructed alveoli, thus worsening oxygenation (6). This overstretching of the alveoli also induces synthesis and secretion of proinflammatory chemokines such as interleukin 8 (7). Therefore, the effective airway toilet with removal of the obstructing materials is important in determining the outcome of patients with thermal injury.
Previously, we have shown that airway obstructing material is composed of fibrin, neutrophils, mucus, and epithelial cell debris, and we reported that prevention of fibrin clot formation in the airways using different anticoagulants such as heparin (8) and antithrombin (9) is beneficial in sheep with smoke inhalation and pneumonia. Unfortunately, none of the above-mentioned anticoagulants have any effect on the already formed fibrin clot. Therefore, we hypothesized that the lysis of this already formed fibrin clot would improve pulmonary gas exchange. In the present study, we demonstrate a beneficial effect of tissue plasminogen activator (TPA) nebulization in acute lung injury induced by combined burn and smoke inhalation injury.
MATERIALS AND METHODS
The model of burn/smoke injury has been described in detail previously (1, 2). Briefly, 24 adult female sheep (30–40 kg) were surgically prepared for the study under halothane anesthesia. To evaluate changes in systemic lymph flow, an efferent lymphatic from the prefemoral lymph node was cannulated (Silastic catheter 0.025-in ID, 0.047-in OD; Dow Corning, Midland, MI). After a 7-day recovery period, the sheep were anesthetized with halothane and were given a burn (40% total body surface area [TBSA], third degree) and inhalation injury (48 breaths of cotton smoke, <40°C). After burn/smoke injury, all sheep were placed on a ventilator with positive end-expiratory pressure set to 5 cm H2O and tidal volume maintained at 15 mL/kg. All animals were provided fluid resuscitation with Ringer’s solution strictly according to the Parkland formula (4 mL/kg/% TBSA burned/24 h). The experiment was continued for 48 h. The sheep were divided randomly into five groups: sham (noninjured, nontreated; n = 6), control (injured, nontreated; n = 6), saline (injured, nebulized with saline; n = 6), TPA 1 mg (injured, nebulized with 1 mg of TPA; n = 6), and TPA 2 mg (injured, nebulized with 2 mg of TPA; n = 6). For treatment, we used recombinant human TPA (Alteplase; Genentech, San Francisco, CA). This compound is clinically used mainly for lysis of acute pulmonary thromboembolism or acute coronary arterial thromboembolism and for maintenance of intravascular catheters. TPA activates plasminogen by converting it into the natural fibrinolytic agent plasmin, thereby breaking the formed fibrin clot. TPA (1 or 2 mg) was nebulized every 4 h by an ultrasonic nebulizer (Misty-Neb; Airlife, Baxter, CA). For the nebulization, 1 or 2 mg of TPA was dissolved in 15 mL of saline. Nebulization was started 4 h after the combined burn and smoke inhalation injury. Sham animals received no injury but were surgically prepared like control and treated animals, placed on a ventilator, and given fluid resuscitation. The saline group was nebulized with 15 mL of saline every 4 h. Activated clotting time was monitored during the experiment (Hemochron, model 801; International Technidyne, Edison, NJ). The Animal Care and Use Committee of the University Texas Medical Branch approved the experimental protocol and all the animals were handled according to guidelines established by the American Physiology Society and the National Institutes of Health.
Arterial and mixed venous blood samples were taken at different time points for measurement of blood gases (Blood gas analyzer 1302 IL; Instrumental Laboratory, Lexington, MA). PaO2/FiO2 ratio was measured to help assess pulmonary gas exchange. The pulmonary microvascular permeability was evaluated by measuring the lung lymph flow. Sheep were sacrificed under deep isoflurane anesthesia 48 h after injury. The right lung was then removed, and a 1-cm-thick section was taken from the middle of lower lobe, injected with 10% formalin, and immersed in formalin. Four tissue samples were taken at predetermined sites for histological examination. Fixed samples were embedded in paraffin, sectioned at 4 μm, and stained with hematoxylin and eosin. A pathologist without knowledge of the group assignments evaluated the lung histology. The pathologist then evaluated all bronchi, bronchioles, and respiratory bronchioles in sections of the four tissue samples, and for each, estimated the percentage of the surface area of the lumen obstructed by cast material (0%–100%) (4). The remaining lower one-half of the right lower lobe was used for the determination of bloodless wet-to-dry weight ratio (10). Pulmonary shunt fraction (Qs/Qt) was calculated using standard equations.
