Role of Inhaled Corticosteroids in The Management of Acute Asthma

The role of inhaled corticosteroids
in the management of acute asthma

B. H. Rowe, D. Vethanayagam
DOI: 10.1183/09031936.00119907 Published 1 December 2007
Acute exacerbations are common occurrences for asthmatics. Contact with airway
irritants (e.g.viral upper respiratory tract infections, aero-allergens) and nonadherence
to controller medications, along with the natural history of the disease can result in
deterioration in lung function, increased symptoms and an increased need for reliever
medication. It is estimated that nearly 2million emergency department (ED) asthma
visits occur annually in the USA alone 1. Since the frequency of exacerbations is related
to asthma severity on the one hand, and increasing degrees of airway eosinophilia are
associated with increased disease severity on the other 2, understanding the
pathophysiology of exacerbations is critically important to disease control.
The medical consequences of these events can range from minor life interruptions to
severe illness. These severe exacerbations often result in ED presentation or
unscheduled visits to health professionals for urgent care, and may require hospital
admission. While rare, death from exacerbations does occur. The economic
consequences of asthma have been well documented3, 4 and the acute attack has
been estimated to represent 25% of overall asthma costs 5. The control of chronic
asthma with the use of inhaled corticosteroids (ICS), with or without the use of
additional agents (e.g. long-acting -agonists or leukotriene receptor antagonists),
anticholinergics and in some cases newer biological agents, have proven effective in
reducing the frequency and severity of these exacerbations. In addition,
nonpharmacological approaches (regular follow-up, action plans, immunisation, asthma
education) have also proven to be effective but adherence to these can be low 6, 7.
Despite these advances, a gap between what is known and what is practiced hampers
efforts to improve the quality of life of patients with asthma. This gap may be the result
of poor access to care and resources, failure of physicians to treat the disease
aggressively, poor penetration of asthma education to the most needy and/or inability
to afford controller medications. Not surprisingly, asthma visits to EDs and other
settings remain an important health problem and an area of intense research 8. Current
research suggests that patients with acute asthma should be treated with short-acting
inhaled -agonists 9, inhaled ipratropium bromide 10 and systemic corticosteroids (oral
or intravenous) 11. Patients who fail to improve following this approach or who are
severe at presentation may also receive intravenous magnesium sulfate (MgSO 4) 12,
inhaled and injectable adrenaline and/or noninvasive ventilation 13. Other treatments
(e.g. inhaled MgSO4 14 or heliox 15) likely provide small benefit; however, evidence is
limited. Other agents (e.g. intravenous -agonists 16, aminophylline 17, antibiotics 18)
have not been found to be effective.
An emerging area of study is the role of ICS agents in the treatment of acute asthma.
Traditional teaching suggests that the mechanisms for corticosteroids require hours to
days to become established. Transport into the cell and nuclear membrane results in
changes in protein synthesis which are later translated into clinical improvements as
measured by return of symptom control and improved physiological parameters
(e.g. spirometry, challenge testing sensitivity) 19. This theory has been challenged by a
number of researchers and the clinical evidence is summarized in a Cochrane
review 20. Currently, there are a number of high-quality studies in which ICS has been
compared with standard care 20. The review examined the effect of ICS alone and in
addition to systemic corticosteroids in the early treatment of acute asthma. Trials in
which ICS was compared with placebo demonstrate a clear reduction in admissions for
this patient group (relative risk (RR) 0.32; 95% confidence interval (CI) 0.180.58). For
the addition of ICS to systemic corticosteroids, the evidence was homogeneous, yet
somewhat underpowered to draw clear conclusions on admission outcomes (RR 0.56;
95% CI 0.291.09). Moreover, it was only when all ICS studies were pooled that clinically
and statistically significant effects were observed on admissions (RR 0.39; 95% CI 0.25
0.61). Finally, the evidence was heterogeneous and conflicting (pooling not possible) in
the seven trials where ICS was compared with systemic corticosteroids.
The research reported by Belda et al. 21, in the current issue of the European
Respiratory Journal, provides additional understanding regarding the mechanisms at
work during the treatment of an acute exacerbation. In this multiple-blind, doubledummy, randomized controlled trial with concealed allocation, 39 adults with acute
asthma received either high-dose fluticasone (4,000gday 1) or prednisone (30
mgday1) for 4days. The patients were followed with induced sputum and blood
inflammatory markers at baseline, 2, 6 and 24h. The study was designed to identify the
mechanism underlying the early effects seen with the administration of ICS in acute
asthma. The results suggest that the inflammatory markers and clinical condition in
both groups improved over the 24-h period; however, sputum eosinophil counts
improved faster in the fluticasone group while serum eosinophils counts improved faster
in the prednisone group. This reflects, in part, the fact that different compartments
demonstrate differential recovery periods following an exacerbation, which is partially
explained by the route of drug delivery.
This study illustrates several other important facts. First, 15 out of the 39 patients were
not using ICS agents prior to their ED presentation. This is despite the fact that patients
with acute asthma often exhibit many of the risk factors suggestive of poorly controlled
asthma 22. Secondly, using traditional measures (e.g. symptoms, pulmonary functions
and so on) there was no statistical difference between the two groups in their
improvement; however, differences emerged when inflammatory markers were
examined. The use of induced sputum as a diagnostic tool has been available for nearly
60yrs. Protocol standardization 23 for both diagnosis and monitoring of airway
disease 24 has increased the understanding of the role of sputum cell counts and other
markers of inflammation. Consequently, this has resulted in identification of various
phenotypic subtypes of asthma and has been an important advance within the clinical
realm. Unfortunately, the availability of this diagnostic test is limited to some major
centers where tertiary care of asthmatics is provided. The availability of this technique
is, in part, related to a region's ability to perform these inductions with safety measures
in place (e.g. infection precautions, spirometry monitoring, physician supervision) along
with appropriate lab facilities to process the specimens in a timely manner. It is
important to explore alternatives to this method of measurement, especially in children
under the age of 6yrs, where this tool has limited value due to inability of these
patients to expectorate sputum and perform spirometry reliably. Although exhaled nitric
oxide levels have been used in some centers (for both adult and pediatric patients), it
only measures a single parameter, most closely linked to eosinophilic airway
inflammation. This does not assess different inflammatory subtypes noted in
asthma 25. Recent research advances, such as exhaled breath condensates, are
important advances which warrant further study. As the evaluation of newer tools used
to measure inflammation increases, understanding of the application of these measures
within clinical practice in both the diagnosis and ongoing management of asthma will
evolve 26.
This work complements ongoing efforts to improve clinical outcomes using ICS in
conjunction with systemic steroids. What other evidence do we have? Some of the
earliest evidence for the role of ICS in acute respiratory conditions arose from the
treatment of children with croup in the ED. In a small study, researchers showed that
ICS were efficacious in this paediatric airway disease 27. In outpatient asthma, evidence
now suggests that systemic corticosteroids should be used in most patients, with as few
as five patients needing treatment to prevent one relapse 28. The evidence for the
addition of ICS to this regimen arises from yet another Cochrane review 29. In this
review, all of the available evidence has been pooled and suggests that there is a strong
trend in support of treatment of asthmatics with both treatments following discharge
(RR 0.75; 95% CI 0.521.09).
There are, however, many questions that remain unanswered. First, would the ICS effect
be similar in those previously using ICS compared with those who were not? In recent
clinical studies, the prior use of ICS agents was highly predictive of poorer outcomes as
measured by quality of life and relapse rates 30. Secondly, different types of
exacerbations (e.g. viral as opposed to allergen-induced) may produce different degrees
of protein leak, a hallmark of asthma 31. Therefore, the type of exacerbation could
significantly impact the degree of protein leak 32. Thirdly, differential gastrointestinal
absorption of prednisone among individuals is a potentially important unreported
confounder. Finally, most clinicians would prefer to know the physiological benefit of ICS
in addition to systemic corticosteroids in acute asthma, and we eagerly await those
research results.
In summary, Belda et al. 21 provide important pathophysiological evidence of the
importance of inhaled corticosteroids in the management of acute asthma. Some
clinicians have been using this management strategy based on subjective evidence of
improvement in a clinical setting; however, the increasing body of evidence suggests
that addressing both compartments (systemic and airway) is a more effective approach
than treating either alone. Additional work on dose and duration of inhaled
corticosteroid treatment as well as the combination of inhaled corticosteroids and
corticosteroids are needed. However, until then, clinicians treating these patients should
consider the early addition of inhaled corticosteroids in the emergency department and
continuation of these preventive agents following discharge.
Acknowledgments
The authors would like to thank D. Milette (University of Alberta, Edmonton, AB, Canada)
for her secretarial support.
ERS Journals Ltd
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Web of Science
ARTICLE INFORMATION
vol. 30 no. 6 1035-1037
DOI
http://dx.doi.org/10.1183/09031936.00119907
PubMed
18055700
Published By
European Respiratory Society
Print ISSN
0903-1936
Online ISSN
1399-3003
History
Published online November 30, 2007.

