Pulmonary injury from smoke inhalation is common in burn victims, significantly contributing to the morbidity and mortality of fire-related injuries. The impacts of improvement in other aspects of burn care have not been mirrored in treatment of smoke inhalation. Smoke is heterogeneous and unique to each fire; it comprises particulates, respiratory irritants and systemic toxins as well as heat, all contributing to the pathological insult. Thermal injury below the vocal cords is rare because of effective heat dissipation in the upper airway. Particulate matter is the chief contributor to the pathophysiology of smoke inhalation injury, which has been extensively described. Of paramount importance is the cascade of inflammatory mediators following interaction of irritant substances with lung parenchyma, leading to pulmonary oedema, cast formation, airway obstruction, loss of hypoxic pulmonary vasoconstriction and ventilation/perfusion mismatch. Current treatment is based on supportive care, with airway management, mechanical ventilation, humidification and aggressive airway toilet the mainstays. Nebulisation of n2-agonists, heparin and N-acetylcysteine have a role in management, as does more specific treatment of carbon monoxide or cyanide intoxication. Many promising treatments are currently under investigation. The therapeutic strategy of decontaminating the lungs early after smoke exposure to prevent inhalation injury has received little attention and may be of significant value. This could potentially utilise amphoteric, hypertonic chelating agents developed for topical and ocular chemical exposures.

Management of acute smoke inhalation injury

Background and Objectives  Even with the introduction of specific risk-reduction strategies, transfusion-related acute lung injury (TRALI) continues to be a leading cause of transfusion-related morbidity and mortality. Existing small animal models have not yet investigated TRALI resulting from the infusion of heat-treated supernatant from whole blood platelet concentrates. In this study, our objective was the development of a novel in vivo two-event model of TRALI in sheep.



Materials and Methods  Lipopolysaccharide (LPS; 15 μg/kg) as a first event, modelled clinical infection. Transfusion (estimated at 10% of total blood volume) of heat-treated pooled supernatant from date-of-expiry human whole blood platelet concentrates (d5-PLT-S/N) was used as a second event. TRALI was defined by both hypoxaemia that developed either during the transfusion or within two hours of its completion and post-mortem histological evidence of pulmonary oedema.



Results  LPS infusion did not cause lung injury itself, but did result in decreased circulating levels of lymphocytes and neutrophils with evidence of the latter becoming sequestered in the lungs. Sheep that received LPS (first event) followed by d5-PLT-S/N (second event) displayed decreased pulmonary compliance, decreased end tidal CO2 and increased arterial partial pressure of CO2 relative to control sheep, and 80% of these sheep developed TRALI.



Conclusions  This novel ovine two-event TRALI model presents a new tool for the investigation of TRALI pathogenesis. It represents the first description of an in vivo large animal model of TRALI and the first description of TRALI caused by transfusion with heat-treated pooled supernatant from human whole blood platelet concentrates.

A novel in vivo ovine model of transfusion-related acute lung injury (TRALI)

Acute respiratory distress syndrome (ARDS) is an inflammatory process caused by a variety of direct and indirect injuries to the lungs Despite improvements in supportive care and advances in ventilator management, mortality in patients with ARDS remains high Multiple pharmacological interventions have been investigated but have not shown improved survival Clinical trials using corticosteroids, prostaglandins, nitric oxide, prostacyclin, surfactant, lisofylline, ketoconazole, N -acetylcysteine, and fish oil have been unable to show a statistically significant improvement in patient mortality As more is understood about the pathophysiology of ARDS, treatment strategies such as increasing alveolar fluid clearance through activation of sodium channels, enhancing repair of alveolar epithelium with growth factors, inhibiting fibrin deposition, blocking proinflammatory transcription factors, preventing the effect of potent vasocontrictors such as endothelin, and using antibodies against key inflammatory cytokines are being explored This review focuses on the pharmacological treatments studied clinically, proposed reasons for their lack of success, and new concepts emerging in ARDS therapy

Pharmacological Therapy for Acute Respiratory Distress Syndrome

Rationale: Endothelin-1 (ET-1) is increased in patients with high-altitude pulmonary edema and acute respiratory distress syndrome, and these patients have decreased alveolar fluid reabsorption (AFR).Objectives: To determine whether ET-1 impairs AFR via activation of endothelial cells and nitric oxide (NO) generation.Methods: Isolated perfused rat lung, transgenic rats deficient in ETB receptors, coincubation of lung human microvascular endothelial cells (HMVEC-L) with rat alveolar epithelial type II cells or A549 cells, ouabain-sensitive 86Rb+ uptake.Measurements and Main Results: The ET-1–induced decrease in AFR was prevented by blocking the endothelin receptor ETB, but not ETA. Endothelial–epithelial cell interaction is required, as direct exposure of alveolar epithelial cells (AECs) to ET-1 did not affect Na,K-ATPase function or protein abundance at the plasma membrane, whereas coincubation of HMVEC-L and AECs with ET-1 decreased Na,K-ATPase activity and protein abundance at the plasma membrane. Expos...

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Endothelin-1 impairs alveolar epithelial function via endothelial ETB receptor.

An ovine model of smoke inhalation and burn (S+B) injury models the pathophysiology of these injuries in humans. This study examines the degree of airway obstruction, associated histopathology, and bronchial gland cell expression of cytokines during the first 24 hours after S+B injury in sheep. Changes in the mean degree of obstruction were limited to the bronchial airways, showing significant increases in obstruction with time, P<.05. At 4 hours after injury, the obstructive material was predominantly mucus, with neutrophils clustered around and within gland acini. At 8 to 24 hours, bronchial obstruction was characterized by increased inflammatory cell accumulation. Immunohistochemical results showed that gland cells constitutively express and secrete interleukin (IL)-1beta, and that after injury there is an increase in the percentage of gland cells staining for IL-1alpha, IL-8, and tumor necrosis factor (TNF)-alpha, P<.05.

Acute bronchial obstruction in sheep: histopathology and gland cytokine expression.

Studies have suggested that ET-1 (endothelin-1) is associated with lung injury, airway inflammation and increased vascular permeability. In the present study we have tested the hypothesis that treatment with a dual ET-1 receptor antagonist will decrease airway obstruction and improve pulmonary function in sheep with combined S+B (smoke inhalation and burn) injury. Twelve sheep received S+B injury using the following protocol: six sheep were treated with tezosentan, an ETA and ETB receptor antagonist, and six sheep received an equivalent volume of vehicle. Physiological and morphological variables were assessed during the 48 h study period and at the end of the study. There was no statistically significant difference in the PaO2/FiO2 (partial pressure of O2 in arterial blood/fraction of O2 in the inspired gas) ratio of the tezosentan-treated animals compared with controls; however, lung lymph flow was significantly higher (P<0.05) in the treated animals. PVRI (pulmonary vascular resistance index) was significantly reduced (P<0.05) in the tezosentan-treated animals. Assessment of NOx (nitric oxide metabolite) levels in plasma and lymph showed significantly elevated (P<0.05) levels in the tezosentan-treated animals compared with levels in untreated sheep. The degree of bronchial obstruction was similar in both treated and control sheep; however, bronchiolar obstruction was reduced in sheep treated with tezosentan. Histopathologically, no difference in the degree of parenchymal injury was detected. In conclusion, administration of a dual ET-1 receptor antagonist prevented an increase in PVRI after injury and reduced the degree of bronchiolar obstruction in sheep with S+B; however, treated sheep showed higher levels of NOx and increased lung lymph flow. Tezosentan treatment was ineffective in protecting against acute lung injury in this model.

Katahiro Shimoda

Papers

Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury