Inhaled beta-2 agonist salbutamol and acute lung injury: an association with improvement in acute lung injury

Introduction  

β2 agonists have several properties that could be beneficial in acute lung injury (ALI). We therefore chose to study the effect of inhaled β2 agonist use (salbutamol) on duration and severity of ALI.     

Inhaled milrinone attenuates experimental acute lung injury

Purpose  To test whether inhalation of the phosphodiesterase 3 inhibitor milrinone may attenuate experimental acute lung injury (ALI). Methods  In rats, ALI was induced by infusion of oleic acid (OA). After 30 min, milrinone was inhaled either as single dose, or repeatedly in 30 min intervals. In mice, ALI was induced by intratracheal instillation of hydrochloric acid, followed by a single milrinone inhalation. Results  Four hours after OA infusion, ALI was evident as lung inflammation, protein-rich edema and hypoxemia. A single inhalation of milrinone attenuated the increase in lung wet-to-dry weight ratio and myeloperoxidase activity, and reduced protein concentration, neutrophil counts and TNF-α levels in bronchoalveolar lavage. This effect was further pronounced when milrinone was repeatedly inhaled. In mice with acid-induced ALI, milrinone attenuated hypoxemia and prevented the increase in lung myeloperoxidase activity. Conclusions  Inhalation of aerosolized milrinone may present a novel therapeutic strategy for the treatment of ALI.     

Inhaled nitric oxide reduces lung edema during fluid resuscitation in ovine acute lung injury

OBJECTIVE: Fluid resuscitation in sepsis-related lung injury is limited by aggravation of pulmonary edema. Hypovolemia, however, may compromise tissue perfusion and contribute to organ dysfunction. We hypothesized that inhaled nitric oxide would reduce edema formation during fluid therapy. DESIGN AND SETTING: Prospective laboratory investigation in a university research laboratory. PARTICIPANTS: Eighteen chronically instrumented sheep. INTERVENTIONS: The animals were randomly assigned to one of three groups and received endotoxin (S. typhi, 10 ng kg(-1) min(-1)) for 30 h. After 24 h the sheep were anesthetized (ketamine/midazolam), mechanically ventilated with oxygen, and received 0.1 ml kg(-1) oleic acid: oxy group (n=6), an infusion of Ringer's lactate was restricted to 1 ml kg(-1) h(-1); fluid/oxy group (n=6), a bolus of 10 ml kg(-1) Ringer's lactate plus 10 ml kg(-1) h(-1) was given; fluid/NO group (n=6), the sheep were treated as in the fluid/oxy group, except that they inhaled nitric oxide (20 ppm). MEASUREMENTS AND RESULTS: The extravascular lung water index was measured using thermodye dilution. Oleic acid increased extravascular lung water, impaired oxygenation, and reduced cardiac index at 26 h in all groups. After 30 h the extravascular lung water in the fluid/NO group was not higher than in the oxy group and significantly than in the fluid/oxy group. While cardiac index returned to the level of sepsis baseline in fluid/NO and fluid/oxy, it was reduced in the oxy group after 30 h. There were no significant differences in cardiac index between groups. CONCLUSIONS: Inhaled nitric oxide may be an option for reducing edema formation secondary to fluid resuscitation in acute lung injury.     

Inhaled activated protein C: a novel therapy for acute lung injury?

Acute lung injury (ALI) is characterized by the presence of dysregulated coagulation and inflammation. Therefore, Waerhaug and colleagues hypothesized that administration of activated protein C (APC) via the inhaled route would be a novel and effective treatment for ALI. They demonstrated that inhaled APC improved oxygenation and lung aeration in a sheep model of lipopolysaccharide-induced ALI, but did not alter lung water or hemodynamics. Future studies are needed to determine plasma and airspace APC levels when administered by the inhaled route, and to determine if inhaled APC has a similar effect in other models of ALI.     