ERS Journals Ltd
Expert Review of Clinical Immunology
Inhaled Corticosteroids as Rescue Medication in Acute

Severe Asthma
Gustavo J Rodrigo
Disclosures
Expert Rev Clin Immunol. 2008;4(6):723-729.
Abstract and Introduction

Abstract
Systemic corticosteroids (CS) should be considered as first-line treatment for acute
asthma exacerbations, especially severe exacerbations. They may sometimes
require a few hours or more to achieve their maximum effect. This time delay
observed between administration of CS and improvement in lung function or hospital
admissions is consistent with the belief that these effects of CS, involving the
modification of gene expression, occur with a time lag of hours or days (genomic
effect). On the other hand, CS also have effects initiated by specific interactions with
membrane-bound or cytoplasmic receptors for CS, or nonspecific interactions with
the cell membrane, with a much more rapid response (seconds or minutes;
nongenomic effect). This review analyzes the clinical evidence regarding the use of
inhaled CS in acute asthma patients, according to the characteristics of the
nongenomic effect, and presents a proposal for the use of inhaled CS as a rescue
medication in the emergency-department setting.
Introduction
All patients with asthma may experience exacerbations or attacks, characterized by
a progressive increase in shortness of breath, cough, wheezing or chest tightness,
and a decrease in expiratory airflow.[40] Acute asthma is a medical emergency that
must be diagnosed and treated urgently, and its intensity ranges from mild episodes,
which may even go unnoticed by the patient, to extremely serious episodes that
place a patient's life at risk and may even result in death (fatal or near-fatal asthma).
[1]
The severity of the asthma exacerbations determines the treatment administered
and the goals of treatment can be summarized as maintenance of adequate arterial
oxygen saturation with supplemental oxygen, relief of airflow obstruction with
repetitive administration of rapid-acting inhaled bronchodilators (-agonists and
anticholinergics) and reduction of airway inflammation and prevention of future
relapses with early administration of systemic corticosteroids (CS). [2]
Systemic CS should be considered as a first-line treatment for acute asthma
exacerbations, especially severe exacerbations.[3,4,40] These agents are extremely
effective at reducing the airway inflammation present in virtually all asthmatics.
Despite controversy regarding their efficacy, route of delivery and dosage, data
summarized in two systematic reviews suggest that:
Systemic CS require more than 4-6 h to improve pulmonary function and reduce hospitalizations;
Intravenous and oral CS appear to have equivalent effects in most patients with acute asthma;
While precise dose-response relationships are not well described, there is a tendency toward
greater and more rapid improvement in pulmonary function with medium (parenteral
hydrocortisone 100 mg every 6 h) and high (200 mg every 6 h) doses, although these effects are
likely to plateau at very high dosing, without additional benefit. [3,4]
The time delay observed between administration and improvement in lung function
or hospital admissions is consistent with the belief that these effects of CS result
from changes in gene transcription and altered protein synthesis (genomic effect). [5]
Selected Clinical Evidence on the Use of Inhaled CS in

Acute Asthma
A study by Husby et al., published almost 15 years ago, was an important landmark
with regard to the use of inhaled CS in the treatment of severe airway diseases.
[6]
This randomized, controlled trial, which compared the administration of a single
dose of 2 mg of inhaled budesonide or placebo to children hospitalized for severe
croup, reported rapid clinical improvement (within 2 h of treatment) in patients
administered budesonide. A number of subsequent pediatric studies evaluated the
effects of inhaled CS in the treatment of asthma exacerbations. These also
demonstrated early effects on lung function and clinical variables, which did not
seem to be attributable to the action of systemic CS. [7,8]
In the last 10 years, different clinical trials have suggested an early benefit to the use
of inhaled CS in both children and adults with acute asthma. Thus, among others,
Rodrigo and Rodrigo published a randomized, double-blind trial designed to
determine the benefit of very high repeated doses of inhaled flunisolide (1 mg/10
min for 3 h) added to salbutamol, in adult patients with acute severe asthma in the
emergency department (ED).[9] 94 patients were assigned to receive flunisolide or
placebo, administered through a metered dose inhaler (MDI) and spacer. Flunisolide
was associated with a significant benefit in the bronchodilator response, clinical rate
and number of hospital admissions, compared with placebo. More importantly, these
effects were seen as early as 2 h after the first treatment. Likewise, more recently,
Rodrigo compared, in a randomized and double-blinded manner, the effects of
repeated doses of inhaled fluticasone (3 mg/h for 3 h via a MDI and spacer) with the
standard treatment of systemic CS (a bolus of 500 mg given intravenously) in 106
adults with acute severe asthma.[10] In addition, all patients received inhaled
salbutamol and ipratropium. Patients treated with fluticasone showed an early and
significant improvement after 90 min of treatment. In addition, the fluticasone-treated
group exhibited higher rates of patients who obtained the discharge threshold. This
therapeutic benefit was particularly evident in those patients with the most-severe
obstructions.
Despite these and other positive pieces of evidence provided by publications in the
last decade, inhaled CS have not been considered effective in treating asthma
exacerbations. Different state-of-the-art and systematic reviews have concluded that
inhaled CS are not effective for the treatment of patients with acute asthma.
However, these reviews contain potentially important bias that could affect their
validity, including:
Omission of relevant studies [11,12]
Non distinction between genomic and nongenomic effects
Pooled analysis of studies with different doses and timing of administration
[11,13]
[11,13]
For example, in one meta-analysis, the authors pooled the admission rates of
different trials whose protocol duration ranged between 2 and 12 h so they did not
distinguish between early and late effects.[13] As a result, these reviews probably
underestimated the immediate clinical impact of inhaled CS and, therefore, have
conclusions of questionable validity.
On the other hand, some studies have failed to show the beneficial effects of inhaled
CS. For example, Schuh et al. performed a double-blind, randomized trial involving
100 children 5 years of age or older with acute severe asthma. [14] All patients were
treated with bronchodilators and received one dose of either inhaled fluticasone 2
mg/kg through a MDI and spacer or oral prednisone 2 mg/kg of bodyweight. The
degree of improvement in pulmonary function in the initial 4 h among patients
treated with prednisone was approximately twice that shown by patients given
fluticasone. Furthermore, the rate of hospitalization in the fluticasone group was
approximately three-times that of the prednisone group.
Defining the Biological Bases of CS Actions: The

Nongenomic Actions
The understanding of the effects of CS is a fundamental aspect in order to interpret
the evidence from clinical trials on the use of inhaled CS in acute asthma. In fact, the
mechanisms of action of CS on the inflammatory process are complex (Figure 1).

On the one hand, the classic anti-inflammatory effects implicate the activation or
repression of multiple genes involved in the inflammatory process. Thus, CS
produce their effects on cells by activating receptors for CS, which alter transcription
through direct DNA binding or transcription factor inactivation. [15,16] As a
consequence, CS increase the synthesis of anti-inflammatory proteins, or inhibit the
synthesis of many inflammatory proteins through suppression of the genes that
encode them. This effect is also denominated the genomic effect because it implies
the participation of the cellular genome, it affects gene expression and it may be
sensitive to protein synthesis inhibitors. The length of time between CS entry into the
cell and the production of new proteins is in the order of hours or even days. This
fact is in concordance with clinical evidence that shows a 4-12 h delay before the
beneficial effects of systemic CS are able to be detected (Figure 1). [3,4]
(Enlarge Image)
Figure 1.
Mechanisms of action of CS. In the anti-inflammatory (or genomic) effect, depicted on the left of the
diagram, a CS molecule enters the cell cytoplasm and binds with GR. The complex then diffuses
within the cell nucleus, binds to specific DNA sequences and increases the synthesis of mRNA and
new protein molecules. Nongenomic effects, depicted on the right of the diagram, are the result of
the CS molecule binding to a receptor (R) on the cell surface. This receptor then increases the value
of second messengers, such as cAMP; which, in turn, increase the cell permeability of a number of
ions. CS = Corticosteroid; GR = Corticosteroid receptor; R = Receptor. Modified with permission
from [1].
Although the major part of the investigation has been carried out in the last decade,
already in 1942, Selye had observed that some CS-induced effects (anesthesia)
occurred only minutes after their application, constituting the first notification of a
nongenomic effect of CS.[17] Two decades later, acute cardiovascular effects of
aldosterone (within 5 min of its administration) were reported in humans. [18]Lately, CS
have also been shown to acutely decrease nasal itching in allergic rhinitis patients.
[19]
These rapid effects are initiated by specific interactions with membrane-bound or
cytoplasmic CS receptors, or nonspecific interactions with the cell membrane,
and the responses are much more rapid (seconds or minutes). Membrane
receptor inactivation has been shown to induce rapid effects on a variety of secondmessenger systems.[16] In addition, CS could bind to other receptors, ion channels,
enzymes or transporters.
[20,21]
In the last decade, research has been focused on the rapid, or nongenomic, effects
of inhaled CS on airway smooth muscle tone, and particularly on the study of the
mucosal blood flow of asthmatic and healthy people. [20-24] Thus, membrane-binding
sites for CS have been demonstrated in smooth muscle cells isolated from human
airway blood vessels.[25] Studies also show that asthmatics have a significant
increase in airway mucosal blood flow in comparison with healthy subjects (24-77%
higher in asthmatics), and that inhalation of one dose of fluticasone (880 g) or
budesonide (400 g) decreases blood flow in both groups. [20-26] This effect is
transient, reaching a maximum approximately 30 min after inhalation, and returning
to basal values after 60-90 min. This blood-flow decrease is dose dependent (doses
of 880 and 1700 g caused a significant decrease), with a greater effect in
asthmatics than in healthy subjects (Figure 2). Finally, the effect was not specific for
fluticasone or budesonide, and it was also demonstrated for beclometasone.
However, fluticasone and budesonide had a greater effect than beclometasone.
[22]
Evidence suggests that inhaled CS decrease airway blood flow by modulating
sympathetic control of vascular tone, potentiating noradrenergic neurotransmission
in the airway vasculature.[23,24] After release from sympathetic terminals,
norepinephrine must be taken up by postsynaptic cells for inactivation by
intracellular enzymes. Because uptake of norepinephrine is inhibited by CS, this
could lead to an increased norepinephrine concentration at the neuromuscular
junction, explaining the CS-induced vasoconstriction. Furthermore, this decrease in
airway blood flow is likely to enhance the action of inhaled bronchodilators by
diminishing their clearance from the airway.[27]Thus, simultaneous administration of
inhaled CS and bronchodilators could be of clinical significance. To distinguish
genomic actions from the effects occurring acutely following steroid administration,
the latter effects have been referred to as nongenomic. Very useful in this matter is
the definition of nongenomic effects recently given by Losel and Wehling: "any
action that does not directly and initially influence gene expression, but rather drives
more rapid effects such as the activation of signaling cascades". [16]This definition
recognizes that the distinction between the two modes of action is not always clear
cut. It is certain that there is no direct proof to support the involvement of either
nongenomic pathways or airway blood-flow responses in the observed clinical or