Data are presented as means ± SEM. Results were compared through analysis of variance and either Scheffe’s post hoc test or the unpaired t test. A value of P < 0.05 was accepted as statistically significant.
All animals survived during the 48-h experimental period after the combined injury with 40% TBSA burn and smoke inhalation. Fluid resuscitation strictly followed the Parkland formula. There was no statistically significant difference in the mean arterial carboxyhemoglobin levels measured immediately after smoke exposure between the TPA 2 mg, TPA 1 mg, saline, and injured control groups (67% ± 6%, 64% ± 5%, 58% ± 8%, and 63% ± 8%, respectively). The treatment did not result in a bleeding tendency in any of the groups. The activated clotting time was 161 ± 4 s at baseline, 167 ± 20 s at 24 h, and 164 ± 8 s at 48 h in the TPA 2 mg group and 152 ± 15 s at baseline, 175 ± 17 s at 24 h, and 170 ± 23 s at 48 h in the nebulized saline group. In Figure 1, we showed a photograph of obstructive cast taken 48 h after combined burn and smoke inhalation injury in injured nontreated control sheep. Table 1 shows a comparison of effects of saline or TPA 1 mg nebulization on pulmonary gas exchange (PaO2/FiO2 ratio and Qs/Qt) and pulmonary transvascular fluid flux (lung lymph flow). There was a significant decrease in PaO2/FiO2 and an increase in pulmonary shunt fraction and lung lymph flow in the control group as compared with the sham group at 24, 36, and 48 h after the combined burn and smoke inhalation injury. Saline nebulization had a slight tendency to reverse these variables, but the difference was not statistically significant. Nebulization of 1 mg of TPA also had a tendency to attenuate the changes seen in animals with burn and inhalation injury. The only statistically significant changes noted with the use of nebulized TPA at a dose of 1 mg were found in the PaO2/FiO2 at 36 and 48 h and in pulmonary shunt fraction and lung lymph flow at 36 h, as compared with the control group. However, none of the variables revealed a statistically significant difference between the saline and TPA 1 mg groups.
As a result of this finding, we increased dose of TPA up to 2 mg for each nebulization and compared the results with those of the saline-treated group. Figure 2 shows the effect of TPA 2 mg nebulization on pulmonary gas exchange. PaO2/FiO2 ratio (Fig. 2A) was significantly decreased in animals nebulized with saline as compared with sham animals. Nebulization of 2 mg of TPA attenuated the fall in this variable. Statistically significant differences were observed at 30, 36, 42, and 48 h after insult. An increase in pulmonary shunt fraction (Fig. 2B) seen in the saline group was significantly attenuated by TPA 2 mg nebulization at 36 and 42 h after the combined injury.
Lung lymph flow, a characteristic of pulmonary transvascular fluid flux, was markedly increased in injured, saline nebulized animals compared with the sham group (Fig. 3). The lymph flow began to increase 12 h after the insult and a peak was observed at 42 h (7-fold increase as compared with sham group). However, nebulization of 2 mg of TPA reversed this increase in pulmonary transvascular fluid flux and significant differences were observed between the groups (saline and TPA 2 mg) at 18, 24, 30, 36, 42, and 48 h after the combined injury.
Lung bloodless wet-to-dry weight ratio, a measure of lung water content, was significantly increased at 48 h after insult in the saline group as compared with the sham group (Fig. 4). However, the nebulization of 2 mg of TPA significantly reduced this increase.
The airway obstruction score revealed a significant increase in mean obstruction of bronchi (Fig. 5) in the saline group as compared with the sham group. Treatment with 2 mg TPA significantly reduced the obstruction score.
Figure 6 shows the effect of TPA 2 mg nebulization on the increase in ventilatory pressures. The airway pressures (peak, Fig. 6A; pause, Fig. 6B) were stable in the sham group but were markedly increased in the saline group during the second one-half of the experiment, and the values were almost doubled in those animals 48 h after the insult. However, nebulization of TPA at 2 mg reduced these increases almost to normal levels.