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

OBJECTIVES: To study the effects of an inhaled endothelin A (ET(A)) receptor antagonist on hemodynamics and pulmonary gas exchange in experimental acute lung injury (ALI). DESIGN AND SETTING: Prospective, randomized, and controlled study in a university laboratory. PARTICIPANTS AND INTERVENTIONS: Sixteen pigs were ventilated in a volume controlled mode during general anesthesia. ALI was induced by surfactant depletion using repetitive lung lavages until the PaO2/FIO2 ratio was below 100 mmHg. The animals were then randomly assigned to receive either a nebulized ET(A) receptor antagonist (LU-135252, 3 mg/kg, inhaled over 1 h; LU group) or nebulization of saline (5-10 ml inhaled over 1 h) with no further intervention (controls). MEASUREMENTS AND RESULTS: Parameters of hemodynamics and gas exchange were measured for 6 h after induction of ALI. In the LU group intrapulmonary right-left shunting (QS/QT) decreased from 58 +/- 8% at the onset of ALI to 27 +/- 12% 3 h and 24 +/- 9% 6 h after ALI (p < 0.05); PaO2 increased from 55 +/- 12 to 257 +/- 148 mmHg 3 h and 270 +/- 136 mmHg 6 h after ALI. (p < 0.05), whereas in controls QS/QT and PaO2 did not improve over the 6 h after onset of ALI. In the LU group mean pulmonary artery pressure was stable for 6 h after ALI (26-29 mmHg), while in controls it increased from 28 +/- 2 to 41 +/- 2 mmHg (p < 0.05). Inhaled LU-135252 reduced cardiac output by 31 +/- 11% (p < 0.05) and increased systemic vascular resistance by 60 +/- 29 % (p < 0.05), while these parameters remained stable in controls. CONCLUSION: In this porcine model of ALI the inhalation of an ET(A) receptor antagonist improved arterial oxygenation and maintained a stable pulmonary artery pressure without inducing systemic vasodilatation.     

Effects of salbutamol on exhaled breath condensate biomarkers in acute lung injury: prospective analysis

Introduction  

The benefits of β-adrenergic stimulation have been described in acute lung injury (ALI), but there is still no evidence of its anti-inflammatory effect in these patients. Biomarkers in exhaled breath condensate (EBC) were used to study the effects of salbutamol on lung inflammation in mechanically ventilated patients with ALI.     

Effects of beta-2 agonist on metabolic regulation in the fetal lamb lung

To study the effects of beta-2 agonist on metabolic regulation in fetal lamb lung, ritodrine hydrochloride, a preferential beta-2 agonist, was infused i.v. at a rate of 1.3 +/- 0.4 micrograms/kg/min (mean +/- S.D.) for 24 hr into six twin chronically catheterized fetal lambs starting between 0.86 and 0.91 gestation. Lung glycogen was depleted 56% in the ritodrine-infused twins and glycogen phosphorylase a activity was increased 1.8-fold whereas glycogen synthase activity remained unchanged. Cyclic AMP-dependent protein kinase activity increased 1.7-fold, calcium-calmodulin-dependent protein kinase (phosphorylase kinase) activity increased 1.4-fold and calcium-phospholipid-dependent protein kinase (protein kinase C) activity increased 1.6-fold. In addition, the maximal binding capacity of pulmonary beta receptors decreased 49% in the ritodrine-infused twins. However, lung cyclic AMP content was unchanged after 24 hr of ritodrine infusion. We conclude that beta-2 agonist activates protein kinases, depletes glycogen and reduces the binding capacity of beta receptors in the fetal lamb lung. We speculate that these adrenergic mechanisms are involved in regulating the effects of beta-2 agonist on fetal lung liquid and surfactant production.     

Inhaled nitric oxide down-regulates intrapulmonary nitric oxide production in lipopolysaccharide-induced acute lung injury

OBJECTIVE: To examine whether inhaled nitric oxide (NO) affected the intrapulmonary production of NO, reactive oxygen species, and nuclear factor-kappaB in a lipopolysaccharide (LPS)-induced model of acute lung injury. DESIGN: Prospective, randomized, laboratory study. SETTING: Experimental laboratory at a biomedical institute. SUBJECTS: Twenty male rabbits weighing 2.5-3.5 kg. INTERVENTIONS: Saline or LPS (5 mg/kg of body weight) was administered intravenously with or without NO inhalation (10 ppm) in each group of five rabbits. MEASUREMENTS AND MAIN RESULTS: LPS increased the lung leak index, the neutrophils and NO levels in bronchoalveolar lavage fluid, and NO levels produced by resting and stimulated alveolar macrophages. Inhaled NO decreased the lung leak index, the neutrophils and NO levels as measured by nitrite levels in the lavage fluid, and NO produced by the resting and stimulated alveolar macrophages. Inhaled NO also blocked the activities of reactive oxygen species and nuclear factor-kappaB binding to DNA in lavage cells and in alveolar macrophages. CONCLUSION: Inhaled NO attenuates LPS-induced acute lung injury, possibly by decreasing NO production in the lungs. The mechanism of reducing NO production resulting from inhaled NO may involve, in part, the activities of reactive oxygen species and/or nuclear factor-kappaB.     

