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Severe Asthma
Abstract
Asthma is a clinically heterogeneous inflammatory disorder characterized by variable and recurring symptoms of airflow obstruction. This chapter briefly describes the genetic and environmental factors that lead to development of various phenotypic expressions of asthma. An understanding of asthma pathophysiology is crucial to the evaluation, assessment, and treatment of the severe asthmatic patient. Accurate and focused evaluation of pediatric patients with acute asthma exacerbation guides medical management to improve outcomes. An algorithm containing three therapeutic tiers serves as a treatment guideline for the multidisciplinary team.
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Asthma is characterized by mucus abnormalities. Airway epithelial hyperplasia and metaplasia result in changes in stored and secreted mucin and the production of a pathologic mucus gel. Mucus transport is impaired, culminating in mucus plugging and airway obstruction-a major cause of morbidity in asthma. The polymeric mucins MUC5AC and MUC5B are integral components of airway mucus. MUC5AC and MUC5B gene expression is altered in asthma, and recent work sheds light on their contribution to asthma pathogenesis. Herein, we review our current understanding of the role of MUC5AC and MUC5B in mucus dysfunction in asthma.
Vocal cord dysfunction (VCD)-associated symptoms are not rare in pediatric patients. Dyspnea, wheezing, stridor, chest pain or tightness and throat discomfort are the most commonly encountered symptoms. They may occur either at rest or more commonly during exercise in patients with VCD, as well as in asthmatic subjects. The phase of respiration (inspiration rather than expiration), the location of the wheezing origin, the rapid resolution of symptoms, and the timing occurring in relation to exercise, when VCD is exercise induced, raise the suspicion of VCD in patients who may have been characterized as merely asthmatics and, most importantly, had not responded to the appropriate treatment. The gold standard method for the diagnosis of VCD is fiberoptic laryngoscopy, which may also identify concomitant laryngeal abnormalities other than VCD. However, as VCD is an intermittent phenomenon, the procedure should be performed while the patient is symptomatic. For this reason, challenges that induce VCD symptoms should be performed, such as exercise tests. Recently, for the evaluation of patients with exercise-induced VCD, continuous laryngoscopy during exercise (such as treadmill, bicycle ergometer, swimming) was used. A definite diagnosis of VCD is of importance, especially for those patients who have been erroneously characterized as asthmatics, without adequate response to treatment. In these cases, another therapeutic approach is necessary, which will depend on whether they suffer solely from VCD or from both conditions.
Background:
Asthma is the most common obstructive airway disease in children and adults. Nasal high flow (NHF) is a recent device that is now used as a primary support for respiratory distress. Several studies have reported use of NHF as a respiratory support in status asthmaticus; however, there are no data to recommend such practice. We therefore conducted this preliminary study to evaluate NHF therapy for children with status asthmaticus admitted to our PICU in order to prepare a multicentre randomized controlled study.
Results:
Between November 2009 and January 2014, 73 patients with status asthmaticus were admitted to the PICU, of whom 39 (53%) were treated with NHF and among these 10 (26%) presented severe acidosis at admission (pH < 7.30). Thirty-four less severe children (41%) were treated with standard oxygen. For one child (2.6%) NHF failed and was then switched to non-invasive ventilation. NHF was discontinued in another patient because of the occurrence of pneumothorax after 31 h with NHF; the patient was then switched to standard oxygen therapy. Mean ± SD heart rate (165 ± 21 vs. 141 ± 25/min, p < 0.01) and respiratory rate (40 ± 13 vs. 31 ± 8/min, p < 0.01) decreased significantly, and blood gas improved in the first 24 h. In the subgroup of patients with acidosis, median [IQR] pH increased significantly between hour 0 and 2 (7.25 [7.21-7.26] vs. 7.30 [7.27-7.33], p = 0.009) and median [IQR] pCO2 decreased significantly (7.27 kPa [6.84-7.91 vs. 5.85 kPa [5.56-6.11], p = 0.007). No patient was intubated.
Conclusion:
This retrospective study showed the feasibility and safety of NHF in children with severe asthma. Blood gas and clinical parameters were significantly improved during the first 24 h. NHF failed in only two patients, and none required invasive ventilation.
Asthma runs in families, and children of asthmatic parents are at increased risk of asthma. Prediction of disease risk is pivotal for the clinician when counselling atopic families. However, this is not always an easy task bearing in mind the vast and ever-increasing knowledge about asthma genetics. The advent of new genotyping technologies has made it possible to sequence in great detail the human genome for asthma-associated variants, and accordingly, recent decades have witnessed an explosion in the number of rare and common variants associated with disease risk. This review presents an overview of methods and advances in asthma genetics in an attempt to help the clinician keep track of the most important knowledge in the field.
Asthma is prevalent but treatable: adherence to evidence-based treatment lessens impairment and lowers the risk of future exacerbations.
This report details recent trends in asthma prevalence, health care use, and mortality since 2001 and presents an overview of trends since 1980.