spirometric responses.[20,21] However, because the use of genomic-pathway inhibitors
in clinical trials is not possible, a short timeframe (minutes) is one of the strongest
pieces of evidence in favor of a nongenomic effect. Thus, this initial effect is a good
candidate by covering the link between molecular pathways and the clinical effects
of the actions of CS, and it is unlikely that early clinical effects (seen as early as 60
min) are due to a genomic mechanism.
Figure 2.
Effect produced by 880 g of inhaled fluticasone on airway mucosal blood flow (Qaw) in ten asthmatic subjects
and ten healthy subjects (mean standard error). *Healthy subjects: p = 0.01 in relation to baseline.
Asthmatic subjects: p = 0.01 in relation to baseline. Redrawn with permission from [20].
Analysis of the Clinical Evidence in Agreement With the

Characteristics of Nongenomic Fffects
The analysis of evidence confirmed that the clinical trials using repeated doses of
inhaled CS in short time intervals (three or more doses administered in at least 30min intervals for 90-120 min) showed early benefits (1-2 h onset) in terms of clinical
and spirometric variables.[28] Of the eight studies that compared inhaled CS to
placebo, four involved multiple doses of CS administered at short intervals (every
10-30 min) ( Table 1 ).[9,29-31] All showed rapid (after 2 h of treatment) and significant
benefits favoring inhaled CS in terms of pulmonary function, clinical index, oxygen
saturation and hospitalizations. Two other studies for which no significant effects
were observed used multiple doses of inhaled CS at substantially lengthier
administration intervals (every 60 min).[32,33] Finally, a single dose of inhaled CS was
administered in two studies and an early effect on lung function (after 60 min) was
observed in one of the studies,[7] whereas no difference between groups was
observed in the other.[34]
Inhaled and systemic CS used to treat severe asthma were compared in a total of
six clinical trials, five involving children and adolescents [14,35-38]and one involving
adults only.[10]Analysis of the three studies in which multiple doses of inhaled CS
were administered (at 10-30-min intervals) revealed significant early effects (after 2
h of treatment) in the variables studied (lung function, symptoms and signs,
discharges and admissions) ( Table 2 ).[10,35,36] Of the three studies based on inhaled
CS single-dose protocols, no significant differences in the different study variables
were observed between groups in two of the studies. [37,38] The third study, however,
merits special attention.[14] This well-designed study of children and adolescents with
moderate-to-severe acute asthma compared the administration of a single dose of
inhaled fluticasone (2 mg) with a standard dose of oral prednisone (2 mg/kg), each
administered at the commencement of the protocol. The patients treated with
prednisone experienced significantly greater increases in spirometric values and
their hospitalization rates were significantly lower. As the only study of those
analyzed demonstrating systemic CS to be superior to inhaled CS, it is noteworthy
that the protocol was based on a single dose of inhaled CS, and the earliest
measurement of the variables was 4 h after protocol was begun. Prednisone
superiority, therefore, may be explained by the fact that the genomic or anti-
inflammatory effects of the drug may have already been triggered by the time the
variables were measured.
More recently, a systematic review with a meta-analysis was performed to analyze
the best available evidence on the early (1-4 h) clinical and objective impact of
inhaled CS for patients with acute asthma in the ED setting. [39] In total, 17 studies
met criteria for inclusion in the review (470 adults and 663 children and
adolescents). After 2-4 h of the protocol, a greater reduction in admission rates was
observed with trials that used multiple doses of inhaled CS (odds ratio [OR]: 0.30;
95% confidence interval [CI]: 0.16-0.55), especially when CS were compared with
placebo. Patients treated with inhaled CS also displayed a faster clinical
improvement compared with those administered placebo or systemic CS, increasing
the probability of an early ED discharge by almost five-times (OR: 4.70; 95% CI:
2.97-7.42). The advantage of using inhaled CS was also demonstrated in
spirometric and clinical measures as early as 60 min. These benefits were obtained
only when patients received multiple doses of inhaled CS along with -agonists
compared with placebo or systemic CS. This is a very relevant finding, since hospital
admissions count for the largest part of the direct health costs for asthma. A second
finding of this review was that patients who received inhaled CS in multiple doses
displayed a faster improvement compared with patients receiving placebo or
systemic CS, increasing the probability of an early ED discharge. On the contrary,
those trials that used single doses of inhaled CS or multiple doses in very prolonged
intervals presented smaller beneficial effects or no differences between groups.
Therefore, the most important parameter would not be the total dose administered,
but rather the relationship between the dose and the timing of administration.
2
Expert Commentary & Five-year View

The characteristics of nongenomic effects of CS are:
Acute
Transitory
Dose dependent
Correlate (directly) with baseline airway blood flow
More powerful with budesonide or fluticasone than with beclometasone
Can improve 2-adrenergic bronchodilation
These vascular effects of inhaled CS on the airways could be expected to have

