Robert A Cox

University of Texas Medical Branch at Galveston, Galveston, Texas, United States

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Publications (79)268.48 Total impact

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    ABSTRACT: Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS.
    Thorax 06/2014; · 8.38 Impact Factor
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    ABSTRACT: 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. Prospective, randomized, controlled laboratory experiment. University animal research facility. Forty-five chronically instrumented sheep. 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. 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. 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.
    Critical care medicine 03/2014; · 6.37 Impact Factor
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    ABSTRACT: This study measured airway obstruction and bacterial invasion in systematically sampled lung tissue of burn victims at autopsy. Lung tissue from victims of combined smoke inhalation and burn injury (n = 5) and burn injury alone (n = 9) was examined histologically and the degree of bronchial and bronchiolar obstruction was measured. The walls of both bronchi and bronchioles were examined for bacterial invasion. Correlation analysis was performed for the association of airway obstruction with TBSA burn, number of ventilatory days, maximum inspiratory pressure, and days after injury. There was no significant difference in the mean degree of airway obstruction in smoke inhalation and burn victims compared with victims of burn-only injury (P > .05). Increased bronchiolar obstruction scores were detected in victims with pneumonia (55.3 ± 24.2%) compared with victims without pneumonia (9.3 ± 0.2%; P = .03). Bacterial invasion of the bronchial wall was present in one case, and invasion into the walls of bronchioles was seen in five cases. Burned children who died had extensive bronchiolar obstruction whether or not they had smoke inhalation injury. There was bacterial invasion into the airway wall in six of 14 cases (43%). Improved understanding of the mechanisms of airway obstruction is important for improved care of burned children.
    Journal of burn care & research: official publication of the American Burn Association 02/2014; · 1.54 Impact Factor
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    ABSTRACT: Abstract The effects of tiotropium bromide on ERK 1/2, SMAD 2/3 and NFκB signaling in bronchial submucosal gland (SMG) cells of sheep after smoke inhalation and burn injury (S+B) were studied. We hypothesized that tiotropium would modify intracellular signaling processes within SMG cells after injury. Bronchial tissues were obtained from uninjured (sham, n=6), S+B injured sheep 48 h after injury (n=6), and injured sheep nebulized with tiotropium (n=6). The percentage (mean ± SD) of cells showing nuclear localization of phosphorylated ERK 1/2, pSMAD 2/3, and NFkB (p65) was determined by immunohistochemistry. Nuclear pERK 1/2 staining was increased in injured animals as compared to sham, (66 ± 20 vs 14 ± 9), p = 0.0022, as was nuclear pSMAD, 84 ±10 vs 20 ±10, p = 0.0022. There was a significant decrease in pERK 1/2 labeling in the tiotropium group compared to the injured group (31 ± 20 vs 66 ± 20, p = 0.013), and also a decrease in pSMAD labeling, 62 ± 17 vs 84 ±10, p = 0.04. A significant increase for NFkB (p65) was noted in injured animals as compared to sham (73 ±16 vs 7 ±6, p = 0.0022). Tiotropium treated animals showed decreased p65 labeling as compared to injured (35 ± 17 vs 74 ± 16, p = 0.02). The decrease in nuclear expression of pERK, pSMAD and NFkB molecules in SMG cells with tiotropium treatment is suggestive that their activation after injury is mediated in part through muscarinic receptors.