Asthma prevalence estimates were obtained from the National Health Interview Survey (2001-2010). Physician office visit data were obtained from the National Ambulatory Medical Care Survey, hospital outpatient department and emergency department (ED) visit data from the National Hospital Ambulatory Medical Care Survey, hospitalization data from the National Hospital Discharge Survey, and death data from the National Vital Statistics System (2001-2009). Two types of rates were calculated: population-based rates based on the total population and risk-based rates based on the population with asthma.
Current asthma prevalence increased from 2001 to 2010. There were no significant changes in rates for hospital outpatient department visits, ED visits, or hospitalizations, whereas risk-based rates for private physician office visits declined. Asthma death rates decreased from 2001 to 2009. Over the long term, asthma prevalence rose more slowly after 2001 than during 1980-1996, asthma hospitalizations declined since 1984 and deaths declined since 1999. Disparities by race and sex for adverse outcomes remained high despite these declines.
Since 2001, asthma prevalence increased, risk-based rates for visits to private physician offices and deaths declined, and risk-based rates for other types of ambulatory visits and for hospitalizations showed no clear trend.
To determine whether children with severe acute asthma treated with large doses of inhaled salbutamol, inhaled ipratropium, and intravenous steroids are conferred any further benefits by the addition of aminophylline given intravenously.
Randomised, double blind, placebo controlled trial of 163 children admitted to hospital with asthma who were unresponsive to nebulised salbutamol.
The placebo and treatment groups of children were similar at baseline. The 48 children in the aminophylline group had a greater improvement in spirometry at six hours and a higher oxygen saturation in the first 30 hours. Five subjects in the placebo group were intubated and ventilated after enrollment compared with none in the aminophylline group.
Aminophylline continues to have a place in the management of severe acute asthma in children unresponsive to initial treatment.
It is easy to underestimate the effects of ventilation on the cardiovascular system, or to misinterpret cardiopulmonary interactions as primary cardiovascular events. We have described how simple ventilatory interventions can sometimes be used to obviate the unnecessary escalation of pharmacological support, and have discussed how in other situations, anticipatory management with fluids or vasoactive agents can minimise cardiovascular compromise during mechanical ventilation. Mechanical ventilation playsa crucial role in the haemodynamic management of critically ill children, and application of the principles that have been described are an essential part of intensive care management.
Acute asphyxial asthma (AAA) is well described in adult patients and is characterized by a sudden onset that may rapidly progress to a near-arrest state. Despite the initial severity of AAA, mechanical ventilation often restores gas exchange promptly, resulting in shorter durations of ventilation. We believe that AAA can occur in children and can lead to respiratory failure that requires mechanical ventilation. Furthermore, children with rapid-onset respiratory failure that requires intubation in the emergency department (ED) are more likely to have AAA and a shorter duration of mechanical ventilation than those intubated in the pediatric intensive care unit (PICU).
An 11-year retrospective chart review (1991-2002) was conducted of all children who were aged 2 through 18 years and had the primary diagnosis of status asthmaticus and required mechanical ventilation.
During the study period, 33 (11.4%) of 290 PICU admissions for status asthmaticus required mechanical ventilation. Thirteen children presented with rapid respiratory failure en route, on arrival, or within 30 minutes of arrival to the ED versus 20 children who progressed to respiratory failure later in their ED course or in the PICU. Mean duration of mechanical ventilation was significantly shorter in the children who presented with rapid respiratory failure versus those with progressive respiratory failure (29 +/- 43 hours vs 88 +/- 72 hours). Children with rapid respiratory failure had greater improvements in ventilation and oxygenation than those with progressive respiratory failure as measured by pre- and postintubation changes in arterial carbon dioxide pressure, arterial oxygen pressure/fraction of inspired oxygen ratio, and alveolar-arterial gradient. According to site of intubation, 23 children required intubation in the ED, whereas 10 were intubated later in the PICU. Mean duration of mechanical ventilation was significantly shorter in the ED group versus the PICU group (42 +/- 63 hours vs 118 +/- 46 hours). There were significantly greater improvements in ventilation and oxygenation in the ED group versus the PICU group as measured by pre- and postintubation changes in arterial carbon dioxide pressure and arterial oxygen pressure/fraction of inspired oxygen ratio.
AAA occurs in children and shares characteristics seen in adult counterparts. Need for early intubation is a marker for AAA and may not represent a failure to maximize preintubation therapies. AAA represents a distinct form of life-threatening asthma and requires additional study in children.
To evaluate the effectiveness of intravenous magnesium sulphate in the treatment of acute asthmatic attacks in children by meta-analysis.
A systematic and comprehensive search of the literature was performed to identify controlled clinical trials of magnesium sulphate in paediatric acute asthma which evaluated outcomes of hospitalisation or short term pulmonary function tests or symptom scores. Unpublished data were searched by personal contacts with authors and specialists. Two reviewers independently assessed trial qualities and synthesised data. Heterogeneity among studies was evaluated by the Cochrane Q test. Outcome data were pooled by random or fixed effect models depending on presence or absence of heterogeneity.