Inhaled aerosolized insulin ameliorates hyperglycemia-induced inflammatory responses in the lungs in an experimental model of acute lung injury

Introduction

Previous studies have shown that patients with diabetes mellitus appear to have a lower prevalence of acute lung injury. We assumed that insulin prescribed to patients with diabetes has an anti-inflammatory property and pulmonary administration of insulin might exert beneficial effects much more than intravenous administration.

Methods

Twenty-eight mechanically ventilated rabbits underwent lung injury by saline lavage, and then the animals were allocated into a normoglycemia group (NG), a hyperglycemia group (HG), an HG treated with intravenous insulin (HG-VI) group or an HG treated with aerosolized insulin (HG-AI) group with continuous infusion of different fluid solutions and treatments: normal saline, 50% glucose, 50% glucose with intravenous insulin, or 50% glucose with inhaled aerosolized insulin, respectively. After four hours of treatment, the lungs and heart were excised en bloc, and then high-mobility group B1 concentration in bronchoalveolar lavage fluid, interleukin-8 and toll-like receptor 4 mRNA expression in bronchoalveolar lavage fluid cells, and lung myeloperoxidase activity were measured.

Results

Treatment with both aerosolized insulin and intravenous insulin attenuated toll-like receptor 4 mRNA expressions in the bronchoalveolar lavage fluid cells. Interleukin-8 and toll-like receptor 4 mRNA expression was significantly lower in the HG-AI group than in the HG-IV group. The lung myeloperoxidase activity in the normal healthy group showed significantly lower levels compared to the NG group but not different compared to those of the HG, HG-VI and HG-AI groups.

Conclusions

The results suggest that insulin attenuates inflammatory responses in the lungs augmented by hyperglycemia in acute lung injury and the insulin''s efficacy may be better when administered by aerosol.     

Alveolar pressure monitoring: an evaluation in a lung model and in patients with acute lung injury

OBJECTIVES: We evaluated an algorithm for continuous on-line monitoring of alveolar pressure over time in a lung model with lower and upper inflection points and variable resistance ratios and in patients with acute lung injury. The algorithm is based on "static" pressure/volume curves obtained from tracheal pressure measurements under dynamic conditions. DESIGN AND SETTING: Experimental and clinical evaluation of algorithm in a university hospital laboratory and intensive care unit. PATIENTS: Ten patients undergoing postoperative respiratory therapy (feasibility of tracheal measurement) and ten patients with acute lung injury undergoing ventilator treatment (evaluation of algorithm). MEASUREMENTS AND RESULTS: Direct tracheal pressure measurements with a catheter inserted through the endotracheal tube. Comparison of measured alveolar and the dynostatic alveolar pressure vs. time in a lung model with changes in five ventilatory parameters. Examples of clinical monitoring are reported. In the model there was excellent agreement between alveolar pressures obtained by the algorithm, the dynostatic alveolar pressure, and measured alveolar pressure at all ventilator settings. For inspiratory/expiratory resistance ratios between 1:2.1-2.1:1, the dynostatic alveolar pressure was within +/-1.5 cm H(2)O of measured alveolar pressure. In patients the technique for direct tracheal pressure measurement using a catheter inserted through the endotracheal tube functioned satisfactorily with intermittent air flushes for cleansing. CONCLUSIONS: Using a thin tracheal pressure catheter inserted through the endotracheal tube alveolar pressure allows continuous bedside monitoring with ease and precision using the dynostatic algorithm. The method is unaffected by tube and connector geometry or by secretions.     