    Toxicology mechanisms and methods 01/2014; · 1.37 Impact Factor
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    ABSTRACT: Pulmonary coagulopathy has become an important therapeutic target in adult respiratory distress syndrome (ARDS). We hypothesized that combining intravenous recombinant human antithrombin (rhAT), nebulized heparin, and nebulized tissue plasminogen activator (TPA) more effectively improves pulmonary gas exchange compared with a single rhAT infusion, while maintaining the anti-inflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. Following burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn, and 4 × 12 breaths of cold cotton smoke), 18 chronically instrumented sheep were randomly assigned to receive intravenous saline plus saline nebulization (control), intravenous rhAT (6 IU/kg/h) started 1 hour after injury plus saline nebulization (AT i.v.) or intravenous rhAT combined with nebulized heparin (10,000 IU every 4 hours, started 2 hours after injury), and nebulized TPA (2 mg every 4 hours, started 4 hours after injury) (triple therapy, n = 6 each). All animals were mechanically ventilated and fluid resuscitated according to standard protocols during the 48-hour study period. Both treatment approaches attenuated ARDS compared with control animals. Notably, triple therapy was associated with an improved PaO2/FiO2 ratio (p = 0.007), attenuated pulmonary obstruction (p = 0.02) and shunting (p = 0.025), as well as reduced ventilatory pressures (p < 0.05 each) versus AT i.v. at 48 hours. However, the anti-inflammatory effects of sole AT i.v., namely, the inhibition of neutrophil activation (neutrophil count in the lymph and pulmonary polymorphonuclear cells, p < 0.05 vs. control each), pulmonary transvascular fluid flux (lymph flow, p = 0.004 vs. control), and systemic vascular leakage (cumulative net fluid balance, p < 0.001 vs. control), were abolished in the triple therapy group. Combining intravenous rhAT with nebulized heparin and nebulized TPA more effectively restores pulmonary gas exchange, but the anti-inflammatory effects of sole rhAT are abolished with the triple therapy. Interferences between the different anticoagulants may represent a potential explanation for these findings.
    The journal of trauma and acute care surgery. 01/2014; 76(1):126-33.
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    ABSTRACT: ABSTRACT Fire victims often suffer from burn injury and concomitant inhalation trauma, the latter significantly contributing to the morbidity and mortality in these patients. Measurement of blood carboxyhemoglobin levels has been proposed as a diagnostic marker to verify and, perhaps, quantify the degree of lung injury following inhalation trauma. However, this correlation has not yet been sufficiently validated. A total of 77 chronically instrumented sheep received sham injury, smoke inhalation injury, or combined burn and inhalation trauma following an established protocol. Arterial carboxyhemoglobin concentrations were determined directly after injury and correlated to several clinical and histopathological determinants of lung injury that were detected 48 hours post-injury. The injury induced severe impairment of pulmonary gas exchange and increases in transvascular fluid flux, lung water content, and airway obstruction scores. No significant correlations were detected between initial carboxyhemoglobin levels and all measured clinical and histopathological determinants of lung injury. In conclusion, the amount of arterial carboxyhemoglobin concentration cannot predict the degree of lung injury at 48 hours after ovine burn and smoke inhalation trauma.
    Experimental Lung Research 12/2013; · 1.47 Impact Factor
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    ABSTRACT: 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. Randomized controlled laboratory experiment. University animal research facility. Eighteen chronically instrumented sheep. 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. 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. 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.
    Critical care medicine 10/2013; · 6.37 Impact Factor
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    ABSTRACT: Burns are associated with hyperglycemia leading to increased incidence of infections with pneumonia being one of the most prominent and adverse complications. Recently, various studies in critically ill patients indicated that increased pulmonary glucose levels with airway/blood glucose threshold over 150mg/dl lead to an overwhelming growth of bacteria in the broncho-pulmonary system, subsequently resulting in an increased risk of pulmonary infections. The aim of the present study was to determine whether a similar cutoff value exists for severely burned pediatric patients. One-hundred six severely burned pediatric patients were enrolled in the study. Patients were divided in two groups: high (H) defined as daily average glucose levels >75% of LOS >150mg/dl), and low (L) with daily average glucose levels >75% of the LOS <150mg/dl). Incidences of pneumonia, atelectasis, and acute respiratory distress syndrome (ARDS) were assessed. Incidence of infections, sepsis, and respiratory parameters were recorded. Blood was analyzed for glucose and insulin levels. Statistical analysis was performed using Student's t-test and chi-square test. Significance was set at p<0.05. Patient groups were similar in demographics and injury characteristics. Pneumonia in patients on the mechanical ventilation (L: 21%, H: 32%) and off mechanical ventilation (L: 5%, H: 15%), as well as ARDS were significantly higher in the high group (L: 3%, H: 19%), p<0.05, while atelectasis was not different. Patients in the high group required significantly longer ventilation compared to low patients (p<0.05). Furthermore, incidence of infection and sepsis were significantly higher in the high group, p<0.05. Our results indicate that systemic glucose levels over 150mg/dl are associated with a higher incidence of pneumonia confirming the previous studies in critically ill patients.