Five randomised placebo controlled trials involving a total of 182 patients were identified. They compared intravenous magnesium sulphate to placebo in treating paediatric patients with moderate to severe asthmatic attacks in the emergency department, with co-therapies of inhaled beta2 agonists and systemic steroids. The studies were of high quality with results judged to be valid. Four studies showed that magnesium sulphate was effective, while one study found it ineffective. There was no significant heterogeneity in the primary outcome of hospitalisation. In the fixed effect model, magnesium sulphate is effective in preventing hospitalisation (OR 0.290, 95% CI 0.143 to 0.589). The number needed to treat is 4 (95% CI 3 to 8). Secondary outcomes of short term pulmonary function tests and clinical symptom scores also showed significant improvement.
Intravenous magnesium sulphate probably provides additional benefit in moderate to severe acute asthma in children treated with bronchodilators and steroids.
Acute severe asthma induces marked alterations in respiratory mechanics, characterized by a critical limitation of expiratory flow and a heterogeneous and reversible increase in airway resistance, resulting in premature airway closure, lung, and chest wall dynamic hyperinflation and high intrinsic PEEP.
These abnormalities increase the work of breathing and can lead to respiratory muscle fatigue and life-threatening respiratory failure, in which case mechanical ventilation is life-saving. When instituting mechanical ventilation in this setting, a major concern is the risk of worsening lung hyperinflation (thereby provoking barotrauma) and inducing or aggravating hemodynamic instability. Guidelines for mechanical ventilation in acute severe asthma are not supported by strong clinical evidence. Controlled hypoventilation with permissive hypercapnia may reduce morbidity and mortality compared to conventional normocapnic ventilation. Profound pathological alterations in respiratory mechanics occur during acute severe asthma, which clinicians should keep in mind when caring for ventilated asthmatics.
We focus on the practical management of controlled hypoventilation. Particular attention must be paid to ventilator settings, monitoring of lung hyperinflation, the role of extrinsic PEEP, and administering inhaled bronchodilators. We also underline the importance of deep sedation with respiratory drive-suppressing opioids to maintain patient-ventilator synchrony while avoiding as much as can be muscle paralysis and the ensuing risk of myopathy. Finally, the role of noninvasive positive pressure ventilation for the treatment of respiratory failure during severe asthma is discussed.
Anaesthetic management in asthmatic patients has been focused on avoiding bronchoconstriction and inducing bronchodilation. However, the definition of asthma has changed over the past decade. Asthma has been defined as a clinical syndrome characterized by an inflammatory process that extends beyond the central airways to the distal airways and lung parenchyma. With this concept in mind, and knowing that asthma is a common disorder with increasing prevalence rates and severity worldwide, a rational choice of anaesthetic agents and procedures is mandatory. Thus, we pursued an update on the pharmacologic and technical anaesthetic approach for the asthmatic patient. When feasible, regional anaesthesia should be preferred because it reduces airway irritation and postoperative complications. If general anaesthesia is unavoidable, a laryngeal mask airway is safer than endotracheal intubation. Lidocaine inhalation, alone or combined with albuterol, minimizes histamine-induced bronchoconstriction. Propofol and ketamine inhibit bronchoconstriction, decreasing the risk of bronchospasm during anaesthesia induction. Propofol yields central airway dilation and is more reliable than etomidate or thiopental. Halothane, enflurane, and isoflurane are potent bronchodilators and can be helpful even in status asthmaticus. Sevoflurane has shown controversial results in asthmatic patients. Vecuronium, rocuronium, cisatracurium, and pancuronium do not induce bronchospasm, while atracurium and mivacurium can dose-dependently release histamine and should be cautiously administered in those patients. Further knowledge about the sites of action of anaesthetic agents in the lung, allied with our understanding of asthma pathophysiology, will establish the best anaesthetic approach for people with asthma.
Objectives:
To assess the efficacy of high-flow nasal cannula (HFNC) oxygen therapy and safety in children with asthma and moderate respiratory failure in the emergency department (ED).
Study design:
This was a prospective randomized pilot trial of children (aged 1-14 years) presenting to a tertiary academic pediatric ED with moderate-to-severe asthma exacerbations between September 2012 and December 2015. Patients with a pulmonary score (PS) ≥6 or oxygen saturation <94% with a face mask despite initial treatment (salbutamol/ipratropium bromide and corticosteroids) were randomized to HFNC or to conventional oxygen therapy. Pharmacologic treatment was at the discretion of attending physicians. The primary outcome was a decrease in PS ≥2 in the first 2 hours. Secondary outcomes included disposition, length of stay, and need for additional therapies.
Results:
We randomly allocated 62 children to receive either HFNC (n = 30) or standard oxygen therapy (n = 32). Baseline patient characteristics were similar in the 2 groups. At 2 hours after the start of therapy, PS had decreased by ≥2 points in 16 patients in the HFNC group (53%) compared with 9 controls (28%) (P = .01). Between-group differences in disposition, length of stay, and need for additional therapies were not significant. No side effects were reported.
