American journal of respiratory medicine : drugs, devices, and other interventions最新文献

Pregnancy rhinitis is defined as nasal congestion in the last 6 or more weeks of pregnancy, without other signs of respiratory tract infection and with no known allergic cause, with complete resolution of symptoms within 2 weeks after delivery. Pregnancy rhinitis occurs in approximately one-fifth of pregnancies, can appear at almost any gestational week, and affects the woman and possibly also the fetus. The pathogenesis of pregnancy rhinitis is not clear, but placental growth hormone is suggested to be involved. Smoking and sensitization to house dust mites are probable risk factors. It is often difficult to make a differential diagnosis from sinusitis: nasendoscopy of a decongested nose is the diagnostic method of choice. In some cases ultrasound or x-ray may be necessary. Sinusitis should be treated aggressively with increased doses of beta-lactam antibiotics and antral irrigation. Nasal decongestants give good temporary relief from pregnancy rhinitis, but they tend to be overused, leading to the development of rhinitis medicamentosa. Corticosteroids have not been shown to be effective in pregnancy rhinitis, and their systemic administration should be avoided during pregnancy. Nasal corticosteroids may be administered to pregnant women when indicated for other sorts of rhinitis. Nasal alar dilators and saline washings are safe means to relieve nasal congestion, but the ultimate treatment for pregnancy rhinitis remains to be found.

It is important to find interventions that will reduce the frequency and severity of exacerbations of COPD, because of their effect on morbidity and healthcare expenditure. A Cochrane systematic review included 23 studies that had evaluated the effects of treatment with mucolytic agents in patients with chronic bronchitis or COPD. Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease. Patients who received treatment with mucolytic agents were twice as likely to remain exacerbation-free in the study period than if they had received placebo, with six patients needing regular treatment with mucolytic agents for 3-6 months to achieve one less exacerbation over that time. Treatment with mucolytic agents resulted in nearly 7 days less illness per patient per year. How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, antioxidation, or antibacterial or immunostimulatory effects. They do not appear to affect the decline in lung function that occurs in COPD. The treatment appears to be without any adverse effects, apart from the need to take oral medication daily. Cost-effectiveness analysis suggests that the point at which the costs of treatment and non-treatment were equal was 1.2 less exacerbations per year. This is higher than the effect observed in the Cochrane review, suggesting that treating everyone with COPD with mucolytic agents would not be cost effective. Those with more frequent and severe exacerbations appear to have the most to gain.

Beta2-adrenoceptor agonists (beta2-agonists) such as albuterol (salbutamol) and terbutaline and their long-acting analogs salmeterol and formoterol are widely used as bronchodilators in the treatment of asthma. They are chiral drugs historically marketed as racemic mixtures of an active (eutomer) and essentially inactive (distomer) stereoisomer. Despite their obvious therapeutic value and widespread use, beta2-agonists have been implicated, somewhat controversially, in causing an increase in asthma mortality and a deterioration of asthma control by a mechanism that remains elusive. Inherent toxicity of the distomers has been widely touted as an explanation and has given rise to pressure for the replacement of the racemates with pure eutomer formulations (the so-called chiral or racemic switch). This has culminated in the recent introduction into clinical practice of the single active stereoisomer of albuterol (levalbuterol) and the promise of other pure beta2-agonist eutomer formulations to follow. This article examines the evidence on which these chiral switches are based. Clinical studies designed to reveal negative effects of beta2-agonists have searched for reductions in lung function, increases in airway responsiveness to bronchoconstrictor mediators and worsening of asthma control. Crossover studies administering the pure stereoisomers and racemate of albuterol have not shown a clear superiority of the pure eutomer formulation over the racemate in terms of either bronchial hyperresponsiveness, tachyphylaxis to bronchoprotective effects or improvements in lung function. Clinical toxicity of beta2-agonist distomers on any aspect of asthmatic lung function has also not been demonstrated in the relatively short-term inhalational studies (single dose or repeated dose studies <1 week) that have been carried out. In animal studies, the administration of beta2-agonist racemates and distomers has been shown to enhance bronchial hyperresponsiveness but only in ovalbumin-sensitized animals where the relevance to humans is questionable. The pharmacokinetics and metabolism of beta(2)-agonist stereoisomers appear to be essentially similar whether administered as single stereoisomers or as racemates. Levalbuterol may be slightly more potent than an equivalent dose given as racemate, but there is some evidence that it forms a small amount of the distomer in vivo which detracts somewhat from its purported benefits over use of the racemate. Whilst there remains a clear need for studies of longer duration with sensitive clinical endpoints to evaluate the benefits of beta2-agonist eutomers and to investigate distomer toxicity, the chiral switch for beta2-agonists in general, and for albuterol in particular, does not appear to be justified on the basis of the evidence available to date.

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.

Exogenous surfactant therapy has been part of the routine care of preterm neonates with respiratory distress syndrome (RDS) since the beginning of the 1990s. Discoveries that led to its development as a therapeutic agent span the whole of the 20th century but it was not until 1980 that the first successful use of exogenous surfactant therapy in a human population was reported. Since then, randomized controlled studies demonstrated that surfactant therapy was not only well tolerated but that it significantly reduced both neonatal mortality and pulmonary air leaks; importantly, those surviving neonates were not at greater risk of subsequent neurological impairment. Surfactants may be of animal or synthetic origin. Both types of surfactants have been extensively studied in animal models and in clinical trials to determine the optimum timing, dose size and frequency, route and method of administration. The advantages of one type of surfactant over another are discussed in relation to biophysical properties, animal studies and results of randomized trials in neonatal populations. Animal-derived exogenous surfactants are the treatment of choice at the present time with relatively few adverse effects related largely to changes in oxygenation and heart rate during surfactant administration. The optimum dose of surfactant is usually 100 mg/kg. The use of surfactant with high frequency oscillation and continuous positive pressure modes of respiratory support presents different problems compared with its use with conventional ventilation. The different components of surfactant have important functions that influence its effectiveness both in the primary function of the reduction of surface tension and also in secondary, but nonetheless just as important, role of lung defense. With greater understanding of the individual surfactant components, particularly the surfactant-associated proteins, development of newer synthetic surfactants has been made possible. Despite being an effective therapy for RDS, surfactant has failed to have a significant impact on the incidence of chronic lung disease in survivors. Paradoxically the cost of care has increased as surviving neonates are more immature and consume a greater proportion of neonatal intensive care resources. Despite this, surfactant is considered a cost-effective therapy for RDS compared with other therapeutic interventions in premature infants.