    Burns: journal of the International Society for Burn Injuries 09/2013; · 1.95 Impact Factor
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    ABSTRACT: To investigate the efficacy of sea buckthorn (SBT) seed oil - a rich source of substances known to have anti-atherogenic and cardioprotective activity, and to promote skin and mucosa epithelization - on burn wound healing, five adult sheep were subjected to 3rd degree flame burns. Two burn sites were made on the dorsum of the sheep and the eschar was excised down to the fascia. Split-thickness skin grafts were harvested, meshed, and fitted to the wounds. The autograft was placed on the fascia and SBT seed oil was topically applied to one recipient and one donor site, respectively, with the remaining sites treated with vehicle. The wound blood flow (LASER Doppler), and epithelization (ultrasound) were determined at 6, 14, and 21 days after injury. 14 days after grafting, the percentage of epithelization in the treated sites was greater (95±2.2% vs. 83±2.9%, p<0.05) than in the untreated sites. Complete epithelization time was shorter in both treated recipient and donor sites (14.20±0.48 vs. 19.60±0.40 days, p<0.05 and 13.40±1.02 vs. 19.60±0.50 days, p<0.05, respectively) than in the untreated sites, confirmed by ultrasound. In conclusion, SBT seed oil has significant wound healing activity in full-thickness burns and split-thickness harvested wounds.
    Burns: journal of the International Society for Burn Injuries 09/2013; · 1.95 Impact Factor
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    ABSTRACT: INTRODUCTION: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following 40% of total body surface area, 3rd degree flame burn and 4x12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IUkg-1h-1 recombinant human antithrombin (rhAT) or normal saline (control group; n=6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas RESULTS: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4000ml at the end of the study period. Contrary, in rhAT-treated animals there was only an initial fluid accumulation until 24h that was reversed back to the level of sham animals during the second day. CONCLUSIONS: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.
    Critical care (London, England) 05/2013; 17(3):R86. · 4.72 Impact Factor
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    ABSTRACT: ABSTRACT Large animal models are valuable tools in biological and medical lung research. Despite the existence of established large animal models, the scientific progress requires more detailed description and expansion of established methods. Previously, we established an ovine model of acute lung injury and subsequent bacterial instillation into the lungs. The current study was designed to assess the time course of early lung histopathological alterations in a large animal model. Injury was induced by smoke inhalation and instillation of live Pseudomonas aeruginosa into the lungs. After 4, 8, 12, 18, and 24 hours, respectively, lung tissue was harvested and histopathological changes were evaluated (n = 4 each). Additional four sheep received no injury and only lung tissue was taken. In injured animals, bronchial obstruction score increased over time and was significantly elevated from 12 to 24 hours (P < .05 versus no injury). Inflammation score was significantly increased at 12 and 18 hours (P < .05 versus no injury). Hemorrhage score was increased at 8 and 12 hours (P < .05 versus no injury). Alveolar edema score was significantly higher in injured sheep at 8, 18, and 24 hours (P < .05 each versus no injury). In conclusion, bronchial obstruction and alveolar edema scores significantly increased over time and reached a plateau, while both inflammation and hemorrhage scores were transiently increased peaking around the 12-hour time point. This information improves the understanding of lung histopathological alterations following acute lung injury and pulmonary infection and may help optimizing the timing of study interventions and evaluation time points in future experiments with this model.