Conclusion:
HFNC appears to be superior to conventional oxygen therapy for reducing respiratory distress within the first 2 hours of treatment in children with moderate-to-severe asthma exacerbation refractory to first-line treatment. Further studies are needed to demonstrate its overall efficacy in the management of asthma and respiratory failure in the ED.
Trial registration:
EudraCT: 2012-001771-36.
Background:
Diffuse airway mucus obstruction is an important feature of severe and fatal asthma. MUC5AC and MUC5B are the principal gel-forming mucins found in airway mucus. The mucin composition of airway mucus likely affects its functional properties.
Methods:
We quantified the principal airway mucins MUC5AC and MUC5B in the sputum of age-matched children with acute and stable asthma and healthy controls using Western blotting.
Results:
Sputum samples from 38 children (13 acute asthma, 15 stable asthma, 10 controls) were obtained. Sputum MUC5AC concentrations were 7.6 μg/ml in controls, 22.4 μg/ml in stable asthma (p=0.17) and 44.7 μg/ml in acute asthma (p<0.05). Concentration of MUC5B showed less variation with, 156.2 μg/ml, 222.3 μg/ml and 254.8 μg/ml in healthy controls, stable and acute asthma respectively. The greater MUC5AC concentration in acute asthma resulted in a significantly altered MUC5B:MUC5AC ratio between healthy control and acute asthma (p<0.05). Significant differences in MUC5B glycoforms were present between the groups, with the low-charge-only glycoform being uniquely found in acute asthma.
Conclusions:
Increased MUC5AC and the presence of a low-charge-only MUC5B glycoform significantly alters mucin composition in children with acute asthma. These changes may be important contributory factors to the airway mucus obstruction observed during acute asthma.
Asthma exacerbation is a common reason for children to present to the emergency department. If primary therapies fail to halt the progression of an asthma flare, status asthmaticus often leads to hospital, and potentially ICU, admission. Following the initial administration of inhaled β agonists and systemic corticosteroids, a wide array of adjunct medical therapies may be used to treat status asthmaticus. Unfortunately, the data supporting the use of these adjunct therapies are often unclear, conflicting, or absent. This review will present the physiologic basis and summarize the supporting data for a host of adjunct therapies, including ipratropium, intravenous β agonists, methylxanthines, intravenous and inhaled magnesium, heliox (helium-oxygen mixture), ketamine, antibiotics, noninvasive ventilation, inhaled anesthetics, and extracorporeal membrane oxygenation. Finally, we present a suggested care map for escalating to these therapies in children with refractory status asthmaticus.
Severe asthma in children is a complicated and heterogeneous disorder that is extremely challenging to treat. Although most children with asthma derive clinical benefit from daily administration of low-to-medium-dose inhaled corticosteroid (ICS) therapy, a small subset of children with "severe" or "refractory" asthma require high doses of ICS and even systemic corticosteroids to maintain symptom control. These children with severe asthma are at increased risk for adverse outcomes including medication-related side effects and recurrent and life-threatening exacerbations that significantly impair quality of life. This review highlights findings on severe asthma in school-age children (age 6-17 years) from the National Heart, Lung and Blood Institute's Severe Asthma Research Program (SARP) over a 10-year period, between 2001 and 2011. Although SARP has advanced knowledge of the unique clinical, biological, and molecular attributes of severe asthma in children, considerable gaps remain for which additional studies are needed.
Background:
Childhood asthma prevalence doubled from 1980 to 1995 and then increased more slowly from 2001 to 2010. During this second period, racial disparities increased. More recent trends remain to be described.
Methods:
We analyzed current asthma prevalence using 2001-2013 National Health Interview Survey data for children ages 0 to 17 years. Logistic regression with quadratic terms was used to test for nonlinear patterns in trends. Differences between demographic subgroups were further assessed with multivariate models controlling for gender, age, poverty status, race/ethnicity, urbanicity, and geographic region.
Results:
Overall, childhood asthma prevalence increased from 2001 to 2009 followed by a plateau then a decline in 2013. From 2001 to 2013, multivariate logistic regression showed no change in prevalence among non-Hispanic white and Puerto Rican children and those in the Northeast and West; increasing prevalence among 10- to 17-year-olds, poor children, and those living in the South; increasing then plateauing prevalence among 5- to 9-year-olds, near-poor children, and non-Hispanic black children; and increasing then decreasing prevalence among 0- to 4-year-olds, nonpoor, and Mexican children and those in the Midwest. Non-Hispanic black-white disparities stopped increasing, and Puerto Rican children remained with the highest prevalence.
Conclusions:
Current asthma prevalence ceased to increase among children in recent years and the non-Hispanic black-white disparity stopped increasing due mainly to plateauing prevalence among non-Hispanic black children.
Objective
To evaluate, by systematic review, the efficacy of heliox on respiratory mechanics and outcomes in patients with acute asthma.
Methods
The search strategy included searching electronic databases (MEDLINE, EMBASE, and The Cochrane Library) and the references of relevant articles. Study quality was assessed based on allocation concealment. Randomized controlled trials (RCTs) comparing heliox to an air-oxygen mixture (airO2) as an adjunct treatment in patients with acute asthmatic attacks were analyzed. For the qualitative portion of the analysis, all reports of the use of heliox in patients with acute asthma were included.