Infused salbutamol accentuates acid-induced lung injury in the rat

The effect in the rat of salbutamol infusion (1 microgram min-1 kg-1) on acid-induced lung injury has been determined. Severity of lung injury was assessed by two techniques: the pulmonary clearance of 99mTc-diethylenetriaminepenta-acetate (99mTc-DTPA) and the lung wet/dry weight ratio, giving indices of alveolar epithelial permeability and transendothelial water filtration respectively. Mean half-time of clearance of 99mTc-DTPA was increased significantly in rats who had intratracheal acid-induced injury and control (saline) intravenous infusion (19.4 +/- 2.6 min) compared with non-acid-treated rats (98.1 +/- 7.2) (P less than 0.0001). However, those animals who had intratracheal acid injury and subsequent salbutamol intravenous infusion had significantly faster clearance (11.5 +/- 1.9) than the acid and control infusion group (P less than 0.05). Gravimetric lung water in the acid-only rats (expressed as wet/dry weight ratio) was increased significantly (6.4 +/- 0.3) compared with the non-acid-treated controls (5.4 +/- 0.2) (P less than 0.01). Acid-treated rats who had salbutamol infused had dramatically increased lung water (10.0 +/- 0.6) (P less than 0.001 vs acid and control infusion). Intravenous salbutamol infusion itself produced no significant difference in the results for both techniques, compared with the non-acid-treated time-course controls. Infused salbutamol accentuates acid-induced lung injury in the rat. Possible factors responsible for these findings include beta 2-adrenergic agonist mediated inhibition of hypoxic pulmonary vasoconstriction (HPV) and a predominant beta 1-adrenergic agonist inotropic effect of salbutamol with resultant rise in pulmonary artery pressure.     

Biomarkers in acute lung injury: insights into the pathogenesis of acute lung injury

Studies of potential biomarkers of acute lung injury (ALI) have provided information relating to the pathophysiology of the mechanisms of lung injury and repair. The utility of biomarkers remains solely among research tools to investigate lung injury and repair mechanisms. Because of lack of sensitivity and specificity, they cannot be used in decision making in patients with ALI or acute respiratory distress syndrome. The authors reviewed known biomarkers in context of their major biologic activity. The continued interest in identifying and studying biomarkers is relevant, as it provides information regarding the mechanisms involved in lung injury and repair and how this may be helpful in identifying and designing future therapeutic targets and strategies and possibly identifying a sensitive and specific biomarker.     

Science review: Mechanisms of beta-receptor stimulation-induced improvement of acute lung injury and pulmonary edema

Acute lung injury (ALI) and the acute respiratory distress syndrome are complex syndromes because both inflammatory and coagulation cascades cause lung injury. Transport of salt and water, repair and remodeling of the lung, apoptosis, and necrosis are additional important mechanisms of injury. Alveolar edema is cleared by active transport of salt and water from the alveoli into the lung interstitium by complex cellular mechanisms. Beta-2 agonists act on the cellular mechanisms of pulmonary edema clearance as well as other pathways relevant to repair in ALI. Numerous studies suggest that the beneficial effects of beta-2 agonists in ALI include at least enhanced fluid clearance from the alveolar space, anti-inflammatory actions, and bronchodilation. The purposes of the present review are to consider the effects of beta agonists on three mechanisms of improvement of lung injury: edema clearance, anti-inflammatory effects, and bronchodilation. This update reviews specifically the evidence on the effects of beta-2 agonists in human ALI and in models of ALI. The available evidence suggests that beta-2 agonists may be efficacious therapy in ALI. Further randomized controlled trials of beta agonists in pulmonary edema and in acute lung injury are necessary.     

Desensitization of the beta-2 adrenoceptor-mediated vasodilation in rat aorta after prolonged treatment with the beta-2 adrenoceptor agonist clenbuterol

Administration to rats of the selective beta-2 adrenoceptor agonist (+/-)-clenbuterol (CLEN) (0.3 mg.kg-1 s.c., twice daily for 14 days) decreased the relaxant responses to the beta adrenoceptor agonist (-)-isoproterenol (IS) and to CLEN in KCl-contracted aortic rings. The treatment did not modify the vasodilation induced by forskolin (a direct activator of the catalytic subunit of the adenylate cyclase), 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), adenosine or acetylcholine. IS increased (cAMP) cyclic AMP levels dose-dependently in rat aorta, and this effect was reduced markedly in arteries from CLEN-treated rats. By contrast, the treatment did not modify the forskolin-induced cAMP production. The contractile response to (-)-norepinephrine (NE) was inhibited in the presence of IS or CLEN in control aortic rings. However, this modulatory effect was not seen in arteries from CLEN-treated rats. Preincubation of the arteries with either cholera toxin (an activator of the stimulatory guanine nucleotide binding protein, Gs) or forskolin reduced NE-induced vasoconstriction to the same extent in aortic rings from both control and CLEN-treated rats. The chronotropic response to NE in rat atria (beta-1-mediated) was not affected by the treatment. These results suggest that prolonged administration of CLEN to rats induced desensitization of beta-2 adrenoceptor-mediated vascular relaxation by alterations at the level of the beta-2 adrenergic receptor, but not in the mechanisms related to Gs, adenylate cyclase or in those distal to cAMP production.     