We have previously described the pathophysiology of acute lung injury in sheep with combined burn and smoke inhalation injury (1). An increase in airway blood flow, increased pulmonary vascular permeability, airway obstruction, and pulmonary shunting are major factors that result in pulmonary dysfunction. In the present study, we report the importance of dissolution of fibrin in the maintenance of pulmonary function in the condition of thermal injury associated with smoke inhalation. In Figure 1, we showed a photograph of cast material taken from a sheep with combined burn and smoke inhalation injury. This solid mass of formed cast material nearly 30 cm long can be seen to maintain the shape of the branching airways it occupied. This material is secreted into the airway and forms a solid, gelatinous mass, narrowing or occluding the lumen. Airway obstruction caused by cast material may cause alveolar hypoxia (11) and promote bronchopneumonia. Failure to remove such obstructive cast material can create a life-threatening problem (12, 13). Thus, it is important to clear the airways to maintain adequate pulmonary or extrapulmonary organ function. Because airway obstruction is mainly caused by mucus secretion, airway epithelial cell debris, influx of inflammatory cells, and airway microvascular leakage leading to formation of a fibrin clot (4, 8, 14), pathophysiologic therapy should be designed considering those pathogenic factors. Previously, we have shown that inhibition of inducible nitric oxide synthase (iNOS)-derived excessive NO resulted in reduced airway obstruction by reducing airway blood flow in the same model (3). Using a sepsis model, our colleagues reported a beneficial effect of thrombin inhibitors, which prevent fibrin formation (8, 9). In this sepsis model induced by smoke inhalation and airway instillation of Pseudomonas aeruginosa, airways were obstructed to the same extent as in the present burn and smoke inhalation model (8, 9, 15). Soejima et al. (16) reported that smoke inhalation alone caused the acute lung injury, and the degree of tissue injury is higher in sheep with smoke inhalation alone then those with burn alone (1). Although there are no data showing the effect of smoke inhalation alone on the airway obstruction score in these studies (1, 16), significant increase of ventilatory pressures (peak and pause airway pressures) (17) could suggest that toxic smoke components could contribute to the airway obstruction. However, the combined burn and smoke inhalation induced significantly grater lung injury compared with smoke alone or burn alone groups (1). Thus, we chose the combined burn and smoke inhalation to induce the acute lung injury model in the present study.
Patients who are not immediately treated after burn and inhalation injury often develop airway casts that are hard to remove by tracheobronchial toilet. Therefore, our aim in the present study was to dissolve casts that have already formed using the fibrinolytic agent TPA. To maximally mimic a clinical situation involving delayed treatment of burn and inhalation injury, we started the nebulization of this compound 4 h after the injury. To exclude the effect of the nebulization procedure itself, we first compared the pulmonary variables in groups of injured animals without treatment or treated with nebulization of saline or TPA at 1 mg per dose. As shown in Table 1, saline itself had some positive effects on pulmonary function. The saline nebulization had a slight tendency to improve pulmonary gas exchange, but the differences were not statistically significant as compared with the control group. Nebulization of 1 mg TPA had a better effect, but still there were no statistically significant differences versus the saline group. Therefore, we increased the dose of TPA up to 2 mg and compared the effects with the saline group. The initial (1 mg) dose was chosen considering the recommendation to use the TPA (2 mg/2mL) for reestablishing the patency of occluded intravenous catheters. It was shown that doses of 1 to 2 mg of TPA effectively used for maintenance of central venous catheters (18). In addition, we successfully use TPA (0.5 mg/mL) in our laboratory for restoring of the occluded catheters inserted into lymph vessel. For this purpose, we mix the sheep plasma with TPA. The TPA mixed with sheep plasma also effectively reduced, in vitro, the size of cast material taken from sheep with combined burn and smoke inhalation injury (data not shown), suggesting that recombinant TPA might interact with sheep plasma plasminogen. This possibility should be investigated more precisely in future studies.
In the present study, the saline group of animals showed a typical cardiopulmonary response to burn/smoke injury (1, 3). The pathophysiological changes in those animals were characterized by deterioration of pulmonary gas exchange and a marked increase in pulmonary vascular permeability with formation of lung tissue edema. There was also a dramatic increase in airway obstruction associated with increased airway pressures. Although the exact mechanism remains unknown, the nebulization of the higher dose of TPA reversed these pathological changes.
