Beta-agonist Therapy Research Articles

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Inhaled corticosteroid (ICS) therapy in combination with long-acting beta-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting beta-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 mug daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 mug daily, and addition of the LABA formoterol to budesonide (800 mug) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV(1) and the rate of exacerbations. A reduction in the rate of decline in FEV(1) of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases.

β2 adrenergic agonists in acute lung injury? The heart of the matter

Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of β2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of β agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of β agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

Should Acute Treatment with Inhaled Beta Agonists be Withheld from Patients with Dyspnea Who May Have Heart Failure?

In patients with dyspnea, prehospital and emergency providers make therapeutic decisions before a diagnosis is established. Inhaled beta-2 agonists are frontline treatment for patients with dyspnea due to asthma or chronic obstructive pulmonary disease (COPD) exacerbations. However, these agents have been associated with increased adverse events when administered chronically to heart failure patients. Our goal was to determine the safety and efficacy of acute administration of inhaled beta-2 agonists to patients with heart failure. MEDLINE and EMBASE searches were performed using the terms "beta agonists," "albuterol," "congestive heart failure," and "pulmonary edema." Bibliographies of relevant articles were searched. Only studies addressing acute effects of beta-2 agonists were included for analysis. Twenty-four studies comprising 434 patients were identified that addressed the acute delivery of beta-2 agonists in subjects with heart failure--five studies with inhaled administration and 19 with systemic administration. No study directly evaluated the effects of inhaled beta-2 agonists to patients with acutely decompensated heart failure. Treatment of heart failure patients with beta-2 agonists resulted in transient improvements in pulmonary function and cardiovascular hemodynamics. Only one investigation reported an association between beta-2 agonist use and an increase in malignant dysrhythmias. Investigations in animal models of heart failure and acute lung injury demonstrated resolution of pulmonary edema with beta agonist administration. There is insufficient evidence to suggest that acute treatment with inhaled beta-2 agonists should be avoided in patients with dyspnea who may have heart failure. Based on small studies and indirect evidence, administration of beta-2 agonists to patients with heart failure seems to improve pulmonary function, cardiovascular hemodynamics, and resorption of pulmonary edema. Although an increase in adverse effects with the use of beta-2 agonists cannot be ruled out based on these data, there was no evidence of an increase in clinically significant dysrhythmias, especially when administered by inhalation. Based on these findings, further study should focus on the clinical outcomes of patients with acutely decompensated heart failure who are treated with inhaled beta-2 agonist therapy.

Asthma Worsenings: Approaches to Prevention and Management from the Asthma Worsenings Working Group

Most asthma patients prescribed maintenance asthma therapies still experience periods of asthma worsenings characterized by daytime or night-time symptoms, or an increased need for rescue medication. In fact, these episodes are highly prevalent even in patients with well-controlled disease. Published literature suggests that asthma worsenings likely represent a window of opportunity during which patients could intervene early to prevent exacerbations or further deterioration of asthma symptoms. However, current evidence suggests that most patients fail to respond or to self-manage appropriately during these periods.To address the issue of asthma worsenings, an interdisciplinary committee of respirologists, allergists, family physicians, pharmacists and certified asthma educators from across Canada developed a practical definition of asthma worsenings and provided approaches to the prevention and management of these episodes based on current literature. To date, combination inhaled corticosteroid/long-acting beta-agonist therapy, particularly single inhaler maintenance and reliever therapy, appears to be an effective strategy for preventing asthma worsenings and exacerbations. Addressing the potential barriers to appropriate patient self-management of asthma worsenings, such as failure to adequately identify and respond to worsenings, low expectations for controlling asthma, low health literacy and poor patient-health care professional communication, are also critical to the successful prevention and management of these episodes. Finally, an interdisciplinary team approach involving patients and their families, certified asthma educators, primary care physicians, pharmacists and specialists is likely to have the greatest impact on the identification, prevention and management of asthma worsenings.

