The inducible nitric oxide synthase inhibitor BBS-2 prevents acute lung injury in sheep after burn and smoke inhalation injury

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.     

胸腔血容量指数与外肺水指数对烧伤患者肺水肿的早期预测价值

目的研究胸腔血容量指数与外肺水指数对烧伤患者肺水肿的早期预测价值。方法选取2013年1月到2014年12月在我院烧伤科接受治疗及Pi CCO检测且伤后10天内发生肺水肿的严重烧伤患者42例,根据患者肺水肿类型分为肺损伤型组与静水压型组,对比两组Pi CCO监测指标及肺损伤评分,探索EVLWI与ITBVI、氧合指数的相关性。结果两组患者EVLWI水平相差不大,但静水压型组ITBVI及氧合指数均明显大于非损伤组,Murray评分明显低于肺损伤组;EVLWI与ITBVI呈显著正相关性,r=0.921,P0.05;EVLWI与氧合指数呈明显的负相关性,r=-0.718,P0.05。结论烧伤早期实行监测胸腔血容量指数与外肺水指数对患者发生肺水肿预测和鉴别具有重要参考意义。     

Correlation between increased airway responsiveness and severity of pulmonary edema

To determine whether the severity of the pulmonary edema in sheep models of cardiogenic and non-cardiogenic pulmonary edema correlate with concomitant alterations in airway responsiveness using three separate measures of pulmonary edema: post-mortem wet-to-dry lung weight ratio (W/D), chest radiograph (CXR) scores, and small airway wall area. Cardiogenic pulmonary edema was induced by increasing left atrial pressure (increase PLA) and non-cardiogenic pulmonary edema was induced by intravenous administration of Perilla ketone (PK). There was a significant negative correlation between changes in airway responsiveness and changes in CXR grade (r=-0.749, P<0.05), W/D (r=-0.662, P<0.05), airway wall areas (r=0.784, P<0.05) after increases in both PLA and PK. Chest radiograph score, W/D, and airway wall area correlated with each other (CXR score and W/D r=0.657, P<0.05; CXR score and airway wall area r=0.678, P<0.05; airway wall area and W/D r=0.704, P<0.05). We speculate that the increased airway responsiveness observed during pulmonary edema may result from the mechanical effects of edema formation within the airways.     

Acute bronchial obstruction in sheep: histopathology and gland cytokine expression

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.     

Smoke inhalation injury

Smoke inhalation injuries are the leading cause of fatalities from burn injury. The major forms of inhalation injuries are carbon monoxide toxicity, injury to the upper airway, and pulmonary parenchymal damage. The compromised airway is protected by tracheal intubation, and respiratory failure is treated with assisted ventilation. Maintenance of good pulmonary hygiene, optomized fluid resuscitation, and routine invasive hemodynamic monitoring are the mainstays of therapy. The development of acute pulmonary insufficiency, pulmonary edema, or bronchopneumonia requires a comprehensive approach to all aspects of the illness. Acute pathophysiologic responses to inhalation injury are complex. Future therapies will target improved ventilatory strategies and the redundant host inflammatory response.     

Effects of High-Frequency Oscillatory Ventilation on Oleic Acid-Induced Lung Injury in Sheep

High-frequency oscillatory ventilation (HFOV) is a possible mechanical method for open lung strategies. The aim of this study was to examine whether HFOV has a beneficial effect on oleic acid-induced lung injury, with emphasis on changes in extravascular lung water. Thirteen anesthetized sheep prepared with a lung lymph fistula and vascular catheters for monitoring were randomly allocated to two experimental groups. In experiment 1, sheep (n = 6) were ventilated using conventional mechanical ventilation [CMV; 10 ml/kg of tidal volume, 70% oxygen, and positive end-expiratory pressure (PEEP) of 6 cmH(2)O after oleic acid administration (0.08 ml/kg)]. In experiment 2, sheep (n=7) were ventilated using HFOV (frequency=15 Hz, stroke volume=120 ml, mean airway pressure=15 cmH(2)O) after administration of the same dose of oleic acid as in experiment 1. Observation was continued for 4 h after oleic acid administration, then bronchoalveolar lavage (BAL) was performed and the lung wet-to-dry weight ratio was determined. Compared with CMV, HFOV significantly improved the deteriorated oxygenation during the late phase (2-4 h) of oleic acid-induced lung injury without any deterioration effects on pulmonary or systemic hemodynamics. HFOV showed significantly reduced lung lymph protein clearance, which paralleled significant decreases in wet-to-dry ratios and neutrophil counts in BAL fluid in the HFOV group. These findings suggest that HFOV could contribute to decreased lung lymph filtration in pulmonary microcirculation and improved oxygenation following oleic acid-induced lung injury in sheep.     