Several mechanisms may exist by which airway obstruction could contribute to the pathophysiology of acute lung injury in the ovine model of combined burn and smoke inhalation injury. Near total obstruction of a few bronchi would prevent ventilation of individual lung segments (19), whereas partial obstruction would be expected to reduce ventilatory flow, producing hypoxia. Ventilation/perfusion mismatching in occluded areas can result in pulmonary shunt formation leading to poor gas exchange. On the other hand, overventilation of alveolae supplied by airways without obstruction, if mechanical ventilation is present, can cause so called ventilation-induced lung injury or barotrauma (6). In addition, overstretching of the alveolar wall activates proinflammatory cytokines such as interleukin 8 (IL-8) (7), and hypoxia itself also can modulate proinflammatory cytokines (20–22). Narimanbekov et al. (23) demonstrated that hyperventilation increased cytokine-dependent lung injury in rabbits. Cox et al. (4) demonstrated a correlation between the airway obstruction score and pulmonary gas exchange (PaO2/FiO2 ratio) in sheep with combined burn and smoke inhalation injury. The authors showed that the bronchial obstruction score was predictive of PaO2/FiO2 ratio with a correlation coefficient of 0.76. It has been reported that acute hypoxemia, sufficient to produce cyanosis, has been attributed to obstructive casts in patients with inhalation injury (14); removal of the cast was shown to resolve the critical situation and reduce airway pressures almost immediately, returning arterial oxygen tension to normal levels (13). Pruitt et al. (24) suggested that obstructive airway cast after smoke inhalation might promote atelectasis, pneumonia, and barotraumas. Taken together, the results of our present study and these previous studies suggest that airway obstruction may contribute to the acute lung injury in sheep with combined burn and smoke inhalation injury and that clearance of this obstructing cast is crucial in maintaining adequate pulmonary function. The present study suggests a potential therapeutic tool that may help to alleviate the consequences of focal airway obstruction.
Previously, we have shown the pathophysiology of acute lung injury in same model (1) and described some factors that cause lung tissue injury, including excessive nitric oxide and its toxic products such as peroxynitrite, cyclooxygenase products, proinflammatory cell accumulation, and an increase in pulmonary and bronchial microvascular permeability. Thus, we do not exclude that the above-mentioned factors participated in the pathogenesis of lung injury in this model. However, overall, evidence gathered from this study involving the use of TPA nebulization suggests that airway obstruction profoundly contributes to pulmonary function deterioration, worsening the severity of acute lung injury.
Of particular interest, alveolar and interstitial fibrin is found in the acute respiratory distress syndrome (25). An extravascular fibrin deposition characterizes most forms of acute and chronic lung injury (26). In the alveolar space, fibrin or fibrinogen can impair surfactant function (27), thereby contributing to atelectasis. Fibrin and its byproducts can influence migration of macrophages and fibroblasts (28, 29). Both fibrin and fibrinogen provide adhesion sites for inflammatory cells that are recruited to the site of tissue damage (30). Thus, fibrin could cause or worsen the lung injury in a variety of ways. Although we did not determine the fibrin deposition in this study, we do not exclude the possibility that aerosolized TPA may inhibit the fibrin or fibrinogen in alveolar or in interstitial space, thereby ameliorating the pulmonary function. This possibility should be examined in future studies. Darien et al. (31) showed that intravenous injection of heparin improved pulmonary function in porcine model of acute lung injury. Because both intravascular and intra-alveolar fibrin deposits play an important role in pathogenesis of acute respiratory distress syndrome (32, 33), the intravenous administration of TPA also should be considered in future studies.
Taken together, aerosolized TPA could be useful therapeutic agent for managing patients with thermal injury associated with smoke inhalation. Previously, we have shown beneficial effects of various aerosolized anticoagulants in prevention of airway obstruction. However, these anticoagulants have no effect on already formed fibrin clots, which are often present in patients with thermal injury, especially with delayed admission. Clinically used potent fibrinolytic agent, TPA, could be a good candidate for airway management of these patients. The reasonable cost and absence of obvious negative effects on hemostasis, if it aerosolized, raises the significance of this compound.
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