Three Generations of Ongoing Controversies Concerning the Use of Short Acting Beta-Agonist Therapy in Asthma: A Review

An increase in asthma mortality in 1960s noted by British authors stirred a debate about the use of beta-adrenergic therapy that has persisted in the medical literature. The cause appears to be isoproterenol and fenoterol overuse. A second debate evolved around the possible deleterious, pro-inflammatory effects, of the albuterol distomer. Most clinical studies showed improved bronchodilatation, but limited benefits from using levalbuterol. Recently, genotyping has uncovered a single nucleotide polymorphism at codon 16 that appears to affect the long term response to both regular and as needed use of albuterol, calling for a new genotype based therapeutic approach in asthma.

Effect of ADRB2 polymorphisms on response to longacting β 2-agonist therapy: a pharmacogenetic analysis of two randomised studies

New evidence has suggested that people with asthma who are homozygous for arginine at aminoacid 16 of the beta2-adrenergic receptor (ADRB2) might not benefit from longacting beta2-agonist therapy. We, therefore, investigated whether ADRB2 polymorphisms affect response to longacting beta2-agonists in combination with inhaled corticosteroids. Asthmatics were stratified by ADRB2 genotype in two studies to assess the effects of inhaled corticosteroids plus longacting beta2-agonists on asthma exacerbations. In study 1 (double-blind), 2250 asthmatics were randomly assigned to budesonide plus formoterol maintenance and reliever therapy, fixed-dose budesonide plus formoterol, or fixed-dose fluticasone plus salmeterol for 6 months. Study 2 (open-label) consisted of 405 asthmatics and compared an adjustable regimen of budesonide plus formoterol with fixed-dose budesonide plus formoterol and fixed-dose fluticasone plus salmeterol for 7 months. The relation between ADRB2 polymorphism, severe asthma exacerbations, and other asthma outcomes was analysed. Primary endpoints for studies 1 and 2 were severe asthma exacerbation and asthma control as assessed by measures of exacerbations, respectively. In study 1, Gly16Arg genotype had no effect on the percentage of participants with severe exacerbations across all treatment groups (99 [12%] of 833 Gly/Gly, 110 [11%] of 1028 Gly/Arg, and 32 [9%] of 361 Arg/Arg participants). Secondary endpoints, including forced expiratory volume in 1 s, peak expiratory flow, use of as-needed medication, and number of nights with awakenings were similar between genotype groups. No relation was recorded between ADRB2 haplotype and primary and secondary endpoints. In study 2, the frequency of asthma exacerbations (15 [9%] of 168 Gly/Gly, 13 [8%] of 169 Gly/Arg, and 6 [9%] of 67 Arg/Arg participants) and other study endpoints were closely similar for all ADRB2 genotypes. Since we showed no pharmacogenetic effect of ADRB2 variation on therapeutic response in asthma, patients, irrespective of their genotype, can continue to receive inhaled corticosteroids plus longacting beta2-agonists.

Uso do sulfato de magnésio por via venosa e nebulização para o tratamento da asma aguda na emergência

Magnesium sulfate has been shown to benefit asthmatic children and adults with poor responses to initial beta-agonist therapy and systemic corticoids in the emergency department. The aim of this study was to realize a no systematic review about the treatment of the acute asthma with intravenous and nebulized magnesium sulfate in the emergence. The first investigations that demonstrate the benefit in the use of the magnesium sulfate in asthma date to 1938. The effects of magnesium sulfate may be mediated through its action as a calcium antagonist or through its function as a cofactor in enzyme systems involving ion flux across cell membranes. We realized a literature review using MedLine database of the last six years (2000 to 2006). Articles published in English were included by the crossing of keywords asthma and magnesium sulfate. The routine administration of intravenous and nebulized magnesium sulfate to severely ill patients with acute asthma presents in the emergence department is not recommended, however as an adjunct therapy brings some benefit.