Results
Four RCTs (n = 278) were found to have a common respiratory parameter (peak expiratory flow rate as a percentage of predicted) suitable for meta-analysis. Within the 92% confidence interval (CI), there was a small benefit with the use of heliox compared to airO2 (weighted mean difference, + 3%; 95% CI, − 2 to + 8%). There was also a slight improvement in the dyspnea index (weighted mean difference, 0.60; 95% CI, 0.04 to 1.16) with the use of heliox over airO2. Overall, five RCTs, one nonrandomized unblinded parallel trial, one retrospective case-matched control trial, three case series, and one case report had results in favor of heliox; one RCT and one case series showed no improvement with heliox; one RCT showed a possible detrimental effect with heliox; and 1 small RCT was inconclusive. Most investigators did not prevent entrainment of room air during heliox use or compensate for the lower nebulizing efficiency of heliox.
Conclusion
Based on surrogate markers, heliox may offer mild-to-moderate benefits in patients with acute asthma within the first hour of use, but its advantages become less apparent beyond 1 h, as most conventionally treated patients improve to similar levels, with or without it. The effect of heliox may be more pronounced in more severe cases. There are insufficient data on whether heliox can avert tracheal intubation, or change intensive care and hospital admission rates and duration, or mortality.
Asthma is a common and potentially life threatening childhood condition. Asthma involves not only chronic airway remodeling, but may also include frequent exacerbations resulting from bronchospasm, edema, and mucus production. In children with severe exacerbations, standard therapy with β2-agonists, anti-cholinergic agents, oxygen, and systemic steroids may fail to reverse the severe airflow obstruction and necessitate use of adjunctive therapies. These therapies include intravenous or inhaled magnesium, inhaled helium-oxygen mixtures, intravenous methylxanthines, intravenous β2-agonists, and intravenous ketamine. Rarely, these measures are not successful and following the initiation of invasive mechanical ventilation, inhaled anesthetics or extracorporeal life support may be required. In this review, we discuss the mechanisms and evidence for adjunctive therapies in the setting of severe acute asthma exacerbations in children.
Status asthmaticus (SA) is a severe, refractory form of asthma that can result in rapid respiratory deterioration and death. Treatment of SA with inhaled anesthetics is a potentially life-saving therapy, but remarkably few data are available about its mechanism of action or optimal administration. In this paper, we will review the clinical use of inhaled anesthetics for treatment of SA, the potential mechanisms by which they dilate constricted airways, and the side effects associated with their administration. We will also introduce the concept of ‘targeted’ delivery of these agents to the conducting airways, a process which may maximize their therapeutic effects while minimizing associated systemic side effects. Such a delivery regimen has the potential to define a rapidly translatable treatment paradigm for this life-threatening disorder.
Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.
A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.
When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.
Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
Study objective
To determine the effect of the addition of heliox to standard medical care on the course of acute asthma.
Design
Systematic review of randomized and nonrandomized prospective, controlled trials of children and adults that compared heliox to placebo when used in conjunction with other standard acute treatments.
Main outcome measures
Pulmonary function tests, hospital admissions, physiologic measures, side effects, and clinical outcomes.
Results
Seven trials were selected for inclusion, with a total of 392 patients with acute asthma. Six studies involved adults, and one study dealt solely with children. The main outcome variable was spirometric measurements (peak expiratory flow or FEV1) in six trials. Two studies evaluated the effect of heliox on airways resistance. No significant differences were demonstrated between heliox or oxygen/air groups (standardized mean difference [SMD], − 0.20; 95% confidence interval [CI], − 0.91 to 0.51; p = 0.6). However, the four studies that used heliox to deliver nebulized therapy showed a nonsignificant increase in pulmonary function (SMD, − 0.21; 95% CI, − 0.43 to 0.01; p = 0.06). In two studies of the same subgroup, heliox mixtures produced a significantly greater increase of heart rate than oxygen/air (weighted mean difference, 9.0; 95% CI, 1.27 to 16.8; p = 0.02). However, the four studies that used heliox to deliver nebulized therapy reported a nonsignificant difference in hospital admissions (odds ratio, 1.07; 95% CI, 0.46 to 2.48; p = 0.9). Overall, heliox appears to be safe and well tolerated.
Conclusions
The existing evidence does not provide support for the administration of helium-oxygen mixtures to emergency department patients with moderate-to-severe acute asthma. However, these conclusions are based on between-group comparisons and small studies, and these results should be interpreted with caution.