therapeutic implications for the management of acute asthma and its characteristics
are fundamental to establish the optimum dose and timing of administration in the
ED setting. Inhaled CS should, essentially, be administered frequently and in high
doses in order to maintain their effects, most particularly in patients with severe
obstruction. Since inhaled CS induce vasoconstriction peaks between 30 and 60 min
following drug administration, their use in intervals of at least 30 min seems
adequate.
There is clinical evidence that supports the use of inhaled CS for the treatment of
children and adults with asthma exacerbations as rescue medication in the ED.
Even though systemic CS remain the treatment of choice for acute asthma, this
early and probably nongenomic effect may be significant in the treatment of the most
severe cases. Thus, on the basis of this evidence, the use of inhaled fluticasone or
budesonide through a MDI and spacer or nebulization every 10-30 min could be
recommended ( Box 1 ). Although there was important variation between studies,
the evidence suggests that the minimum effective nebulized doses for fluticasone
and budesonide would be 500 g every 15 min, and 800 g every 30 min,
respectively. The use of 400 g every 30 min of budesonide via a MDI and spacer
was also effective, and greater doses (fluticasone 500 g every 10 min by a MDI)
generated larger benefits. These doses would have to be administered over a
minimum of 90 min, although more prolonged periods of administration could
generate a greater benefit. Nevertheless, future studies would have to clarify the
relationship between the dose administered, acute asthma severity and response to
treatment.
Sidebar: Key Issues
Systemic corticosteroids (CS) should be considered as first-line treatment for acute asthma
exacerbations, especially those that are severe.
A few hours or more may be required for systemic CS to achieve their maximum effect in terms of
pulmonary function or hospital admissions.
The time delay seen is consistent with the modification of gene expression (genomic effect).
Clinical evidence shows that inhaled CS present early benefits (within 1-2 h) for the treatment of
children and adults with acute asthma.
Patients (children and adults) who received inhaled CS along with 2-agonists in multiple doses
displayed a faster improvement compared with placebo or systemic CS.
This short timeframe (minutes) is one of the strongest pieces of evidence in favor of a nongenomic
effect.
The most important consideration is not the total dose administered, but rather the relationship
between the dose and the timing of administration.
Future studies are needed to clarify the relationship between the dose administered, acute asthma
severity and response to treatment (e.g., by age and gender).
References
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Rodrigo GJ, Rodrigo C, Nannini LJ. Fatal or near-fatal asthma: clinical entity or incorrect
management? Arch. Bronconeumol. 40, 24-33 (2004).
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Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults. A review. Chest 125, 1091-2002 (2004).
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Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of adult acute asthma
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Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment
of acute asthma with systemic corticosteroids. Cochrane Database Syst. Rev. 1, CD002178 (2001).
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Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann. Intern. Med. 139, 359-370
(2003).
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Husby S, Agertof L, Mortesen S, Pedersen S. Treatment of croup with nebulized steroid (budesonide):
a double-blind, placebo controlled study. Arch. Dis. Child. 68, 352-355 (1993).
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Pansegrouw DF. Acute resistant asthma caused by excessive -2-adrenoceptor agonist inhalation and
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Scarfone RJ, Loiselle JM, Wiley JF, Decker JM, Henretig FM, Joffe MG. Nebulized dexamethasone
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Rodrigo G, Rodrigo C. Inhaled flunisolide for acute severe asthma. Am. J. Respir. Crit. Care Med. 157,
698-703 (1998).
10. Rodrigo GJ. Comparison of inhaled fluticasone with intravenous hydrocortisone in the treatment of
adult acute asthma. Am. J. Respir. Crit. Care Med. 171, 1231-1236 (2005).
11. Foresi A, Paggiaro P. Inhaled corticosteroids and leukotriene modifiers in the acute treatment of
asthma exacerbations. Curr. Opin. Pulm. Med. 9, 52-56 (2003).
12. Hendeles L, Sherman J. Are inhaled corticosteroids effective for acute exacerbations of asthma in
children? J. Paediatr. 142, S26-S33 (2003).
13. Edmonds ML, Camargo CA Jr, Pollack CV Jr, Rowe BH. Early use of inhaled corticosteroids in the
emergency department treatment of acute asthma. Cochrane Database Syst. Rev. 3, CD002308
(2003).
14. Schuh S, Reisman J, Alshehri M et al. A comparison of inhaled fluticasone and oral prednisone for
children for severe acute asthma. N. Engl. J. Med. 343, 689-694 (2000).
15. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann. Intern. Med. 139, 359-370
(2003).
16. Losel R, Wehling M. Nongenomic actions of steroid hormones. Nat. Rev. Mol. Cell Biol. 4, 46-56
(2003).
17. Selye H. Correlations between the chemical structure and the pharmacological actions of the
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18. Klein K, Henk W. Clinical experimental studies on the influence of aldosterone on hemodynamics and
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19. Tillmann HC, Stuck BA, Feuring M et al. Delayed genomic and acute nongenomic action of
glucocorticosteroids in seasonal allergic rhinitis. Eur. J. Clin. Invest. 34, 63-73 (2004).
20. Kumar SD, Brieva JL, Danta I, Wanner A. Transient effect of inhaled fluticasone on airway mucosal
blood flow in subjects with and without asthma. Am. J. Respir. Crit. Care Med. 161, 918-921 (2000).
21. Paredi P, Kharitonov SA, Barnes PJ. Correlation of exhaled breath temperature with bronchial blood
flow in asthma. Respir. Res. 6, 15 (2005).
22. Mendes ES, Pereira A, Danta I, Duncan RC, Wanner A. Comparative bronchial vasoconstrictive
efficacy of inhaled glucocorticosteroids. Eur. Respir. J. 21, 989-993 (2003).
23. Wanner A, Horvath G, Brieva JL, Kumar SD, Mendes ES. Nongenomic actions of glucocorticosteroids
on the airway vasculature in asthma. Proc. Am. Thorac. Soc. 1, 235-238 (2004).
24. Horvath G, Wanner A. Inhaled corticosteroids: effects on the airway vasculature in bronchial
asthma. Eur. Respir. J. 27, 172-187 (2006).
25. Horvath G, Sutto Z, Torbati A, Conner GE, Salathe M, Wanner A. Norepinephrine transport by the
extraneuronal monoamine transporter in human bronchial arterial smooth muscle cells. Am. J. Physiol.
Lung Cell Mol. Physiol.10, 1152-1158 (2003).
26. Kumar SD, Emery MJ, Atkins ND, Danta I, Wanner A. Airway mucosal blood flow in bronchial
asthma. Am. J. Respir. Crit. Care Med. 158, 153-156 (1998).
27. Kelly L, Kolbe J, Mitzner W, Spannhake EW, Bromberger-Barnea B, Menkes H. Bronchial blood flow
affects recovery from constriction in dog lung periphery. J. Appl. Physiol. 60, 1954-1959 (1986).
28. Rodrigo GJ. Inhaled corticosteroids in the treatment of asthma exacerbations: essential
concepts. Arch. Bronconeumol. 42, 533-540 (2006).
29. Singhi SC, Banerjee S, Nanjundaswamy HM. Inhaled budesonide in acute asthma. J. Paediatr. Child
Health 35, 483-487 (1999).
30. Rodrigo GJ, Rodrigo C. Triple inhaled drug protocol for the treatment of acute severe
asthma. Chest 123, 1908-1915 (2003).
31. Estrada-Reyes E, Del Rio-Navarro BE, Rosas-Vargas MA, Nava-Ocampo AA. Co-administration of
salbutamol and fluticasone for emergency treatment of children with moderate acute asthma. Paediatr.
Allergy Immunol. 16, 609-614 (2005).
32. Afilalo M, Guttman A, Colacone A et al. Efficacy of inhaled steroids (beclomethasone dipropionate) for
treatment of mild to moderately severe asthma in the emergency department: a randomized clinical
trial. Ann. Emerg. Med.33, 304-309 (1999).
33. Sekerel BE, Sackesen C, Tuncer A, Adalioglu G. The effect of nebulized budesonide treatment in
children with mild to moderate exacerbations of asthma. Acta Paediatr. 94, 1372-1377 (2005).
34. Tsai YG, Lee MY, Yang KD, Chu DM, Yuh YS, Hung CH. A single dose of nebulized budesonide
decreases exhaled nitric oxide in children with acute asthma. J. Paediatr. 139, 433-437 (2001).
35. Tsai YG, Lee MY, Yang KD, Chu DM, Yuh YS, Hung CH. A single dose of nebulized budesonide
decreases exhaled nitric oxide in children with acute asthma. J. Paediatr. 139, 433-437 (2001).
36. Devidayal Singhi S, Kumar L, Jayshree M. Efficacy of nebulized budesonide compared with oral
prednisolone in acute bronchial asthma. Acta Paediatr. 88, 835-840 (1999).
37. Volovitz B, Bentur L, Finkelstein Y et al. Effectiveness and safety of inhaled corticosteroids in
controlling acute asthma attacks in children who were treated in the emergency department: a
controlled comparative study with oral prednisolone. J. Allergy Clin. Immunol. 102, 605-609 (1998).
38. Milani GKM, Rosrio Filho NA, Riedi CA et al. Nebulized budesonide to treat acute asthma in
children. J. Paediatr. 80, 106-112 (2004).
39. Rodrigo GJ. Rapid effects of inhaled corticosteroids in acute asthma. An evidence-based
evaluation. Chest 130, 1301-1311 (2006).
40. Global strategy for asthma management and prevention (2007) www.ginasthma.com (Accessed on 8
June, 2008)
Role of inhaled steroids in acute asthma exacerbations

By Dr. Julian Marsden on April 30, 2012
Receive 0.25 Mainpro M1* or MOC Section 2* study credits per article, click on the
link below, between votes and comments. Credits directly uploaded to CFPC and
RCPSC!
Dr. Julian Marsden (biography and disclosures)

What I did before
When faced with most asthma exacerbations my practice was often to treat with oral steroids for 7
days along with a salbutamol inhaler and leave the discussion regarding the prescription of a steroid
inhaler to their family physician that they were to follow-up with. I never thought that the addition of
an inhaled corticosteroid would add anything if they were taking it orally.
What changed my practice
I had a case of a young lady who I treated with salbutamol and prednisone and had follow-up at the
end of her course of prednisone. She made an appointment for the day after the prednisone was
completed. She presented to her family doctor in such respiratory distress that she had to be
referred back (to me) and spent several hours in the Emergency Department and ultimately being
admitted. Although in the end, she did well, this led me to reconsider how I treated asthma
exacerbations and based on an article by Dr Brian Rowe, I have now made it routine practice to
prescribe both oral and inhaled steroids to my asthma patients on discharge.
In 1999, Rowe, from Edmonton, published a definitive study on the role of inhaled steroids in the
acute asthma exacerbations. It was a placebo controlled double-blind randomized trial involving
1006 consecutive patients age 16 60 years and after excluding those already on steroids, 188
were enrolled in the study. All patients received oral prednisone 50 mg/day for 7 days and received
either inhaled budesonide 1600 g/d or placebo for 21 days. After 21 days, 12 (12.8%)of 94 patients
in the budesonide group experienced a relapsecompared with 23 (24.5%) of 94 in the placebo
group, a 48% relapsereduction (P=.049).
What I do now
Given their effectiveness, safety, and ability to prevent relapses inhaled corticosteroids are now part
of my discharge prescription for asthma exacerbations. I further justify it because some patients
may not be able to follow up with a family physician and because this approach reinforces the value
of inhaled steroids to the patient.
Additional reading:
1.
BC Guideline on
Asthma: http://www.bcguidelines.ca/guideline_asthma.html#recommendation3
2.
FitzGerald JM. Asthma guidelines: Global to local. Ann Thorac Med [serial online] 2009
[cited 2012 Apr 30];4:161-2. Available from: http://www.thoracicmedicine.org/text.asp?
2009/4/4/161/56006
Reference:
Rowe BH, Bota GW, Fabris L, et al. Inhaled budesonide in addition to oral corticosteroids to prevent
asthma relapse following discharge from the emergency department: a randomized controlled trial.
JAMA 1999; 281:21192126
http://jama.ama-assn.org/content/281/22/2119.full.pdf+html or with CPSBC
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Role of inhaled steroids in acute asthma exacerbations
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14 responses to Role of inhaled steroids in acute asthma