ADRB2 Arg16Gly polymorphism, lung function, and mortality: results from the Atherosclerosis Risk in Communities study.

BackgroundGrowing evidence suggests that the Arg16Arg genotype of the beta-2 adrenergic receptor gene may be associated with adverse effects of beta-agonist therapy. We sought to examine the association of beta-agonist use and the Arg16Gly polymorphism with lung function and mortality among participants in the Atherosclerosis Risk in Communities study.Methodology and Principal FindingsWe genotyped study participants and analyzed the association of the Arg16Gly polymorphism and beta-agonist use with lung function at baseline and clinical examination three years later and with all-cause mortality during 10 years of follow-up. Lung function was characterized by percent-predicted forced expiratory volume in 1 second. Associations were examined separately for blacks and whites. Black beta-agonist users with the Arg/Arg genotype had better lung function at baseline and at the second clinical visit than those with Arg/Gly and Gly/Gly genotypes. Adjusted mean percent-predicted FEV1 was 21% higher in Arg/Arg subjects compared to Gly/Gly at baseline (p = 0.01) and 20% higher than Gly/Gly at visit 2 (p = 0.01). Arg/Gly subjects had adjusted percent-predicted FEV1 17% lower than Arg/Arg at baseline but were similar to Arg/Arg subjects at visit 2. Although black beta-agonist users with the Arg/Arg genotype appeared to have better crude survival rates, the association between genotype and all-cause mortality was inconclusive. We found no difference in lung function or mortality by genotype among blacks who did not use beta-agonists or among whites, regardless of beta-agonist use.ConclusionsBlack beta-agonist users with the ADRB2 Arg16Arg genotype had better lung function, and, possibly, better overall survival compared to black beta-agonist users with the Gly16Gly genotype. Our findings highlight the need for additional studies of sufficient size and statistical power to allow examination of outcomes among beta-agonist users of different races and genotypes.

Acidose métabolique dans un contexte d'asthme aigu grave

In a context of asthma, lactic acidosis may occur during beta 2-agonist therapy. Several cases have been reported during its administration by intravenous and/or inhaled route. This side-effect seems rather unknown and the mechanism for compensation of metabolic acidosis by hyperventilation may worsen dyspnoea and mislead clinicians. Other causes of lactic acidosis such as a major hypoxemia, a cardiovascular collapse or sepsis may also be experienced in this context and must be ruled out before attributing the lactic acidosis to beta 2-agonist treatment. We report the case of a 50-year-old man hospitalized for an acute major asthma, who received a salbutamol continuous infusion associated with inhaled terbutaline. A serum lactate level of 13 mmol/l was noted eight hours after the introduction of the bronchodilator treatment. After reducing doses of beta 2-agonists, the evolution was favourable, regarding both respiratory and metabolic aspects, with a rapid decrease of the serum lactate level, which finally returned to normal level after 32 hours of hospitalization.

Effect of Polymorphisms in the Beta 2-Adrenergic Receptor Gene ( ADRB2) on Response to Long-Acting Beta 2-Agonist (LABA) Therapy

Effect of Polymorphisms in the Beta 2-Adrenergic Receptor Gene ( ADRB2) on Response to Long-Acting Beta 2-Agonist (LABA) Therapy