BACKGROUND: Conventional albuterol is a racemic mixture of (S)-albuterol and (R)-albuterol (levalbuterol). Levalbuterol is therapeutically active component of albuterol whereas (S)-albuterol is considered inert with some unwanted effects. OBJECTIVES: to evaluate efficacy and safety of levalbuterol versus albuterol in acute asthma. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Pubmed and Cochrane databases. Trial eligibility criteria, participants, and interventions: Randomized control trials comparing levalbuterol versus albuterol for acute asthma in all age groups. Data extraction and result synthesis: Two authors extracted data independently. Meta-analyses were performed using Review Manager Software. RESULTS: Seven trials including a total of 1625 participants fulfilled the eligibility criteria. Respiratory rate, oxygen saturation, and percentage change in FEV1 and clinical asthma score were not significantly different between the groups with mean difference (95% CI) of 0·35 (-0·81, 1·51), -0·29 (-0·68, 0·10), -28·3 (-59·95, 3·33) and -1·01 (-5·30, 3·28) respectively. There were no significant differences in side effects between groups. LIMITATIONS: Data were not available for two probable eligible trials. A few assumptions and some calculated values were used for meta-analysis. CONCLUSIONS: Levalbuterol was not superior to albuterol regarding efficacy and safety in subjects with acute asthma. We suggest that levalbuterol should not be used over albuterol for acute asthma.
Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits.
About 9% of children have asthma, corresponding to almost 6.8 million children in the USA and 1.1 million in the UK. Asthma exacerbations are the leading cause of pediatric emergency room visits and impose a large burden on the individual, family, and society. There is mounting evidence that therapeutic failure of inhaled beta-agonists is associated with polymorphisms of the beta(2)-adrenergic receptor gene (ADRB2); specifically, mutations leading to amino acid changes at positions 16 and 27, which alter down-regulation of the beta(2)-adrenergic receptor (beta(2)AR), induce resistance to the smooth-muscle relaxing effect of beta(2)-adrenergic agonists.
We conducted a meta-analysis to examine the association between ADRB2 polymorphisms and the response to inhaled beta(2)-adrenergic agonists in children with asthma. We included all published studies until November 2008, in which asthmatic children underwent testing for acute bronchodilator response, defined as > or = 15% improvement in forced expiratory volume in 1 second (FEV(1)) and single nucleotide polymorphism (SNP) genotyping for positions 16 and/or 27 of the beta(2)AR. Individual and summary odds ratios were calculated using a random effects model.
We identified three case-control or family-based studies involving 960 asthmatic children (692 children with negative beta(2)-bronchodilator response, defined as < 15% improvement in FEV(1) and 268 children with positive bronchodilator response). We found a significant association between favorable therapeutic response to inhaled beta(2)-adrenergic agonists in asthmatic children and the Arg/Arg phenotype at position 16 of the beta(2)AR [OR = 1.77; 95% CI (1.01; 3.1); p = 0.029], compared with the Arg/Gly or Gly/Gly phenotypes. The beneficial effect of Arg at position 16 of the beta(2)AR was most pronounced in African-American asthmatic children [OR = 3.54; 95% CI (1.37, 9.13)]. There was no association between clinical response to beta(2)-agonists and polymorphism at amino acid position 27 of the beta(2)AR (OR = 1.04; 95% CI [0.76,1.42]).
Failure of bronchodilator response to inhaled beta-agonists in asthmatic children is associated with the Gly allele (Arg/Gly and Gly/Gly genotypes) at position 16 of the beta(2)-adrenergic receptor. Genetic typing for beta(2)AR polymorphism may help identify children with drug-resistant asthma.
To assess the use of high-dose continuous levalbuterol (LEV), the single active (R)-enantiomer of racemic albuterol (RAC), in the treatment of status asthmaticus.
Children age 6 to 18 years with severe asthma exacerbation were enrolled in this randomized, double-blind trial if they failed initial emergency department (ED) therapy with RAC and systemic steroids. Subjects received equipotent doses of RAC (20 mg/hour) or LEV (10 mg/hour) within a standardized inpatient protocol. Blood samples for measurements of albuterol enantiomer, potassium, and glucose levels were obtained from the first 40 subjects. The median time until discontinuation of continuous therapy was compared using the rank-sum test, and other outcomes were compared using general linear mixed models.
A total of 81 subjects (40 in the RAC group and 41 in the LEV group) were enrolled; the 2 groups were similar at baseline. Both groups tolerated continuous therapy with similar changes in heart rate and serum potassium and glucose levels but higher serum (S)-albuterol concentrations in the subjects treated with RAC. The median time for continuous therapy was similar in the RAC and LEV groups (18.3 hours vs 16.0 hours), as were the other clinical measures.
Substituting high-dose continuous LEV for RAC did not reduce the time on continuous therapy and had similar adverse effects in children who had failed initial treatment with RAC.
Ninety-seven acutely ill patients with bronchial asthma were enrolled in a double-blind, placebo-controlled, randomized trial of intravenous methylprednisolone (125 mg), given on presentation in the emergency room in addition to standard emergency treatments for asthma. Subjective and spirometric indexes of the severity of the asthma were similar on entry into the study in all patients, but only 9 of 48 patients (19 percent) treated with methylprednisolone required hospital admission, as compared with 23 of 49 patients (47 percent) in the control group (P less than 0.003). Our results suggest that prompt use of glucocorticoids in the emergency treatment of severe asthma can prevent significant morbidity, reduce the number of hospitalizations, and effect substantial savings in health care costs.