Perilla ketone: a model of increased pulmonary microvascular permeability pulmonary edema in sheep

A model of increased microvascular permeability pulmonary edema was developed in chronically instrumented unanesthetized sheep using perilla ketone (PK). PK did not cause changes in pulmonary hemodynamics but did cause marked increases in the flow of protein-rich lung lymph. The changes in lung lymph flow were accompanied by radiographic evidence of both interstitial and alveolar pulmonary edema as well as hypoxemia. PK did not cause acute changes in lung mechanics. Dynamic compliance of the lungs and FRC decreased later, concomitant with the changes in lung lymph flow, radiographic evidence for pulmonary edema, and hypoxemia. Resistance to air flow across the lungs and specific conductance did not change significantly after PK infusion. The severity of the radiographic evidence for pulmonary edema observed after PK correlated with the severity of the concomitant hypoxemia and changes in dynamic compliance of the lungs. PK did not cause increases in the concentrations of cyclooxygenase products of arachidonic acid in lung lymph or plasma or changes in blood leukocyte counts. We conclude that PK causes increased lung microvascular permeability pulmonary edema without acute changes in pulmonary hemodynamics. This model permits study of the pathophysiologic aspects of increased lung microvascular permeability without the concomitant functional alterations that complicate most other experimental models of diffuse lung injury.     

Treatment of smoke-induced pulmonary injury with nebulized dimethylsulfoxide

Inhalation injury was produced in sheep that were chronically prepared for study. The injury was induced by insufflating them with smoke from burning cotton cloth. One group of animals was treated with the oxygen-free radical scavenger dimethylsulfoxide (DMSO) and heparin. Another group received heparin treatment alone, and a third was untreated. The drugs were nebulized into the tracheostomy at 4-hr intervals beginning 1 hr after injury. Following the inhalation injury, lung lymph flow and extravascular lung water measured by thermal-dye dilution technique were both increased. These elevations were associated with minor increases in pulmonary artery pressure, and, thus, since the lymph to plasma protein ratio was unchanged, this increased extravascular fluid formation was probably the result of an elevated microvascular permeability. These changes were associated with a reduction in alpha 2 macroglobulin antiprotease activity. The treated groups showed much smaller responses to the inhalation insult. This was especially true in the animals that received the DMSO. These findings support the concept that oxygen free radicals are responsible for the pulmonary edema associated with inhalation injury.     

The pulmonary lesion of smoke inhalation in an ovine model

Inhalation injury was induced in chronically instrumented sheep (n = 9) by insufflating them with smoke from burning cotton cloth. Sham animals (n = 9) were insufflated with air. There were no temporal changes in any measured parameter of the sham animals. Smoke induced a depression in PaO2. There was a threefold elevation in protein-rich pulmonary lymph which was sustained for over 48 hours. The lymph-to-plasma oncotic pressure ratio was increased. The cardiac index, left atrial pressure, and pulmonary arterial pressure remained unchanged in both groups. After smoke inhalation, the interstitial levels of neutrophils increased while interstitial antiprotease activity was depressed. The lung lymph concentration of 6-keto prostaglandin F1a, the major metabolite of prostacyclin, was increased. These data suggest that the pulmonary injury following smoke inhalation is the result of an increase in lung microvascular permeability to protein with resultant pulmonary edema. The mechanisms responsible for these changes appear to be related to direct injury to the tracheobronchial tree by cytotoxic agents in the smoke; polymorphonuclear leukocytes; and, possibly, eicosanoids.     

Upper airway obstruction due to inhalation of a tracheal T-tube resulting in pulmonary edema.

Acute upper airway obstruction may present with pulmonary edema. Following is a report of pulmonary edema secondary to acute upper airway obstruction due to inhalation of a Montgomery tracheal T-tube. The principal factor causing pulmonary edema is the generation of large negative transpulmonary pressures. This may be enhanced by changes in the cardiovascular function due to the Müller maneuver.     

Bronchiectasis: a cause of pulmonary symptoms in heroin addicts.

Extensive and severe bronchiectasis was found in 7 heroin-addicted individuals with pulmonary symptoms whose chest roentgenograms were not suggestive of severe airway disease. Abnormalities consisted of varicose and cylindrical alterations. Pulmonary function tests revealed airflow obstruction, decreased lung volumes, and diffusion capacity impairment. Arterial blood gas analysis demonstrated mild hypoxemia in all patients and chronic hypocapnia in 4. Serial pulmonary function tests in 2 patients revealed only modest improvement in the degree of airflow obstruction. The occurence of bronchiectasis appeared to be related to episodes of heroin-induced pulmonary edema and infection.     