Trends in Beta-2 Agonist Therapy

Trends in Beta-2 Agonist Therapy

Ipratropium bromide versus short acting beta-2 agonists for stable chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a condition associated with high morbidity, mortality and cost to the community. Patients often report symptomatic improvement with short-acting beta-2 agonists (SABA) and anticholinergic bronchodilator medications, and both are recommended in COPD guidelines. These medications have different mechanisms of action and therefore could have an additive effect when combined. To compare the relative efficacy and safety of regular long term use (at least four weeks) of ipratropium bromide and short- acting beta-2 agonist therapy in patients with stable COPD. The Cochrane Airways Group Specialised Register of Trials was searched. Bibliographies were checked to identify relevant cross-references. Drug companies were contacted for relevant trial data. The searches are current to August 2005. All randomised controlled trials comparing at least 4 weeks of treatment with an anticholinergic agent (ipratropium bromide) alone or in combination with a beta-2 agonist (short acting) versus the beta-2 agonist alone, delivered via metered dose inhaler or nebuliser, in non-asthmatic adult subjects with stable COPD. Data extraction and study quality assessment was performed independently by three reviewers. Authors of studies and relevant manufacturers were contacted if data were missing. Eleven studies (3912 participants) met the inclusion criteria of the review. Small benefits of ipratropium over a short-acting beta-2 agonist were demonstrated on lung function outcomes. There were small benefits in favour of ipratropium on quality of life (HRQL), as well as a reduction in the requirement for oral steroids. Combination therapy with ipratropium plus a short-acting beta-2 agonist conferred benefits over a short-acting beta-2 agonist alone in terms of post-bronchodilator lung function. There was no significant benefit of combination therapy in subjective improvements in HRQL, but again there was a reduction in the requirement for oral steroids. The available data from the trials included in this review suggest that the advantage of regular long term use of ipratropium alone or in combination with a short-acting beta-2 agonist or over a beta-2 agonist alone are small, if the aim is to improve lung function, symptoms and exercise tolerance. Until further data are available, the strategy of providing a short-acting beta-2 agonist on a PRN basis, and then either continuing with the short-acting beta-2 agonist regularly or conducting an "n of 1" trial of regular beta-2 agonist or regular anticholinergic to determine the treatment that gives the best relief of symptoms (and continuing with it), would seem cost effective. This strategy does need formal evaluation. Patient preference is also important, as is the relative importance of avoiding the use of systemic corticosteroids.

??2-Adrenergic receptor polymorphisms in African American children with status asthmaticus*

The beta2-adrenergic receptor plays a central role in the bronchodilator response to beta2-agonists in patients with asthma. Genetic polymorphisms within the gene coding for this receptor influence responsiveness of the receptor. A number of these polymorphisms differ in frequency in the African American and white populations. To determine the frequency of specific beta2-adrenergic receptor polymorphisms in African American children with status asthmaticus and to examine whether a specific genotype is associated with the clinical response to therapy. Cohort of African American children diagnosed with status asthmaticus. Tertiary care children's hospital. A total of 31 African American children with status asthmaticus. Blood samples were obtained from children at admission. Genotypes were determined by polymerase chain reaction amplification and restriction enzyme digestion. The requirement for admission to the pediatric intensive care unit, need for mechanical ventilation, institution of various therapies, and length of stay. The genotypes of the polymorphic sites at amino acid positions 16 and 27 in the beta2-adrenergic receptor were determined. There were no significant differences between the various genotypes in the percentage of children requiring pediatric intensive care unit admission, mechanical ventilation, terbutaline treatment, or length of stay. However, in children heterozygous for Glu at position 27 of the beta2-adrenergic receptor, the percentage of patients requiring aminophylline treatment, in addition to beta2-agonist therapy, was significantly higher than that seen in patients homozygous for Gln at that position (5/10 [50%] vs. 1/21 [5%], respectively; p = .002). African American children with status asthmaticus who have the Gln/Glu genotype at amino acid position 27 of the beta2-adrenergic receptor may benefit from aminophylline treatment in addition to beta2-agonist therapy.