To determine the occurrence rate of complications and mortality in patients with severe asthma requiring endotracheal intubation and mechanical ventilation.
Retrospective review of medical records from September 1982 to July 1988.
Urban, teaching hospital serving primarily indigent patients.
Fifty-seven adult patients with asthma requiring tracheal intubation and mechanical ventilation.
None.
Fifty-seven patients requiring tracheal intubation and mechanical ventilation during 69 hospital admissions were identified. Medication noncompliance and upper respiratory tract infections were recorded as the most frequent precipitating events for exacerbation of asthma. Forty-nine intubations were initiated because of a clinical diagnosis of respiratory distress, but multiple indications were present in 42 admissions. One or more complications occurred in 31 episodes of endotracheal intubation and mechanical ventilation (45%). Death occurred in four (6%) of 69 admissions. Three of the four deaths occurred in patients who had a cardiorespiratory arrest before hospital admission.
While complications occurred in 45% of patients with severe asthma requiring intubation and mechanical ventilation, the mortality rate was low. We conclude that intubation and mechanical ventilation in patients with life-threatening asthma are safe and beneficial interventions.
To examine the cardiac toxicity as measured by elevations in serum cardiac troponin T (cTnT) and to compare creatine kinase (CK) and creatine kinase MB (CK-MB) and findings on electrocardiography (ECG) as markers of cardiac toxicity with cTnT during the infusion of intravenous terbutaline for the treatment of severe asthma in children.
Prospective cohort study of patients receiving intravenous terbutaline for severe asthma.
Only 3 (10%) of the 29 patients had elevations in cTnT. Each underwent mechanical ventilation for >72 hours, which was the earliest point at which cTnT elevations were identified. Eighteen (62%) patients had an elevation in CK, and 3 had an elevation in CK-MB fraction without an elevated cTnT. Twenty (69%) patients had ECG findings consistent with ischemia, and 19 of these patients had the ischemic findings on their preterbutaline ECG. Elevations in CK and CK-MB and ischemic changes on ECG did not correlate with elevations in cTnT. Both mechanical ventilation (P =.02) and prolonged administration (>72 hours) of intravenous terbutaline (P =. 02) were significantly associated with elevations in cTnT.
We found no clinically significant cardiac toxicity from the use of intravenous terbutaline for severe asthma as measured by serum cTnT elevations.
Childhood asthma typically begins in infancy with a respiratory syncytial virus (RSV) infection. Although the majority of infants become infected with RSV, lower respiratory illness develops in only about 20%. About 25% to 50% of those subsequently experience recurrent acute asthma from viral respiratory infections (VRI). Children younger than 5 years have a high frequency of VRI and have the highest frequency of hospitalization for asthma of any age group. In a 35-year study of the natural history of asthma, 20% of 7-year-old children were found to have asthma, but most had only episodic illness with VRI. The majority of those children improved with age, but a substantial minority continued to have recurrent episodes as adults, generally induced by VRI or exercise. Persistent asthma developed in only a few. Children who had symptoms of asthma without VRI were more likely to continue having frequent episodic or chronic asthma as adults. Despite generally suboptimal treatment during the 35 years of the study, forced expiratory volume at one second did not deteriorate over time; it remained normal in children who had only episodic asthma, and it was consistently low in the children with severe, persistent asthma.
There is significant interest in early identification and intervention in childhood asthma. Current asthma guidelines identify inhaled corticosteroids (ICS) as the preferred initial long-term control therapy even in young children. ICS clearly improve asthma control in children with mild to moderate persistent asthma, but it is not clear that they can alter the natu-ral history and progression of asthma. New insights regarding the origins of asthma and allergy and their natural history will continue to stimulate questions regarding the appropriate time for intervention and will stimulate the design of new treatment strategies and the discovery of new medications.
Noninvasive ventilation has been shown to be effective in patients with acute respiratory failure due to pulmonary edema and exacerbations of COPD. Its role in an acute asthmatic attack, however, is uncertain. The purpose of this pilot study was to compare conventional asthma treatment with nasal bilevel pressure ventilation (BPV) [BiPAP; Respironics; Murrysville, PA] plus conventional treatment in patients with a severe asthmatic attack admitted to the emergency department.
A prospective, randomized, placebo-controlled study.
An emergency department at a university hospital.
Thirty patients with a severe asthma attack were recruited from a larger group of 124 asthmatic patients seen in the emergency department. Fifteen patients were randomly assigned to BPV plus conventional therapy and 15 patients to conventional therapy alone. The two groups had similar clinical characteristics on hospital admission. Mean (+/- SD) FEV(1) on recruitment was 37.3 +/- 10.7% in the BPV group and 33.8 +/- 10.2% in the control group (p = not significant). Interventions and measurements: BPV with predetermined inspiratory and expiratory pressures was applied for 3 h in the BPV group; in the control group, a similar sham device with subtherapeutic pressures was applied for 3 h. Bedside lung function test results and vital signs were obtained at baseline, and during and at the completion of the study protocol.