The pathophysiology of carbon monoxide poisoning and acute respiratory failure in a sheep model with smoke inhalation injury

A smoke inhalation model was created in 22 adult male sheep with pine smoke inhalation through an endotracheal tube for 6 min. Arterial blood gases, HbCO, HbO2 and pulmonary compliance (Cdyn) were monitored, and the morphology of the tracheobronchial tree and pulmonary parenchyma were studied by light and electron microscopy. Severe carbon monoxide poisoning with fatal levels of HbCO (greater than 50 percent) was found at the end of smoke inhalation. Acute respiratory distress, progressive hypoxemia, decreased pulmonary compliance and increased P(A-a)O2 and Qs/QT occurred after injury. Tracheobronchial blockade by pseudomembrane cast, pulmonary edema, atelectasis and necrosis of pulmonary epithelia were demonstrated pathologically. The mechanisms of CO poisoning and ARF are discussed.     

Effect of catalase on endotoxin-induced acute lung injury in unanesthetized sheep

Administration of endotoxin intravenously to unanesthetized sheep causes an acute lung injury characterized by increased microvascular barrier permeability and subsequent pulmonary edema. Endotoxin-induced sheep lung injury can be attenuated by leukocyte depletion, and may be mediated by toxic metabolites of oxygen. We studied effects of administering catalase, which catalyzes conversion of hydrogen peroxide to oxygen and water, to sheep subsequently infused with endotoxin to test the hypothesis that hydrogen peroxide plays a role in the pathogenesis of lung injury. We found that infusions of endotoxin (1 microgram/kg) into untreated sheep caused the expected biphasic response, a transient, early, marked pulmonary arterial hypertension followed by a prolonged increase in protein-rich lung lymph flow characteristic of increased microvascular permeability filtration in the lungs. Intraperitoneal injections of catalase (50 mg/kg) prior to infusing endotoxin in these same sheep resulted in substantial catalase activity in plasma and in lung lymph, and attenuated the expected changes in pulmonary arterial pressure, lung lymph flow, and arterial leukocyte counts and oxygen tension after endotoxin infusions. Furthermore, mechanical elevation of hydrostatic pressure in the lungs of a catalase-treated sheep infused with endotoxin resulted in increased lung lymph flow with a decreased protein concentration, indicating that the microvascular barrier to fluid and protein was functionally intact. Administration of catalase that was inactivated by reaction with hydrogen peroxide in the presence of aminotriazole or administration of the catalase vehicle, thymol, had no effects on the sheep responses to endotoxin. We conclude that hydrogen peroxide plays a role in the pathogenesis of endotoxin-induced acute lung injury in sheep.     

Corticosteroids prevent acute lung dysfunction caused by thoracic irradiation in unanesthetized sheep

We sought to determine the effect of corticosteroid therapy in a new acute model of oxidant lung injury, thoracic irradiation in awake sheep. Sheep were irradiated with 1,500 rads to the whole chest except for blocking the heart and adjacent ventral lung. Seven experimental sheep were given methylprednisolone (1 g intravenously every 6 h for four doses) and thoracic irradiation; control sheep received only irradiation. In irradiated control sheep, lung lymph flow increased from baseline (7.6 ml/h) to peak at 3 h (13.2), and lung lymph protein clearance increased from 5.1 to 9.7 ml/h. Mean pulmonary artery pressure increased in the irradiated control sheep from 19 to 32.4 cm H2O, whereas the lung lymph thromboxane concentration increased from 0.09 to 6.51 ng/ml at 3 h. Arterial oxygen tension in irradiated control sheep fell gradually from 86 mm Hg at baseline to 65 mm Hg at 8 h. Methylprednisolone administration significantly prevented the increase in lung lymph protein clearance, mean pulmonary artery pressure, and lung lymph thromboxane concentration. Methylprednisolone also prevented the fall in arterial oxygen tension after thoracic irradiation, but did not prevent a further decrease in lymphocytes in blood or lung lymph after radiation. We conclude that corticosteroid therapy prevents most of the acute physiologic changes caused by thoracic irradiation in awake sheep.     

Inhalation injuries

Inhalation injuries occur in approximately one-third of all major burns and account for a significant number of deaths in those burn patients each year. Victims die as a result of carbon monoxide poisoning, hypoxia, and smoke inhalation. These deaths can occur without thermal wounds as well as with burn injuries. There are three distinct problems with inhalation injuries: thermal burns of the upper airway, carbon monoxide poisoning, and smoke inhalation. Each has different symptoms and signs, different treatment, and different prognosis. Thermal burns occurring in the upper airway are usually manifested within 48 hours of injury. Diagnosis is made by direct visualization of the upper airway, looking for signs of thermal injury. Admission for observation with humidified oxygen, attentive pulmonary toilet, bronchodilators as needed, and prophylactic endotracheal intubation as indicated are the mainstays of treatment. Resolution of the injury usually occurs within days. Carbon monoxide poisoning, the most common cause of death in inhalation injury, is a result of combustion. Symptoms and signs correlate with blood levels, but arterial blood gases are used to determine the degree of carbon monoxide intoxication. Treatment is based on the principle that carbon monoxide dissociation occurs much faster if the patient is placed on 100% oxygen. Occasionally the patient's symptoms may persist or get worse despite adequate treatment. Smoke inhalation significantly damages normal respiratory physiology, resulting in injury progressing from acute pulmonary insufficiency to pulmonary edema to bronchopneumonia, depending on the severity of exposure. Diagnosis is based on history, but clinical findings, arterial blood gases, and fiberoptic bronchoscopy are helpful. Treatment is supportive with careful attention paid to fluid resuscitation in the patient with burns.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of pulmonary blood flow by the rebreathing technique in airflow obstruction.