exacerbations
1.
Jack I urtonMay 1, 2012 at 1:06 pmPermalink
I am an asthmatic myself and have discovered this phenomenon from self treatment. It has become
standard therapy for my asthmatic patients.
2.
Natalie AntonenkoMay 1, 2012 at 1:20 pmPermalink
I would be far more likely to treat with an inhaler before an oral steroid and would certainly never
give oral without inhaled. It would seem to be a natural step up treatment to include both.
3.
Patricia MirwaldtMay 1, 2012 at 1:26 pmPermalink
seems like a good idea, I always stopped the inhaled steroids in exacerbation when I added oral
steroids, to save money for the patient, caused me to rethink, good article from Rowe.
Shel GlazerMay 1, 2012 at 1:29 pmPermalink
4.
Julian,
Do you leave patients on steroid inhalers indefinitely? Or is this just a 7-day course or until they see
their regular physician?
5.
Luke TseMay 1, 2012 at 8:15 pmPermalink
Many asthmatic patients presenting to ER have already used the inhaled steroid (or a long acting
beta-agonist + steroid). Do you recommend to try steroid inhalation, or PO steroid under such
circumstance?
6.
Stefanie HoudeMay 3, 2012 at 7:41 pmPermalink
This is a good reminder. And even if they have a steroid, making sure they use it, and they properly
use brings an interesting discussion.
7.
DAISY PAVRIMay 4, 2012 at 7:52 pmPermalink
In pediatrics it is difficult for young patients to comply but I have tried this above regime and it works.
8.
A.S.RankinMay 5, 2012 at 9:19 amPermalink
V interesting
9.
J MatsykMay 11, 2012 at 11:31 amPermalink
Interesting article as it is always nice to hear of evidence that supports what weve noticed in clinical
practice.
10.
P SammarelliMay 12, 2012 at 11:05 pmPermalink
Excellent reminder for me!
11.
A PerezMay 17, 2012 at 6:21 amPermalink
I do this for many years with great results, even extended the time of relapsed between each
episode, and improve the condition of the patient
12.
john dimmaMay 21, 2012 at 8:57 amPermalink
I have usually not given inhaled steroids when I prescribe systemic prednisone, as often my patients
are already on inhaled steroids. But, I will try to be more aware and definitely try this approach.
13.
Narayanappa DayanandaJune 12, 2012 at 8:09 pmPermalink
I would check the technique of using inhaler first, as it may be the cause for failure of inhaler therapy.
Oral steroids are certainly the step 3 of asthma management ( after bronchodilator alone,
bronchodilator and inhaled steroid- always ensuring the technique)
Narayanappa DayanandaJune 27, 2012 at 11:45 amPermalink
14.
SIGN and NICE have recommended step wise treatment of asthma- oral steroids are step3.
JAMA which has been quoted as reference chose patients who were not using initiated into using
inhalers, and less than 10% used ICS-step2. Using short course steroids is not exactly step3, but
patients are clearly educated into step 3, than taking the opportunity of usefulness and technique of
inhaler. Even though this is supposed to have happened in the JAMA Cohort, I guess, with a fair bit
of cynicism that, this will the practice in the crash, bang, wallop ED Patients.
Dispensing steroids will eventually be norm, just like the abused ativans and T3.-where it would have
been an opportunity for education.
It should rather be, check technique, use ICS, and if fails, the, and only then, oral steroids.
And, this is with not to mention, the hassle in primary care it will create with coming for the magic
pill
And, not to mention long term side effects of steroid abuse( yes, yes, I know, we use Ativan and T3
for short term panic attacks and the occasional back pain)
Journal List
Lung India
v.27(4); Oct-Dec 2010
PMC2988175
Lung India. 2010 Oct-Dec; 27(4): 230235.

doi: 10.4103/0970-2113.71957
PMCID: PMC2988175
Nebulized corticosteroids in the management of acute exacerbation of COPD

G. S. Gaude and S. Nadagouda
Author information Copyright and License information
Abstract
Go to:
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality
worldwide and results in an economic and social burden that is both substantial and increasing.
COPD is the fourth leading cause of death in the United States of America (USA) and Europe.[1]
Currently, COPD is a more costly disease than asthma and depending on country, 50% 75% of
the costs are for services associated with exacerbation. According to Global Initiative for chronic
obstructive lung disease (GOLD), COPD is defined as a preventable and treatable disease with
some significant extra pulmonary effects that may contribute to the severity in individual
patients. Its pulmonary component is characterized by airflow limitation that is not fully
reversible. The airflow limitation is usually progressive and associated with an abnormal
inflammatory response of the lung to noxious particles or gases.[2]
Exacerbations are a common cause of morbidity and mortality in COPD patients. COPD in the
USA annually accounts for 16,000,367 office visits, 500,000 hospitalizations and $18 billion in
direct healthcare costs.[3] Despite aggressive medical treatment, approximately one third of
patients discharged from the emergency department with acute exacerbations have recurrent
symptoms within 14 days, and about 17% of patients have relapse and requires hospitalization.
Identification of patients at risk for relapse improves decisions about hospital admissions and
follow-up.[4]
Go to:
ACUTE EXACERBATION OF COPD

An exacerbation of COPD (AECOPD) is defined as an event in the natural course of the disease
characterized by a change in the patients baseline dyspnea, cough, and/or sputum that is beyond
normal day-to-day variations, is acute in onset, and may warrant a change in regular medication
in a patient with COPD.[2] One of the earliest and most quoted definitions is that of Anthonisen,
[5] which is based on an increase in symptoms of dyspnoea, sputum volume and sputum
purulence with or without symptoms of upper respiratory infection and then subdivided
depending on the number of symptoms present: increased sputum volume, increased sputum
purulence and increased dysponea over base line. Severity of AECOPD according Anthonisen
criteria[5] is: Type I: All three major criteria, Type 2: Any two of major criteria and Type 3: Any
one of major criteria plus at least one of the symptom: upper respiratory tract infection in
previous five days, increased wheezing, increased cough, fever without obvious source or 20%
increase in respiratory rate or heart rate above baseline. This definition is based upon the
infective exacerbation of the COPD patients. Patients with COPD often present with acute
exacerbations of increased symptoms that frequently require a change in their usual medications.
These episodes vary in severity from mild exacerbations (normally managed at home by the
patient) to moderate exacerbations (requiring consultation with primary care physicians) and
severe exacerbations (needing hospitalization).
Go to:
PATHOPHYSIOLOGICAL CONSEQUENCES OF AECOPD

Airflow obstruction is almost unchanged during mild exacerbations and only slightly increased
during severe exacerbations. Severe exacerbations are accompanied by a significant worsening
of pulmonary gas exchange (due to increased ventilation-perfusion inequality) and potentially, by
respiratory muscle fatigue. Risk factors for the acute exacerbations of COPD are viral infections,
bacterial infections including atypical organisms like mycoplasma and legionella, environmental
pollutions including active and passive smoking, exposure to air pollution, lack of compliance
with long-term oxygen therapy and bronchodilators, and failure to participate in pulmonary
rehabilitation programs. Relapses in acute exacerbation of COPD are common[6] and vary
between 21% and 40%; and various risk factors associated with the relapses are low pretreatment
forced expiratory volume in one second, need to increased bronchodilator or corticosteroid use,
previous exacerbations (more than three in the last two years), prior antibiotic treatment (mainly
ampicillin), and presence of comorbid conditions (congestive heart failure, coronary artery
disease, chronic renal or liver failure). Vestbo et al.[7] and Kanner et al.[8] for the first time
showed that in patients with airways obstruction, exacerbations might accelerate the decline in
FEV1. There have been several large population studies in COPD,[911] which shows a trivial
number of exacerbations in those with mild disease (FEV1>50% predicted), whereas in moderate
to severe disease exacerbation rates range from 1.5 to 2.5 per year. In a prospective study of a
cohort of 101 patients with moderate to severe COPD, Seemungal et al.[12] observed that the
median number of exacerbations was 2.4 (interquartile range 1.33.84) exacerbations per patient
per year.
Go to:
TREATMENT OF ACUTE EXACERBATION OF COPD WITH INHALED