    Experimental Lung Research 05/2013; · 1.47 Impact Factor
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    ABSTRACT: More than 20,000 burn injury victims suffer from smoke inhalation injury in the United States annually. In an ovine model of acute lung injury, γ-tocopherol had a beneficial effect when nebulized into the airway. We hypothesize that γ-tocopherol scavenges reactive oxygen species (ROS) and reactive nitrogen species resulting from burn and smoke inhalation injury and that these ROS/reactive nitrogen species activate the arginase pathway, leading to increased collagen deposition and decreased pulmonary function. To test this hypothesis, ewes were operatively prepared for chronic study, then they were randomly divided into groups (n = 8): uninjured, injured, or injured with nebulization (γ-tocopherol [950 mg/g] and α-tocopherol [40 mg/g] from hours 3 to 48 after the injury). The injury, under deep anesthesia, consisted of a 20% total body surface burn and 36 breaths of cotton smoke; all animals were killed after 3 weeks. Treatment increased lung γ-tocopherol at 3 weeks after γ-tocopherol nebulization compared with injured sheep (1.75 ± 0.62 nmol/g vs. 0.45 ± 0.06, P < 0.05). The expression of dimethylarginine dimethylaminohydrolase-2, which degrades asymmetrical dimethylarginine, a nitric oxide synthase inhibitor, significantly increases with γ-tocopherol treatment compared with injured sheep (P < 0.05). Arginase activity (0.15 ± 0.02 μM urea/μg protein vs. 0.24 ± 0.009, P < 0.05), ornithine aminotransferase (11,720 ± 888 vs. 13,170 ± 1,775), and collagen deposition (0.62 ± 0.12 μM hydroxyproline/μg protein vs. 1.02 ± 0.13, P < 0.05) significantly decrease with γ-tocopherol compared with injured animals without γ-tocopherol. The decreases in arginase and collagen with γ-tocopherol are associated with significantly increased diffusion capacity (P < 0.05) and decreased lung wet-to-dry ratio (P < 0.05). Smoke-induced chronic pulmonary dysfunction is mediated through the ROS/asymmetrical dimethylarginine/arginase pathway, and ROS scavengers such as γ-tocopherol may be a potential therapeutic management of burn patients with inhalation injury.
    Shock (Augusta, Ga.) 12/2012; 38(6):671-6. · 2.87 Impact Factor
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    ABSTRACT: The objective of this study is to measure the temporal changes in bronchial submucosal gland (SMG) cell proliferation in sheep after smoke inhalation and burn (SB) injury, and to assess the effect of bronchodilators on the proliferative response. Archived main bronchial airways from sheep after SB injury were immunostained for Ki67, and the percentage of ciliated duct and SMG cells expressing nuclear localization of Ki67 was determined for uninjured sheep and in sheep 24, 48, 72, and 96 hours after injury. A semiquantitative measure of lining epithelial exfoliation was made for each tissue. Bronchial tissues from sheep at 48 hours after SB injury that had been nebulized with albuterol or tiotropium bromide (tiotropium) were examined to assess the effect of bronchodilators on the proliferative response. At 48 through 96 hours after injury, both ciliated duct and SMG cell proliferation were significantly increased compared with that of uninjured animals and animals 24 hours after injury, P <.05. A small increase in proliferation was seen in the SMG cells of albuterol-treated sheep compared with nebulized saline controls, P = .048. SMG cells of tiotropium-treated animals showed a significant increase in Ki67 nuclear staining compared with their study controls, P = .001. Extensive injury to the lining epithelium is associated with a proliferative response in both ciliated duct and SMG cells 24 hours after injury. The increase in proliferation in sheep treated with bronchodilators suggests that therapies for inhalation injury modify the glandular proliferative response. Further study to assess the ability of bronchodilators to enhance epithelial repair is warranted.