Pharmacogenetics of β<sub>2</sub>-Agonist Drugs in Asthma

Genetic variation in the structure of the beta2-adrenoceptor (ADRB2) is a potentially important source of variability in the response to beta2-agonist drugs. The relevant polymorphisms are common, with allele frequencies as high as 50% in some cases. "Nonsynonymous" variants result in amino acid substitutions in the receptor structure, of which substitution of Gly for Arg at position 16 and Glu for Gln at position 27 are the most clinically relevant. Other polymorphisms occur in the noncoding flanking regions of the gene and may be important in regulating ADRB2 expression, thus affecting individual drug responses. Linkage disequilibrium involving polymorphisms in both the coding and noncoding regions may explain the diversity of outcomes regarding functional in vitro studies. To date, analysis by haplotype, rather than genotype, has tended to confuse the issues. Functional in vitro studies provide the basis by which these polymorphisms are believed to be relevant in vivo. However, follow-up investigations have not substantiated the conventional wisdom that Gly-16 confers increased propensity to downregulation, whereas Glu-27 confers resistance. The in vivo picture is further complicated by the dynamic status of ADRB2s. Paradoxically, downregulation of receptors with exogenous beta2-agonist drugs may occur more readily in cells that are relatively resistant to downregulation with exposure to endogenous catecholamine. Numerous studies have highlighted that the Arg-16 variant is associated with an enhanced bronchodilator response in vivo, although the picture is not a consistent one. Outcomes during chronic treatment of asthma with beta2-agonists have been more consistent. In patients who are homozygous for Arg-16, reduced lung function and increased frequency of exacerbations occur during chronic treatment with short-acting beta2-agonists. With long-acting beta2-agonists, the overall clinical benefits may be worse for Arg-16 than for the Gly-16 genotype. Therefore, ADRB2 polymorphisms are an important consideration in assessing individual patients with difficult asthma that may be drug-induced for reasons of ADRB2 genotype. They are also relevant in the design of clinical trials involving beta2-agonist therapy.

Molecular Mechanisms of 2-Adrenergic Receptor Function and Regulation

It is now clear that the beta2-adrenergic receptor continuously oscillates between various conformations in the basal state, and that agonists act to stabilize one or more conformations. It is conceivable that synthetic agonists might be engineered to preferentially confine the receptor to certain conformations deemed clinically important while having a less stabilizing effect on unwanted conformations. In addition, studies of genetically engineered mice have revealed previously unrecognized cross-talk between the beta2-receptor and phospholipase C, such that removal of the primary dilating pathway results in downregulation of constrictive pathways and overactivity of the dilating pathway increases the contractile response. These results indicate a dynamic interaction between beta2-receptor activity and Gq-coupled receptors that constrict the airway. Potentially, then, during chronic beta-agonist therapy, expression of phospholipase C is increased, the functions of Gq-coupled constrictive receptors are enhanced, and there may be an increased tendency for clinical decompensation due to asthma and chronic obstructive pulmonary disease triggers. Antagonists to these receptors might be able to act synergistically with chronic beta-agonists to block the effect of phospholipase C. Alternatively, perhaps novel phospholipase C antagonists would provide the most efficacious approach to blocking the physiologic sequelae of cross-talk between the beta2-receptor and phospholipase C.

Cytokines Regulate β-2-Adrenergic Receptor Responsiveness in Airway Smooth Muscle via Multiple PKA- and EP2 Receptor-Dependent Mechanisms

Beta2AR desensitization in airway smooth muscle (ASM) mediated by airway inflammation has been proposed to contribute to asthma pathogenesis and diminished efficacy of beta-agonist therapy. Mechanistic insight into this phenomenon is largely conceptual and lacks direct empirical evidence. Here, we employ molecular and genetic strategies to reveal mechanisms mediating cytokine effects on ASM beta2AR responsiveness. Ectopic expression of inhibitory peptide (PKI-GFP) or a mutant regulatory subunit of PKA (RevAB-GFP) effectively inhibited intracellular PKA activity in cultured human ASM cells and enhanced beta2AR responsiveness by mitigating both agonist-specific (beta-agonist-mediated) desensitization and cytokine (IL-1beta and TNF-alpha)-induced heterologous desensitization via actions on multiple targets. In the absence of cytokine treatment, PKA inhibition increased beta2AR-mediated signaling by increasing both beta2AR-G protein coupling and intrinsic adenylyl cyclase activity. PKI-GFP and RevAB-GFP expression also conferred resistance to cytokine-promoted beta2AR-G protein uncoupling and disrupted feed-forward mechanisms of PKA activation by attenuating the induction of COX-2 and PGE2. Cytokine treatment of tracheal ring preparations from wild-type mice resulted in a profound loss of beta-agonist-mediated relaxation of methacholine-contracted rings, whereas rings from EP2 receptor knockout mice were largely resistant to cytokine-mediated beta2AR desensitization. These findings identify EP2 receptor- and PKA-dependent mechanisms as the principal effectors of cytokine-mediated beta2AR desensitization in ASM.