CORTICOSTEROIDS
Systemic corticosteroids play an important role in the treatment of AECOPD. If given within 24
h hour after admission for acute exacerbation, it reduces dyspnoea and improves the lung
function. In a meta-analysis of Cochrane Database Systemic Review[13] it was observed that
systemic corticosteroid administration (parenteral and oral) modestly reduces treatment failure
rates and duration of hospitalization, and improves FEV1 when given to patients with AECOPD.
Glucocorticoids acts at multiple points within the inflammatory cascade of AECOPD. The major
effect of corticosteroids on suppression of inflammation is exerted by binding to a single class of
glucocorticoid receptor, which is localized to the cytoplasm of target cells. This binding of
corticosteroids to glucocorticoid receptors leads to some conformational changes in the receptor
structure. Receptorcorticosteroid complex then moves into the nucleus of the target cells and
binds to their DNA. This interaction changes the rate of transcription, resulting in either
induction or repression of certain genes. Due to this, the production of some inflammatory
cytokines, chemokines and mediators decreases while the production of some anti-inflammatory
proteins and 2-adrenoceptors increases.[14] Thus, reduction of inflammation leads to
diminishing inflammatory cell infiltration, swelling and exudation within airways. Regarding the
regulatory role of corticosteroids on inflammation, there are some important differences between
administration of corticosteroid preparations in systemic forms and inhaled forms.[15] Data from
large patient studies[9,1618] have observed that there is an improvement in post-bronchodilator
FEV1 and a small reduction in bronchial reactivity in stable COPD patients who were treated
with oral corticosteroids. The onset of action is slow and there is little data to support a doseresponse relationship. In one randomized controlled study,[18] it was observed that patients
treated with oral systemic corticosteroids had fewer treatment failures, better improvement in
spirometry variables and a shorter hospital stay. Furthermore, the risk of treatment failures was
reduced by 10% and the average improvement in FEV1 was 100 ml in the first three days of
treatment, compared with placebo. The study also showed that, a two week and an eight week
course of systemic corticosteroids had similar clinical outcome. Therefore a shorter course of
treatment, which should reduce adverse side effects, is preferred.
The exacerbation rates are significantly higher in some COPD patients, and that these patients
need larger amounts of systemic corticosteroids for the control of exacerbations in a certain
period of time. The major drawbacks of oral and parenteral corticosteroids are various side
effects that develop during its course.[19,20] These include sleep disturbances, increased
appetite, weight gain, hypothalamic-pituitary-adrenal axis (HPA axis) suppression, osteoporosis
particularly in smokers, postmenopausal women and elderly, reduction in growth in children,
muscle weakness, especially of the shoulder muscles and thighs, precipitation or aggravation of
diabetes mellitus, redistribution of body fat, salt retention, raised blood pressure, heart failure,
eye disease, particularly glaucoma and posterior sub-capsular cataracts, psychological effects
including insomnia, mood changes, increased susceptibility to internal infections, especially
when high doses are prescribed (e.g. tuberculosis), peptic ulcer disease, and rarely, avascular
necrosis of the femoral head. The risk of development of severe adverse effects due to repeated
courses of systemic corticosteroids is much higher in this subgroup, and this condition seeks
clinicians to find alternative options. Inhaled corticosteroids are such an option in acute
exacerbation of COPD.
Inhaled corticosteroids have a high level of topical anti-inflammatory activity and a low level of
systemic activity. Mitchell et al.[21] compared the nebulized budesonide with oral prednisolone
in the treatment of severe acute asthma and it was observed that there was no statistical
difference in the clinical efficacy of 20 mg nebulized budesonide and either 30 or 160 mg oral
prednisolone over 24 h. Mathew et al.[22] also observed that nebulized budesonide was as
effective as oral steroids in improving lung function and symptoms severity in acute severe
attacks of bronchial asthma in children. In another study, Devidayal et al.[23] studied the
efficacy of nebulized budesonide compared to oral prednisolone in acute severe bronchial asthma
and it was observed that oxygen saturation, respiratory rate and respiratory distress score
significantly improved in the budesonide group compared to prednisolone group. The proportion
of patients who were fit for discharge at the end of 2 h after the third dose of nebulization was
significantly higher in the budesonide group than in the prednisolone group.
Nebulized budesonide may also be sufficiently efficacious in the management of acute
exacerbation of COPD, but this has yet to be explored sufficiently in large clinical studies. Table
1 summarizes all the studies of use of nebulized budesonide in acute exacerbations of COPD.
Morice et al.[24] studied the role of nebulized budesonide in acute exacerbation of COPD by
comparing with oral prednisolone. Study group received 2 mg nebulized budesonide while the
control group received 30 mg oral prednisolone as a single dose, randomized parallel-group
study of 19 adults with severe acute airway obstruction due to COPD. After five days of the
study, it was observed that baseline FEV1 increased from 1.8L to 2.1 L in the oral corticosteroid
group as compared to 1.9 L to 2.0 L in the group that received nebulized budesonide, with no
significant difference between two groups. All biochemical variables were similar at day one. On
day five, mean urinary corticosteroid metabolites were significantly higher after nebulized
budesonide: 2012 mg/24 h compared with prednisolone treatment 1079 mg/24 h (P< 0.05).
Urinary androgen metabolites were same in both groups. The effect of treatment on serum
osteocalcin was also significant 2.3 ng/ml in budesonide group compared to 0.6 ng/ml in
prednisolone (P<0.05). Twenty four hour urinary calcium to creatinine ratio was significantly
lower in budesonide treated group (0.28) compared with prednisolone treated group (0.53). This
study has shown that the use of short-term parenteral corticosteroids in the treatment of severe
bronchospasm causes a detrimental effect on the biochemical markers related to side effects.
Nebulized budesonide treatment produced a significant improvement in these markers as
compared to oral prednisolone without significant difference in FEV1 recovery rates.
Table 1
Studies showing results of utilization of inhaled corticosteroids in acute exacerbation
of COPD
Maltais et al.[25] conducted a multicentric, randomized, placebo controlled study comparing the
efficacy of nebulized budesonide, oral prednisolone and placebo in 199 patients with acute
exacerbation of COPD. This was a three arm study that compared clinical efficacy of nebulized
budesonide with oral prednisolone and placebo. Patients received from randomization (H(0)) to
72 h (H(72)), 2 mg of budesonide every 6 h (n = 71), 30 mg of oral prednisolone every 12 h (n =
62), or placebo (n = 66). All the patients received standard treatment, including nebulized
beta(2)-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. The mean
change (95% confidence interval) in post-bronchodilator FEV1 from H(0) to H(72) was greater
with active treatments than with placebo: budesonide versus placebo, 0.10 L (0.02 to 0.18 L);
prednisolone versus placebo, 0.16 L (0.08 to 0.24 L). The difference in FEV1 between
budesonide and prednisolone was not significant, -0.06 L (-0.14 to 0.02 L). It was also observed
that nebulized budesonide had less systemic activity than prednisolone as indicated by a higher
incidence of hyperglycemia with prednisolone group. The reduction in Borg scale ratings was of
comparable magnitude in the three groups (Borg scale unit mean SD): budesonide 92.3;
prednisolone, 2.62.3; and placebo, 1.82.6. The decline in PaCO2 was significantly greater in
the two active treatment groups than in the placebo group (-1 mm Hg4, -1 mm Hg5, and 1 mm
Hg6, in the budesonide, prednisolone, and placebo groups, respectively (P < 0.05 between
active treatments and placebo). Both budesonide and prednisolone improved airflow in COPD
patients with acute exacerbations when compared with placebo. Thus it was concluded that high
dose nebulized budesonide might be an alternative to oral prednisolone in the treatment of nonacidotic exacerbations of COPD.
In another study, Mirici et al.[26] compared the efficacy of nebulized budesonide with parenteral
corticosteroids in the treatment of acute exacerbation of COPD. In this study, a total of 40
patients were recruited and 21 patients were administered parenteral corticosteroids treatment
and 19 patients were administered nebulized budesonide treatment. Baseline characteristics of
the groups were not significantly different (P>0.05). In each group, it was observed that increase
in peak expiratory flow rate (PEFR), PaO2and SaO2 values between the two groups were
statistically significant (P<0.001 for all parameters). Changes in pH and PaCO2 values in each
group were not statistically significant (P>0.05). It was observed that there were no significant
differences between percentage changes in PEFR, PaO2, and SaO2 values during the entire period
of assessment (P=0.75, P=1.00 and P=1.00 for PEFR, PaO2 and SaO2, respectively). This study
thus demonstrated that nebulized corticosteroids had similar efficacy to systemic corticosteroids
in the treatment of acute exacerbation of COPD. It was concluded that in acute attacks, a
nebulized form of corticosteroids may be preferred to a systemic form because of fewer adverse
effects.
The role of nebulized budesonide in the treatment of acute exacerbation of COPD was recently
studied by Gunen et al.[27] This was a randomized, parallel group, single blind study. A total of
159 patients hospitalized with AECOPD were randomized into three groups: Group 1 received
only standard bronchodilator treatment (SBDT), Group 2 received systemic corticosteroid -- 40
mg prednisolone plus SBDT and Group 3 received nebulizd budesonide - 1, 500 g sixth hourly
plus SBDT. Spirometric parameters, arterial blood gases and hematological and biochemical
parameters were evaluated in this study at admission, 24 h, 72 h, 7 days and 10 days.
Improvement during 10th day hospitalization was compared with exacerbation and rehospitalization rates after discharge. In this study, arterial blood gas analysis and spirometric
parameters [SaO2, PaO2, FEV1, FVC] demonstrated better improvement rates in corticosteroid
groups than the only bronchodilator arm (SBDT) (P<0.05). More importantly, the nebulized
budesonide group yielded faster return to the baseline in some of these parameters than the
systemic corticosteroid group. The first statistically significant improvement in the
bronchodilator only group appeared in SaO2 at 72 h control. However, in addition to the
significant improvement rates in PaO2 in both corticosteroid groups at 24 h control,
improvements in FEV1 and FVC also became statistically significant only in the nebulized
budesonide group at this early control (24 h). It was also observed that mean forced expiratory
flow between 25% and 75% of forced vital capacity values (FEF25%-75%) in Group 3 was
significantly higher than the values in Groups 1 and 2 (P=0.03 and P=0.027 respectively). In
addition to this, direct comparison of arterial blood gases and spirometry parameters did not
reveal any difference between Groups 1 and 2, FEV1 was also found to be significantly higher in
Group 3 than in Group 1 (P=0.004). Except for blood glucose level, there was no significant
difference between the groups with respect to the hematological and biochemical parameters at
any period. At seven-day and 10-day measurements, mean blood glucose level was found to be
higher in the systemic corticosteroid group than the other groups (P<0.05). Early (at 10 days)
and late (beyond 15 days) discharge rates did not differ between the groups (P>0.05). Repeat
exacerbation and re-hospitalization rates within one month of discharge in the corticosteroid
groups were found to be almost the half that in Group 1 (P>0.05). Thus it was concluded that
nebulized budesonide might be an effective and well tolerated alternative to systemic
corticosteroids in AECOPD.
In a study by Wei et al.,[28] the clinical efficacy of aerosol budesonide was evaluated in acute
exacerbation of COPD. Sixty patients of acute exacerbation of COPD were randomly divided
into three groups: nebulized budesonide, oral prednisolone and control group. At the completion
of the study, it was observed that the dyspnoea score, FEV1 and improvement of arterial blood
gases were significantly better in budesonide group as compared to control group. There was a
statistical significant difference in clinical parameters in budesonide group as compared to
control group. Budesonide group also had less systemic side effects than other groups.
In another study by Guozhong et al.,[29] the clinical efficacy of aerosol budesonide suspension
treatment was studied in patients with acute exacerbation of COPD. Forty cases were randomly
divided into two groups: control group and study group. It was observed that FEV1 and
PaO2 values were higher in the nebulized budesonide group as compared to the control group.
This study suggested that aerosol budesonide can improve lung functions and clinical symptoms
in patients with acute exacerbation of COPD.
Marcus et al.[30] evaluated the role of budesonide inhalation suspension in adults with poorly
controlled asthma or COPD. In this study, 25 patients with poorly controlled asthma or COPD
were studied. It was observed that a transition from commonly used inhaled corticosteroid
formulations administered via dry power inhaler or meter dose inhaler to nebulized budesonide
inhalation suspension or initiation of inhaled corticosteroid treatment with budesonide inhalation
suspension provided marked improvement in disease control for all patients and budesonide
given by nebulization was well tolerated. Exacerbation rates were decreased by more than 70%
in patients with asthma or COPD. Moreover, despite a long-standing history of pulmonary
disease, 83% of patients with asthma and 33% with COPD demonstrated clinical improvement in
FEV1 while receiving budesonide inhalation suspension during the one year observation period.
In this study, inhaler technique was reviewed and proper inhaler use was demonstrated in the
clinic setting at nearly every follow-up. A majority of patients reported an increased feeling of
personal well-being, better symptom control, and increased confidence to be the main advantages
of nebulizer use. Approximately 75% of patients felt their nebulizer was superior to inhalers for
symptom relief.
Gaude and Nemagouda[31] conducted a parallel group longitudinal study in acute exacerbation
of COPD. A total of 125 patients were included in two groups: study group received budesonide
nebulization 2 mg every 12 hourly, and control group received parental hydrocortisone -100
mg every 6 hourly. All the patients were assessed at the end of five days and at discharge with
spirometry, PEFR, dyspnea grade according to MMRC, SaO2, and St. George Respiratory
Questionnaire for health related quality of life. It was observed that nebulized budesonide had
similar range of improvement in spirometry variables including PEFR and SaO2 as that in the
control group. Patients in the nebulized budesonide group had better improvement in HRQL
score as compared to control group. More number of patients in nebulized budesonide group
could be discharged early as compared to control group. Thus it was concluded that nebulized
budesonide was equally as efficacious as parental steroids in acute exacerbation of COPD. There
were no major side effects with budesonide nebulization. There was no higher incidence of
hyperglycemia in budesonide group. During the follow up period, the relapse rates for
readmission for acute exacerbations were similar in both the groups. In this study, it was
observed that nebulized budesonide (2 mg every sixth hourly) was equally as efficacious as
parenteral / oral corticosteroids study intravenous (IV) hydrocortisone 100 mg QID /40 mg of
oral prednisolone) in AECOPD. Also it was observed that nebulized budesonide reduced the
duration of hospitalization and showed better improvement in HRQL as compared to
parenteral /oral steroids. Overall the therapeutic outcome with nebulized budesonide in patients
with AECOPD was good.
Go to:
SUMMARY
High dose nebulized corticosteroids have been tested in a limited number of studies in AECOPD.
The available data suggest that nebulized budesonide might be an alternative to systemic
corticosteroids in the treatment of acute exacerbation of COPD. However, as individual studies
are typically underpowered and have remarkably heterogeneous methodologies, larger studies
are needed to confirm these preliminary findings and determine conclusively any impact of
nebulized corticosteroids in AECOPD. Nebulized budesonide may be an alternative to
parental/oral prednisolone in the treatment of acute exacerbations of COPD but further studies
should be done to evaluate its long-term impact on clinical outcomes after an initial episode of
COPD exacerbation. Also studies are required to evaluate different types of corticosteroids with
different dosages in AECOPD. Obviously, they will also make strong emphasis on the final
conclusion of the place of nebulized corticosteroids in AECOPD.
Go to:
Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
Go to:
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ALLERGY & IMMUNOLOGY 10.08.20100 COMMENTS
Asthma Attacks Not Helped