The use of BPV significantly improved lung function test results. Eighty percents of the patients in the BPV group reached the predetermined primary end points (an increase of at least 50% in FEV(1) as compared to baseline), vs 20% of control patients (p < 0.004). Mean rise in FEV(1) was 53.5 +/- 23.4% in the BPV group and 28.5 +/- 22.6% in the conventional treatment group (p = 0.006). The intention-to-treat analysis of the secondary end point rate of hospitalization included 33 patients. Hospitalization was required for 3 of 17 patients (17.6%) in the BPV group, as compared with 10 of 16 patients (62.5%) in the control group (p = 0.0134).
In selected patients with a severe asthma attack, the addition of BPV to conventional treatment can improve lung function, alleviate the attack faster, and significantly reduce the need for hospitalization.
The development of asthmatic inflammation involves a complex array of cytokines that promote the recruitment and activation of a number of different immune cells. While factors involved in initiating and establishing inflammation are well characterized, the process by which this pro-inflammatory cascade is regulated is less well understood. The identification and characterization of immunomodulatory cytokines in asthma has been a difficult proposition. Many of the putative regulatory factors have pleiotropic bioactivities and have been characterized as pro-inflammatory in association with certain pathologic conditions. This chapter addresses the potential role of several endogenous factors which appear to attenuate asthmatic inflammation. Understanding the integration of these factors into the regulation of the inflammatory process will likely result in novel therapeutic approaches.
Allergic atopic disorders, such as rhinitis, asthma, and atopic dermatitis, are the result of a systemic inflammatory reaction triggered by type 2 T helper (Th2) cell-mediated immune responses against 'innocuous' antigens (allergens) of complex genetic and environmental origin. A number of epidemiological studies have suggested that the increase in the prevalence of allergic disorders that has occurred over the past few decades is attributable to a reduced microbial burden during childhood, as a consequence of Westernized lifestyle (the 'hygiene hypothesis'). However, the mechanisms by which the reduced exposure of children to pathogenic and nonpathogenic microbes results in enhanced responses of Th2 cells are still controversial. The initial interpretation proposed a missing immune deviation of allergen-specific responses from a Th2 to a type 1 Th (Th1) profile, as a result of the reduced production of interleukin-12 and interferons by natural immunity cells which are stimulated by bacterial products via their Toll-like receptors. More recently, the role of reduced activity of T regulatory cells has been emphasized. The epidemiological findings and the experimental evidence available so far suggest that both mechanisms may be involved. A better understanding of this question is important not only from a theoretical point of view, but also because of its therapeutic implications.
Acute exacerbations of asthma can lead to respiratory failure requiring ventilatory assistance. Noninvasive ventilation may prevent the need for endotracheal intubation in selected patients. For patients who are intubated and undergo mechanical ventilation, a strategy that prioritizes avoidance of ventilator-related complications over correction of hypercapnia was first proposed 30 years ago and has become the preferred approach. Excessive pulmonary hyperinflation is a major cause of hypotension and barotrauma. An appreciation of the key determinants of hyperinflation is essential to rational ventilator management. Standard therapy for patients with asthma undergoing mechanical ventilation consists of inhaled bronchodilators, corticosteroids, and drugs used to facilitate controlled hypoventilation. Nonconventional interventions such as heliox, general anesthesia, bronchoscopy, and extracorporeal life support have also been advocated for patients with fulminant asthma but are rarely necessary. Immediate mortality for patients who are mechanically ventilated for acute severe asthma is very low and is often associated with out-of-hospital cardiorespiratory arrest before intubation. However, patients who have been intubated for severe asthma are at increased risk for death from subsequent exacerbations and must be managed accordingly in the outpatient setting.
We review here four recent findings that have altered in a fundamental way our understanding of airways smooth muscle (ASM), its dynamic responses to physiological loading, and their dominant mechanical role in bronchospasm. These findings highlight ASM remodeling processes that are innately out-of-equilibrium and dynamic, and bring to the forefront a striking intersection between topics in condensed matter physics and ASM cytoskeletal biology. By doing so, they place in a new light the role of enhanced ASM mass in airway hyper-responsiveness as well as in the failure of a deep inspiration to relax the asthmatic airway. These findings have established that (i) ASM length is equilibrated dynamically, not statically; (ii) ASM dynamics closely resemble physical features exhibited by so-called soft glassy materials; (iii) static force-length relationships fail to describe dynamically contracted ASM states; (iv) stretch fluidizes the ASM cytoskeleton. Taken together, these observations suggest that at the origin of the bronchodilatory effect of a deep inspiration, and its failure in asthma, may lie glassy dynamics of the ASM cell.
International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma
- K F Chung
- S E Wenzel
- J L Brozek
- KF Chung
Severe acute asthma exacerbation in children: a stepwise approach for escalating therapy in a pediatric intensive care unit
- Iff Nievas
- Kjs Anand
Immunomodulatory cytokines in asthmatic inflammation
- E L Lynch
- F F Little
- K C Wilson
- D M Canter
- W W Cruikshank
- EL Lynch