Nebulizer versus Inhaler with Spacer for Beta-Agonist Treatment in Acute Bronchospastic Disease

Objectives To compare the efficacy of nebulized wet aerosol with metered-dose inhaler with a spacer (MDIS) in the management of acute bronchospasm. Methods It was a retrospective study by reviewing the clinical records of patients with acute exacerbation (chief complaint of shortness of breath) of asthma or chronic obstructive pulmonary disease (COPD) presenting to the Accident and Emergency Department (AED) of Tuen Mun Hospital from 1st to 30th November 2002 and 2003 respectively. All patients received beta-agonist by nebulizer, in the year 2002 (pre-SARS period) while all patients received treatment by MDIS in the year 2003 (post-SARS period). Treatment outcome measures included admission rate, length of hospitalisation for those admitted and AED re-attendance within 7 days for those discharged from the AED. Results Altogether 821 patients were recruited in this retrospective study, 522 belonged to the nebulizer group and 299 were of the MDIS group. The two groups had similar demographic characteristics. Concerning the admission rate (47% in the nebulizer group and 41% in the MDIS group; p=0.089) and re-attendance rate (7% in the nebulizer group and 6% in the MDIS group; p=0.607), the differences were not statistically significant. For the length of hospital stay, it was shorter in the nebulizer group than the MDIS group (3.65±SD 1.88 days vs 4.10±SD 1.94 days; p=0.035). However, the admission rate in the adult subgroup (61% in the nebulizer group and 47% in the MDIS group; p=0.002) was shown to be statistically significant. In multivariate analysis, usage of nebulizer, increase in respiratory rate and age were associated with a higher admission rate. Increase in SpO2, absence of co-morbidity and asthma patients were associated with a lower admission rate. Increase in age, respiratory rate and usage of MDIS were associated with an increase in hospital stay. Asthma was associated with a decrease in AED re-attendance rate as compared to COPD. Conclusions This retrospective study showed that both nebulizer and MDIS were effective for beta-agonist therapy in acute bronchospasm in AED with respect to hospital admission rate and AED re-attendance rate, but the length of hospital stay was slightly prolonged when using MDIS.

Halothane, an Effective Infrequently Used Drug, in the Treatment of Pediatric Status Asthmaticus: A Case Report

Asthma is the most common chronic disease of childhood. Despite a better understanding of the disease process and its management, status asthmaticus continues to be a life-threatening event. The use of volatile inhaled anesthetics is infrequently reported as adjunctive therapy to conventional treatment of this condition. We report the use of halothane in a mechanically ventilated pediatric patient with life-threatening status asthmaticus who was admitted to the pediatric intensive care unit (PICU) after failing to respond to standard medical therapy and noninvasive positive pressure ventilation. A 12-year-old African American male was seen in the emergency department and treated with intravenous corticosteroids, beta-agonist therapy. He deteriorated rapidly and required endotracheal intubation and mechanical ventilation. Two hours later, the patient developed an acute, severe respiratory acidosis (pH = 6.97, PaCO2 = 171, PaO2 = 162, BE = 1.7). Halothane was started at 2% by using the Siemens Servo 900C anesthesia ventilator. Improvement in both arterial blood gases and exhaled tidal volume were noted 30 minutes after initiation of the anesthetic gas. The patient remained on halothane for a total of 36 hours. No adverse effects associated with the use of halothane were noted. The patient was extubated to BiPAP 16/6, FiO2 = 0.30 at 68 hours and was discharged home 5 days later.