by More Inhaled Steroids
Increasing the maintenance dose of inhaled corticosteroid at the beginning of
an asthma attack did not lessen the need for systemic corticosteroids,
according to a Cochrane review.
In the five randomized controlled trials found suitable for review, there was no
significant reduction in the need for oral, intramuscular, or intravenous
corticosteroids in patients randomized to self-regulated increased inhaled
medications, compared with groups continuing their usual daily maintenance
dose (OR 0.85, 95% CI 0.58 to 1.26, P value not given), according to Francine
Ducharme, PhD, of the University of Montreal, and colleagues.
The researchers also found no significant difference in the overall risk of
adverse events associated with the increased inhaled corticosteroid dose
strategy, although the large confidence interval prevents a firm conclusion,
they noted.
The authors noted that inhaled corticosteroids "have an established role" in
chronic asthma management as a long-term therapy, but their role in
managing acute asthma attacks is less clear.
"Inhaled corticosteroids offer a theoretical advantage in the acute setting by
being delivered directly to the airways, thus maximizing lung deposition [and]
resulting in higher local potency and a potentially faster onset of effect," they
wrote.
And in an earlier Cochrane review comparing the use of high-dose inhaled
corticosteroids to a systemic drug in asthma exacerbations following
discharge from the emergency department, no significant differences were

