Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have "systemic inflammatory response syndrome." Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.

In this study we examined the role of inducible nitric oxide synthase (iNOS) in acute respiratory distress syndrome (ARDS) in sheep with severe combined burn and smoke inhalation injury. BBS-2, a potent and highly selective iNOS dimerization inhibitor, was used to exclude effects on the endothelial and neuronal NOS isoforms. Seven days after surgical recovery, sheep were given a burn (40% of total body surface, 3rd degree) and insufflated with cotton smoke (48 breaths, < 40 degrees C) under anesthesia. BBS-2 was provided by constant infusion at 100 microg/kg/hour, beginning 1 hour after injury. During 48 hours, control sheep developed multiple signs of ARDS. These included decreased pulmonary gas exchange, increased pulmonary edema, abnormal lung compliance, and extensive airway obstruction. These pathologies were associated with a large increase in tracheal blood flow and elevated plasma NO2-/NO3- (NOx) levels. These variables were all stable in sham animals. Treatment of injured sheep with BBS-2 attenuated the increases in tracheal blood flow and plasma NOx levels, and significantly attenuated all the pulmonary pathologies that were noted. The results provide definitive evidence that iNOS is a key mediator of pulmonary pathology in sheep with ARDS resulting from combined burn and smoke inhalation injury.

Smoke inhalation injury continues to increase morbidity and mortality in burn patients in both the third world and industrialized countries. The lack of uniform criteria for the diagnosis and definition of smoke inhalation injury contributes to the fact that, despite extensive research, mortality rates have changed little in recent decades. The formation of reactive oxygen and nitrogen species, as well as the procoagulant and antifibrinolytic imbalance of alveolar homeostasis, all play a central role in the pathogenesis of smoke inhalation injury. Further hallmarks include massive airway obstruction owing to cast formation, bronchospasm, the increase in bronchial circulation and transvascular fluid flux. Therefore, anticoagulants, antioxidants and bronchodilators, especially when administered as an aerosol, represent the most promising treatment strategies. The purpose of this review article is to provide an overview of the pathophysiological changes, management and treatment options of smoke inhalation injury based on the current literature.

This animal model closely resembles hyperdynamic sepsis in humans and may be of great value for studies of sepsis with smoke inhalation.

Background 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. Methods Adult sheep (30–40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.5×1011 CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer’s solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5×106 hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×106 hMSCs/kg, n=4. Results By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 97±15 mm Hg; lower dose: 288±55 mm Hg (p=0.003); higher dose: 327±2 mm Hg (p=0.003)). The median lung water content was lower in the higher-dose hMSC-treated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9–5.8] vs control: 6.7 g wet/g dry [IQR 6.4–7.5] (p=0.01)). The hMSCs had no adverse effects. Conclusions Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS. Trail registration number NCT01775774 for Phase 1. NCT02097641 for Phase 2.

Patients with severe burn and/or smoke inhalation injury suffer both systemic and pulmonary vascular hyperpermeability. We hypothesized that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) plays a role in the changes in microvascular permeability seen with this injury. To test the hypothesis, we administered mercaptoethylguanidine (MEG), a selective iNOS inhibitor, to conscious sheep subjected to a combined smoke inhalation and third-degree burn injury to 40% of total body surface area. The sheep were surgically prepared for chronic study with lung and prefemoral lymph fistulas in order to estimate microvascular permeability. Both the groups and a control group of animals showed an increase in iNOS protein and message in their lungs. The control animals showed significant increases in either plasma or lymph NO2-/NO3- (NOx) concentration at 24 h after injury, with associated cardiac depression and hemoconcentration. The airway epithelium stained for nitrotyrosine. In the treatment group, NOx did not increase significantly in plasma or lymph throughout the experiment, there was no nitrotyrosine staining, hemodynamic depression was not observed, and the fluid requirement was significantly less than in the control group. Changes in pulmonary microvascular permeability were significantly suppressed by inhibition of iNOS. However, there was no significant difference between the two study groups in the microvascular permeability of burned tissue. These data suggest that NO produced by iNOS plays an important role in the changes in systemic and pulmonary microvascular permeability in combined smoke inhalation/third-degree burn injury, but does not affect the vascular permeability of third-degree-burned tissue in this type of injury.

Acute lung injury results in a severe inflammatory response, which leads to priming and activation of leucocytes, release of reactive oxygen and reactive nitrogen species, destruction of pulmonary endothelium, extravasation of protein-rich fluid into the interstitium and formation of oedema. Recently, H2S (hydrogen sulfide) has been shown to decrease the synthesis of pro-inflammatory cytokines, reduce leucocyte adherence to the endothelium and subsequent diapedesis of these cells from the microvasculature in in vivo studies, and to protect cells in culture from oxidative injury. In the present study, we hypothesized that a parenteral formulation of H2S would reduce the lung injury induced by burn and smoke inhalation in a novel murine model. H(2)S post-treatment significantly decreased mortality and increased median survival in mice. H2S also inhibited IL (interleukin)-1beta levels and significantly increased the concentration of the anti-inflammatory cytokine IL-10 in lung tissue. Additionally, H2S administration attenuated protein oxidation following injury and improved the histological condition of the lung. In conclusion, these results suggest that H2S exerts protective effects in acute lung injury, at least in part through the activation of anti-inflammatory and antioxidant pathways.

Pseudomonas pneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (<40 degrees C) were inflated into the airway. Afterwards, live Pseudomonas aeruginosa (5 x 10(11) CFU) was instilled into the lung. All sheep were mechanically ventilated with 100% O2 and were divided into four groups: a heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300 U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.