Past, present and future—[formula omitted]-adrenoceptor agonists in asthma management

The beta-adrenoceptor agonists (beta-agonists) have been used to relieve bronchoconstriction for at least 5000 years. beta-agonists are based on adrenaline and early forms, such as isoprenaline, Lacked bronchial selectivity and had unpleasant side effects. Modern beta-agonists are more selective for the beta2-adrenoceptors (beta2-receptors) located in bronchial smooth muscle and have less cardiotoxicity. Traditional beta2-adrenoceptor agonists (beta2-agonists), such as salbutamol, terbutaline and fenoterol, were characterised by a rapid onset but relatively short duration of action. While valuable as reliever medication, their short duration gave inadequate night-time relief and limited protection from exercise-induced bronchoconstriction. beta2-agonists with longer durations of action, formoterol and salmeterol, were subsequently discovered or developed. When combined with inhaled corticosteroids they improved lung function, and reduced symptoms and exacerbations more than an increased dose of corticosteroids. However, tolerance to the bronchprotective effects of long-acting beta2-agonists and cross-tolerance to the bronchodilator effects of short-acting beta2-agonists is apparent despite use of inhaled corticosteroids. The role of beta2-receptor polymorphisms in the development of tolerance has yet to be fully determined. Formoterol is unique in having both a long-lasting bronchodilator effect (> 12 h) and a fast onset of action (1-3min from inhalation), making it effective both as maintenance and reliever medication. The recent change in classification from short- and long-acting beta2-agonists to rapid-acting and/or long-acting agents reflects the ongoing evolution of beta2-agonist therapy.

Clinically relevant concentrations of beta2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury.

To determine whether clinically relevant airspace concentrations of beta2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether beta2 agonist therapy decreased pulmonary edema in experimental acute lung injury. Prospective randomized laboratory investigation. University-affiliated laboratory. Sprague Dawley rats. Dibutyryl cyclic adenosine monophosphate (cAMP), salmeterol, albuterol, and isoproterenol in normal rat lung. Salmeterol in a rat model of acid-induced lung injury. Basal alveolar fluid clearance was 7.6 +/- 2.2 %/hr. Maximal cAMP-dependent alveolar fluid clearance rate was 32.9 +/- 10.9 %/hr (p <.05). Racemic albuterol 10(-5) M, salmeterol 10(-6) M, and isoproterenol 10(-6) M each stimulated alveolar fluid clearance to a level comparable to maximal cAMP-dependent alveolar fluid clearance. Compared with basal rates, alveolar fluid clearance was increased by both racemic albuterol 10(-6) M (14.5 +/- 3.0%, p <.05) and R-enantiomer 10(-6) M (15.0 +/- 4.6%, p <.05), but there was no difference between the two groups. Intra-alveolar salmeterol 10 (-6) M attenuated the degree of pulmonary edema following acid-induced lung injury. Extravascular lung water increased to only 180 +/- 30 microL with salmeterol treatment, compared with 296 +/- 65 microL in saline-treated rats 4 hrs after acid injury (p <.05). This decrease in lung water was accompanied by a 2.4-fold increase in the rate of alveolar fluid clearance at 4 hrs in the salmeterol-treated group. Lung endothelial permeability, expressed as extravascular plasma equivalents, was reduced to 64 +/- 9 microL with salmeterol compared with 119 +/- 51 microL in saline-treated rats 4 hrs after acid injury (p <.05). Clinically relevant airspace concentrations of beta2-adrenergic agonists a) stimulate maximal cAMP-dependent airspace fluid clearance in normal lungs and b) reduce pulmonary edema in acid aspiration-induced lung injury by increasing alveolar fluid clearance and decreasing endothelial permeability. Clinical studies are required to determine whether beta2-adrenergic agonists improve outcome in patients with acute lung injury.