    Journal of burn care & research: official publication of the American Burn Association 10/2012; · 1.54 Impact Factor
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    ABSTRACT: Vasopressin analogues are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Since V2-receptor stimulation induces vasodilation and procoagulant effects, a higher V1a- vs. V2-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V1a-agonist Phe2-Orn8-Vasotocin (POV) is more effective than the mixed V1a-/V2-agonist arginine vasopressin (AVP) for the treatment of vascular and cardiopulmonary dysfunction in MRSA pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP or saline solution (control, each n=6). AVP and POV were titrated to maintain mean arterial pressure above baseline-10mmHg. Compared to control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight-ratio, alveolar and septal edema). However, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, vascular endothelial growth factor and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV: 9±15mL•kg-1 vs. AVP: 110±13mL•kg-1 vs. control: 213±16mL•kg-1, p<0,001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO2/FiO2 ratio) vs. control animals. Highly selective V1a-agonism appears to be superior to unselective vasopressin analogues for the treatment of sepsis-induced vascular dysfunction.
    AJP Heart and Circulatory Physiology 09/2012; · 4.01 Impact Factor
  • The journal of trauma and acute care surgery. 04/2012; 72(4):1121-2; author reply 1122-3.
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    ABSTRACT: Smoke inhalation injury frequently increases the risk of pneumonia and mortality in burn patients. The pathophysiology of acute lung injury secondary to burn and smoke inhalation is well studied, but long-term pulmonary function, especially the process of lung tissue healing following burn and smoke inhalation, has not been fully investigated. By contrast, early burn excision has become the standard of care in the management of major burn injury. While many clinical studies and small-animal experiments support the concept of early burn wound excision, and show improved survival and infectious outcomes, we have developed a new chronic ovine model of burn and smoke inhalation injury with early excision and skin grafting that can be used to investigate lung pathophysiology over a period of 3 weeks. Eighteen female sheep were surgically prepared for this study under isoflurane anesthesia. The animals were divided into three groups: an Early Excision group (20% TBSA, third-degree cutaneous burn and 36 breaths of cotton smoke followed by early excision and skin autografting at 24h after injury, n=6), a Control group (20% TBSA, third-degree cutaneous burn and 36 breaths of cotton smoke without early excision, n=6) and a Sham group (no injury, no early excision, n=6). After induced injury, all sheep were placed on a ventilator and fluid-resuscitated with Lactated Ringers solution (4 mL/% TBS/kg). At 24h post-injury, early excision was carried out to fascia, and skin grafting with meshed autografts (20/1000 in., 1:4 ratio) was performed under isoflurane anesthesia. At 48 h post-injury, weaning from ventilator was begun if PaO(2)/FiO(2) was above 250 and sheep were monitored for 3 weeks. At 96 h post-injury, all animals were weaned from ventilator. There are no significant differences in PaO(2)/FiO(2) between Early Excision and Control groups at any points. All animals were survived for 3 weeks without infectious complication in Early Excision and Sham groups, whereas two out of six animals in the Control group had abscess in lung. The percentage of the wound healed surviving area (mean ± SD) was 74.7 ± 7.8% on 17 days post-surgery in the Early Excision group. Lung wet-to-dry weight ratio (mean ± SD) was significantly increased in the Early Excision group vs. Sham group (p<0.05). The calculated net fluid balance significantly increased in the early excision compared to those seen in the Sham and Control groups. Plasma protein, oncotic pressure, hematocrit of % baseline, hemoglobin of % baseline, white blood cell and neutrophil were significantly decreased in the Early Excision group vs. Control group. The early excision model closely resembles practice in a clinical setting and allows long-term observations of pulmonary function following burn and smoke inhalation injury. Further studies are warranted to assess lung tissue scarring and measuring collagen deposition, lung compliance and diffusion capacity.