Inhaled budesonide in experimental chlorine gas lung injury: influence of time interval between injury and treatment

OBJECTIVE: To examine the time window between injury and treatment during which nebulized corticosteroid lessens lung injury induced by chlorine gas inhalation. DESIGN: An experimental laboratory study. SETTING: Academic research laboratory. SUBJECTS: Twenty-four juvenile female pigs. INTERVENTIONS: Twenty-four mechanically ventilated pigs were exposed to chlorine gas (400 PPM in air) for 20 min, then divided into four groups (six in each group). Nebulized budesonide (BUD) was given immediately (BUD 0 min), 30 min (BUD 30 min) or 60 min (BUD 60 min) after chlorine gas exposure. Six pigs receiving nebulized saline served as controls. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, gas exchange and lung mechanics were evaluated for 5 h after chlorine gas exposure. All animals had an immediate increase in airway and pulmonary artery pressure and a sharp drop of arterial oxygenation. The mean arterial oxygen tension of BUD 0 min and BUD 30 min animals was significantly higher than in the control and the BUD 60 min groups ( p<0.001). The recovery of lung compliance in the BUD 0 min and the BUD 30 min groups was significantly more rapid than in the control and the BUD 60 min groups ( p<0.001). The pulmonary wet to dry weight ratio was greater in the control group than in the BUD-treated groups ( p<0.05). CONCLUSION: Treatment with inhaled budesonide immediately or 30 min after chlorine gas lung injury had similar positive effects on symptoms and signs of pulmonary injury, whereas treatment delayed for 60 min was less effective.     

Transfusion-related acute lung injury reports in the Netherlands: an observational study

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a serious, sometimes fatal complication of transfusion, attributed to white blood cell (WBC)-reactive antibodies present in the blood product. This study investigated incidence and etiology in the Netherlands.
STUDY DESIGN AND METHODS: From January 2005 through July 2007, all TRALI cases reported to the Sanquin Blood Banks were evaluated. Only cases meeting the Canadian Consensus Conference criteria for TRALI were included and investigated for patient, donor, and product characteristics. Patients and donors were screened for HLA Class I, HLA Class II, and granulocyte antibodies.
RESULTS: A total of 56 TRALI cases were reported of which 49 were completely evaluated. Seventy-eight percent of the patients needed monitoring or mechanical ventilation on the intensive care unit, 10 patients died. In 61% of cases large-volume plasma products were involved. WBC-reactive antibodies in donors were found in 73% of cases, with proven incompatibility in 21 of 44 (48%) investigated cases. Possible TRALI cases, as defined by the Canadian Consensus Conference, had significantly lower incompatibility rates compared to TRALI cases, 18% versus 58% (p = 0.036). In the 21 alloimmune cases, a total of 31 implicated donors were found, of which 26 were female, including 12 fresh-frozen plasma (FFP) products.
CONCLUSION: TRALI is the most serious transfusion complication in the Netherlands, causing severe morbidity and mortality. Antibodies were found in the majority of the cases, but causality with proven incompatibility could be established in 21 cases (48%). Female FFP products were involved in 57% of proven alloimmune cases and would theoretically be prevented using male FFP only.     

Alcohol abuse and acute lung injury: epidemiology and pathophysiology of a recently recognized association.

Alcohol is the most commonly used and abused drug in the United States. The deleterious health effects of alcohol can be attributed both to its acute intoxicating effects, which result in temporary impairment of judgment and motor skills, and to its more chronic and toxic effects on the liver, pancreas, heart, and brain, all of which may result in irreversible organ damage. Although recognized for more than a century as a major risk factor for pneumonia, alcohol abuse was until recently perceived to have no significant effects on lung structure and/or function. However, within the past decade, epidemiologic studies have revealed that alcohol abuse independently increases the risk of acute respiratory distress syndrome (ARDS) two- to fourfold in patients with sepsis or trauma and may play a role in ARDS pathogenesis in as many as half of all patients with the syndrome. Although alcohol abuse alone does not cause acute lung injury, it renders the lung susceptible to dysfunction in response to the inflammatory stresses of sepsis, trauma, and other clinical conditions recognized to cause ARDS. Recent investigations in both animal models of chronic ethanol ingestion and in human subjects with a history of alcohol abuse have explored this previously unrecognized connection between alcohol and acute lung injury and have uncovered multiple derangements, which we now characterize as the "alcoholic lung." This review summarizes the epidemiologic association between alcohol abuse and acute lung injury and the recent experimental findings that are unraveling the underlying pathophysiology.