To test the hypothesis that the effect of nonuniform gas distribution on the uptake of inhaled soluble gases in the lung is minimized by rebreathing, we measured pulmonary blood flow by the thermodilution technique, and pulmonary capillary blood flow, combined pulmonary tissue and capillary blood volume, diffusing capacity of the lung for CO, and alveolar volume by a rebreathing technique in conscious sheep before and immediately after inhalation of a histamine aerosol (4% solution). We also measured pulmonary resistance, distribution of ventilation by multiple-breath N2 washout, and arterial blood gases to monitor airway responses. Histamine inhalation produced a mean pulmonary resistance increase to 621% of baseline accompanied by uneven distribution of ventilation and a decrease in arterial Po2. Despite these alterations in airway function, there were no concomitant changes in pulmonary capillary blood flow, combined pulmonary tissue and capillary blood volume, diffusing capacity of the lung for CO, alveolar volume, or the ratio of diffusing capacity for CO to alveolar volume. Mean pulmonary capillary blood flow and pulmonary blood flow did not differ from each other before and after histamine inhalation. We conclude that the rebreathing technique for noninvasive measurement of pulmonary hemodynamics is satisfactory in the presence of airflow obstruction.     

Pulmonary edema due to upper airway obstruction in adults

A report of pulmonary edema following acute upper airway obstruction in an adult is presented, and the literature involving 25 additional cases is reviewed. This form of pulmonary edema appears to be related to markedly negative intrathoracic pressure due to forced inspiration against a closed upper airway resulting in transudation of fluid from pulmonary capillaries to the interstitium. Postanesthetic laryngospasm is the most common cause of pulmonary edema in adults (11/26 cases). The edema usually clears rapidly with supportive care. Aggressive diagnostic and therapeutic interventions may be avoided if the syndrome is recognized. Maintenance of oxygenation and a patent airway are the mainstays of treatment.     

Novel assessment of acute lung injury by in vivo near-infrared spectroscopy.

We investigated the feasibility and validity of near-infrared (NIR) spectroscopy for evaluation of acute lung injury (ALI). In an in vitro model simulating the spectrophotometric characteristics of the lung, NIR spectroscopy could precisely detect changes in water volume, suggesting its ability to assess the extent of pulmonary edema caused by ALI. The different grades of ALI were induced in rats by administering oleic acid and varying the pulmonary ventilation conditions, and NIR spectroscopy was employed to determine lung water content and hemoglobin (Hb) oxygenation of the lungs. NIR spectroscopy detected increased water content even in histologically mild ALI. The changes in lung water content measured by NIR spectroscopy were significantly correlated with gravimetric lung water content (r = 0.877, p < 0.0001). Deoxy-Hb measured by NIR spectroscopy consistently reflected the histological changes in the lungs, and the deoxy-Hb levels correlated with changes in SaO2 (r = -0.798, p < 0.0001). These findings demonstrate that NIR spectroscopy can evaluate lung water content and Hb oxygenation quantitatively, and may be a useful tool for assessing pathological status in ALI.     

Acute upper airway injury in burn patients. Serial changes of flow-volume curves and nasopharyngoscopy

Serial flow-volume curves and fiberoptic nasopharyngoscopy were performed in 36 patients with cutaneous burns and/or smoke inhalation. Baseline flow-volume curve patterns were abnormal in 26 (72.2%) patients, and follow-up studies demonstrated significant reductions (p less than 0.04) in inspiratory and expiratory flow rates in the 6 patients who required endotracheal intubation because of anatomic upper airway obstruction. None of the patients with stable or increased flow rate measurements required intubation. The progression of upper airway edema in 14 patients was characterized by obliteration of the aryepiglottic folds, arytenoid eminences, and interarytenoid areas by boggy, edematous tissue that prolapsed to occlude the airway. These changes correlated with an increased size of cutaneous burns (p less than 0.0001), the presence of burns of the face and neck (p less than 0.05), and more rapid intravenously administered fluid resuscitation (p less than 0.04). Anatomic and physiologic changes consistent with upper airway dysfunction occur frequently in burn victims. Progression of these abnormalities correlates with the severity and distribution of cutaneous injury and is influenced by intravenously administered fluid.