    Burns: journal of the International Society for Burn Injuries 03/2012; 38(6):908-16. · 1.95 Impact Factor
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    ABSTRACT: The formation of oxidative stress in the lung and activation of neutrophils are major determinants in the development of respiratory failure after acute lung injury and sepsis. However, the time changes of these pathogenic factors have not been sufficiently described. Twenty-four chronically instrumented sheep were subjected to cotton smoke inhalation injury and instillation of live Pseudomonas aeruginosa into both lungs. The sheep were euthanized at 4, 8, 12, 18, and 24 h after injury. Additional sheep received sham injury and were euthanized after 24 h. Pulmonary function was assessed by determination of oxygenation index and pulmonary shunt fraction. In addition, lung tissue was harvested at the respective time points for the measurement of malondialdehyde, interleukin 6, poly(ADP ribose), myeloperoxidase, and alveolar polymorphonuclear neutrophil score. The injury induced severe respiratory failure that was associated with an early increase in lipid peroxidation and interleukin 6 expression. The injury further led to an increase in poly(ADP ribose) activity that reached its peak at 12 h after injury and declined afterward. In addition, progressive increases in markers of neutrophil accumulation in the lung were observed. The peak of neutrophil accumulation in the lung was associated with a severe depletion of circulating neutrophils. The results from our model may enhance the understanding of the pathophysiological alterations after acute lung injury and sepsis and thus be useful in exploring therapeutic interventions directed at modifying the expression or activation of inflammatory mediators.
    Shock (Augusta, Ga.) 01/2012; 37(5):468-72. · 2.87 Impact Factor
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    ABSTRACT: We hypothesize that the nebulization of γ-tocopherol (g-T) in the airway of our ovine model of acute respiratory distress syndrome will effectively improve pulmonary function following burn and smoke inhalation after 96 h. Adult ewes (n = 14) were subjected to 40% total body surface area burn and were insufflated with 48 breaths of cotton smoke under deep anesthesia, in a double-blind comparative study. A customized aerosolization device continuously delivered g-T in ethanol with each breath from 3 to 48 h after the injury (g-T group, n = 6), whereas the control group (n = 5) was nebulized with only ethanol. Animals were weaned from the ventilator when possible. All animals were killed after 96 h, with the exception of one untreated animal that was killed after 64 h. Lung g-T concentration significantly increased after g-T nebulization compared with the control group (38.5 ± 16.8 vs. 0.39 ± 0.46 nmol/g, P < 0.01). The PaO(2)/FIO(2) ratio was significantly higher after treatment with g-T compared with the control group (310 ± 152 vs. 150 ± 27.0, P < 0.05). The following clinical parameters were improved with g-T treatment: pulmonary shunt fraction, peak and pause pressures, lung bloodless wet-to-dry weight ratios (2.9 ± 0.87 vs. 4.6 ± 1.4, P < 0.05), and bronchiolar obstruction (2.0% ± 1.1% vs. 4.6% ± 1.7%, P < 0.05). Nebulization of g-T, carried by ethanol, improved pulmonary oxygenation and markedly reduced the time necessary for assisted ventilation in burn- and smoke-injured sheep. Delivery of g-T into the lungs may be a safe, novel, and efficient approach for management of acute lung injury patients who have sustained oxidative damage to the airway.
    Shock (Augusta, Ga.) 01/2012; 37(4):408-14. · 2.87 Impact Factor
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    ABSTRACT: This study tests the hypothesis that muscarinic receptor antagonist therapy with tiotropium bromide (tiotropium; TIO), alone or in combination with tissue plasminogen activator (TPA), can attenuate pulmonary dysfunction in sheep after smoke inhalation and burn injury. The study consisted of four study groups, sham (uninjured), control (injured and untreated), TIO (injured and treated with nebulized TIO), and TIO + TPA (injured and treated with nebulized TIO and TPA). Cardiopulmonary and ventilatory parameters were monitored for 48 hours. After killing the animal, airway obstruction, submucosal gland neutrophilia, parenchyma histopathology, and lung wet to dry weight ratios were measured. PaO2/FiO2 was significantly improved in the TIO group compared with the control group at 48 hours, 301 ± 149 vs 99 ± 33, respectively, P < .05. At 48 hours, peak airway pressures in the control, TIO, and TIO + TPA groups were 35 ± 6, 24 ± 7, and 26 ± 10, respectively, with the mean of the TIO group being significantly different from that of the control group, P < .05. A trend of decreased airway obstruction was seen in the treated animals compared with controls; however, the differences were not statistically significant. The TIO and TIO + TPA groups exhibited significant decreases in gland neutrophilia compared with the control group, P < .05. No differences in parenchyma histopathology and lung edema between injured control and treated groups were observed. Nebulization of TIO was effective in improving pulmonary performance and reducing bronchial submucosal gland neutrophilia in sheep after smoke inhalation and burn injury. There was no additive benefit to the inclusion of nebulized TPA with TIO.
    Journal of burn care & research: official publication of the American Burn Association 12/2011; 33(4):524-31. · 1.54 Impact Factor
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    ABSTRACT: Bronchial circulation plays a critical role in the pathophysiology of burn and smoke inhalation-induced acute lung injury. A 10-fold increase in bronchial blood flow is associated with excessive production of nitric oxide (NO) following smoke inhalation and cutaneous burn. Because an increased release of neuropeptides from the airway has been implicated in smoke inhalation injury, we hypothesized that direct delivery into the bronchial artery of low-dose 7-nitroindazole (7-NI), a specific neuronal NO synthase inhibitor, would attenuate smoke/burn-induced acute lung injury. Eighteen adult female sheep were instrumented for chronic hemodynamic monitoring 5 to 7 days before the injury. The bronchial artery was cannulated via intercostal thoracotomy, while blood flow was preserved. Acute lung injury was induced by 40% total body surface area third-degree cutaneous burn and smoke inhalation (48 breaths of cotton smoke, <40°C) under deep anesthesia. Following injury, animals (35.4 ± 1.1 kg) were divided into three groups: (a) 7-NI group: 1 h after injury, 7-NI (0.01 mg · kg · h, 2 mL · h) was continuously infused into the bronchial artery, n = 6; (b) control group: 1 h after injury, same amount of saline was injected into the bronchial artery, n = 6; (c) sham group: no injury, no treatment, same operation and anesthesia, n = 6. After injury, all animals were ventilated and fluid resuscitated according to an established protocol. The experiment was conducted for 24 h. Injury induced severe pulmonary dysfunction, which was associated with increases in lung edema formation, airway obstruction, malondialdehyde, and nitrate/nitrite. 7-Nitroindazole injection into the bronchial artery reduced the degree of lung edema formation and improved pulmonary gas exchange. The increase in malondialdehyde and nitrate/nitrite in lung tissue was attenuated by treatment. Our data strongly suggest that local airway production of NO contributes to pulmonary dysfunction following smoke inhalation and burn injury. Most mechanisms that drive this pathophysiology reside in the airway.
    Shock (Augusta, Ga.) 12/2011; 36(6):575-9. · 2.87 Impact Factor

Publication Stats

965 Citations
268.48 Total Impact Points

Institutions

  • 2002–2014
    • University of Texas Medical Branch at Galveston
      • • Department of Anesthesiology
      • • Department of Pathology
      Galveston, Texas, United States
  • 2013
    • Tokyo Women's Medical University
      • Department of Plastic and Reconstructive Surgery
      Edo, Tōkyō, Japan
  • 2002–2013
    • Shriners Hospitals for Children
      Tampa, Florida, United States
  • 2012
    • Oregon State University
      Corvallis, Oregon, United States
  • 2006–2012
    • University of California, Davis
      Davis, California, United States
  • 2011
    • Tokyo Woman's Christian University
      Edo, Tōkyō, Japan
  • 2008
    • University of Münster
      • Department of Anaesthesiology and Intensive Care
      Münster, North Rhine-Westphalia, Germany