demonstrated in relapse rates, beta-2 agonist use or adverse events.
"Based on these studies, high-dose inhaled corticosteroids might offer a
promising alternative to oral corticosteroids," the authors theorized. And
increasing the dose of inhaled corticosteroids is often a component of written
asthma action plans, they noted.
To shed more light on the issue, they did an extensive, systematic search in
October 2008 and updated it in 2009. The search turned up five trials that met
their criteria. The trials included 1,250 patients. Three studies included only
adult patients; one study included both adults and adolescents older than 13;
and one study included only children between the ages of 6 and 14.
Patients enrolled in the trials were given either normal maintenance doses or
increased doses of an inhaled corticosteroid such as budesonide (Pulmicort)
at the beginning of an exacerbation.
The trials allowed patients to continue using other baseline co-interventions
for asthma as long as the dose remained unchanged throughout the study
period. Three of five studies permitted the use of long-acting beta agonists at
baseline, while two studies excluded patients using that class of medications.
For rescue medications, depending on the trial involved, patients could use
terbutaline or salbutamol in addition to systemic corticosteroids such as
prednisolone.
All studies were double-blind and followed up patients for exacerbations for at
least six months post-randomization. Only about 35% (range 24% to 53%) of
patients randomized actually required use of the study inhaler.
In an intent-to-treat analysis, two out of six subgroups studied in the trials had
enough data for analysis, but neither showed a substantial effect on the
primary outcome.
The authors found that the need for rescue oral corticosteroids did not differ if
the amount of time elapsed before inhaled corticosteroid treatment initiation
was less than 48 hours, versus greater than or equal to 48 hours following the
onset of an exacerbation (Chi2 0.57, P=0.45).
Furthermore, the need for rescue oral medications was not significantly
different if the inhaled corticosteroid dose was doubled, compared with being
quadrupled (Chi2 2.53,P=0.28).
The impact of other potential confounders -- including age, smoking status,
maintenance inhaled corticosteroid dose, and achieved inhaled corticosteroid
dose -- on the risk of needing oral corticosteroids during an exacerbation
could not be studied because of the low number of trials involved, the
researchers noted.
No serious adverse events were reported in any of the trials.
As for non-serious adverse events, two studies comprising 142 patients found
that those randomized to a higher dose of inhaled corticosteroids following
onset of an asthma exacerbation were not significantly more or less likely to
experience a non-serious adverse event (OR 2.15, 95% CI 0.68 to 6.73).
The authors listed several possible reasons why the increased inhaled
corticosteroid strategy did not appear to result in a benefit for patients. First,
"regular use of inhaled corticosteroids in asthma has proven to be very
effective at preventing exacerbations, thus reducing the need for oral
corticosteroids, and [it] may indeed be the most effective overall strategy,"
they wrote, noting that the low need of study subjects for step-up inhaler
therapy may have led to an underpowering of data needed to detect a
significant difference.
In addition, the small number of trials included in the study resulted in wide
confidence intervals for most outcomes, so that firm conclusions regarding the
strategy's effects were difficult. And although self-reported compliance with the
studies' protocols was high, "actual compliance was possibly lower," the
authors suggested. "Indeed, in a previous study looking at asthma action plan
compliance in a family practice setting, less than 40% properly implemented
their action plan."
They also noted that conclusions could not be reached for children because
only 28 participants in the included trials were children.
Ducharme has received grant support from Merck and GlaxoSmithKline. One
coauthor has done research on industry-funded asthma management projects
including one specifically addressing the issue under review. Other coauthors
reported relationships with Merck-Frosst, GlaxoSmithKline, Topigen,
AstraZeneca, and Altana.
Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine,

Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse
Planner
Primary Source
Cochrane Database of Systematic Reviews
Source Reference: Quon, BS, et al "Increased versus stable doses of inhaled corticosteroids for
exacerbations of chronic asthma in adults and children" Cochrane database of systematic
reviews 2010; DOI: 10.10
ARB Therapy May Slow

Emphysema Progression
Disease stabilization observed for up to 12 months
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by Charles
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Action Points
MONTREAL -- A subset of patients with chronic obstructive pulmonary

disease (COPD) with emphysema appeared to benefit from treatment with an
angiotensin receptor blocker, supporting preclinical evidence of efficacy, a
randomized clinical study suggested.
Overall, patients with COPD treated with losartan (Cozaar) had no
improvement compared with placebo-treated patients. However, the subset of
patients with emphysema at baseline had stabilization of emphysema at 6
months, whereas patients in the placebo group exhibited a 3% rate of
progression (P=0.042). Anatomic analysis also showed a significant difference
for the left upper lobe in favor of losartan (P=0.049).
At 12 months, the overall trend toward stability persisted in the patients who
had emphysema at baseline but was no longer significant. The anatomical
analysis showed a consistent pattern of stability with losartan versus
progression with placebo, achieving statistical significance in the right middle
lobe, Allison Lambert, MD, of Johns Hopkins, reported here at CHEST
2015.
"From these data, we conclude that, among patients with COPD who have
CT-defined emphysema, losartan has the potential to prevent emphysema
progression," said Lambert. "Our secondary outcomes were unchanged.
"The next step in our line of clinical investigation will be to conduct a phase III
clinical trial, supported by the NIH Pulmonary Trials Consortium. We anticipate
recruiting 220 patients with emphysema, which will afford 90% power to detect
differences as identified in our phase II trial."
The emergence of differences between the groups after a relatively brief
treatment period was impressive, but the timing of medication administration
and CT scans could influenced findings, suggested Jay Peters, MD, of the
University of Texas Health Science Center in San Antonio.
"One of my concerns is that [the improvement] was in the left upper lobe early
on and then the right middle lobe at 12 months," said Peters. "How did you
control the time of day that the CT was done and how did that correlate with
the medications? It would seem that somebody who had just taken medication
with air trapping could look quite different."
Alluding to data showing that the right middle lobe is the most common site of
progression with CT-defined emphysema, Lambert responded, "I do think that
this finding within the right middle lobe at 12-month follow-up is true and
perhaps compelling. What was striking to me at the 12-month follow-up was
the trend across all lobes; all the lobes had stopped progressing."
The rationale for using ARBs in emphysema dates back to preclinical
studies of Marfan syndrome. Animals with emphysema-like changes in
alveoli were treated with losartan, which partly reversed the changes.
Subsequent studies in mice showed that losartan attenuated adverse lung
effects of cigarette smoke and restored lung architecture.
Relevant clinical studies include a trial of the ARB irbesartan (Avapro) in
patients with COPD, leading to some changes associated with improved
lung function and architecture. A retrospective case-control study showed
a reduction in COPD hospitalization and mortality among patients treated with
statins and ARBs.
In her presentation here, Lambert reported findings from a randomized, proofof-concept study to determine whether losartan would prove or slow the
progression of emphysema in patients with COPD. Patients with mild to
moderate COPD were randomized to losartan or placebo and followed for 12
months. Outcomes of interest included CT-assessed percent emphysema and
airway wall thickness; spirometry, lung volumes, and diffusing capacity of the
lung for carbon monoxide; and quality of life/health status.
The final analysis included 106 patients, for whom Lambert reported anatomic
and functional outcomes. In the overall population, patients assigned to
losartan did no better than those in the placebo group with respect to any of
the outcomes at 6 or 12 months. However, a prespecified analysis of patients
with CT-confirmed emphysema at baseline (n=46) showed anatomical
changes favoring the losartan group.
At 6 months, total-lung emphysema had decreased by 0.78% in the losartan
group and increased by 3.03% in the placebo group (P=0.042). The lobespecific anatomic analysis showed a 0.86% decrease in emphysema in the
left upper lobe among patients treated with losartan versus an increase of
2.97% in the placebo group (P=0.049). Other lobe-specific values did not differ
significantly between the groups, nor did any of the functional outcomes
assessed.
At 12 months, patients in the losartan group still had an overall decrease in
emphysema (-0.32%) compared with an increase of 2.18% in the placebo
group, but the difference was no longer significant (P=0.064). Emphysema in
the right middle lobe had decreased by 0.72% in the losartan group but
increased by 3.34% in the placebo group (P=0.019).
All of the other lobe-specific assessments showed stable disease in the
losartan arm versus 2% to 3% emphysema progression with placebo,
although the differences did not achieve statistical significance. None of the
functional outcomes differed significantly between treatment groups.
Lambert and colleagues disclosed no relevant relationships with industry.
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of

Nephrology, Yale School of Medicine
Primary Source
CHEST 2015
Source Reference: Lambert A, et al "Antiogensin receptor blockade for COPD: Phase II trial" CHEST 2015;
148(4_MeetingAbstracts): 744A.
Inhalers and nebulizers are two different devices used to deliver quick-relief medicines(also called
rescue or fast-acting medicines) or long-term control medicines (also called controller or maintenance
medicines) directly into the lungs.
Inhalers
Inhalers are portable, handheld devices that are available in two types:
Metered dose inhalers (MDI)are the most commonly prescribed. Like mini-aerosol cans, these
devices push out a pre-measured spray of medicine. When the person squeezes the inhaler, a
measured "puff" of medicine is released. Some MDIs have counters that indicate how many doses
remain. If there's no counter, the number of doses already used should be tracked, so that the inhaler
can be replaced on time.
Kids who use a metered dose inhaler also might use a spacer, which attaches to the inhaler and makes
it easier to use. A spacer is a kind of holding chamber for the medicine, which eliminates the need to
closely coordinate squeezing the inhaler and inhaling the medicine. With an inhaler and spacer, the
medicine can be inhaled slowly when the user is ready. So, it's possible for very young kids and even
babies to receive their medications using a metered dose inhaler with a spacer.
Spacers also make inhalers more effective. Sometimes with an MDI, the medicine will reach the back
of the throat but not get down into the lower airways. A spacer helps to deliver the medicine into the
lower airways, which is where it needs to go to work properly.
Babies and younger kids use a facemask (a plastic cup that covers the mouth and nose) to inhale the
medication held in the spacer, whereas older kids can use a mouthpiece. It usually only takes a couple
of minutes or less to give medication by metered dose inhaler with a spacer.
Dry powder inhalers deliver medicine in powder form, but they don't spray out. The user must do
more of the work, inhaling the powdered medicine quickly and quite forcefully. At around 5 or 6 years
of age, most kids are able to do this.
During an office visit, the doctor may ask your child to demonstrate using the inhaler and offer advice,
if needed.
Nebulizers
Nebulizers are electric- or battery-powered machines that turn liquid asthma medicine into a fine mist
that's inhaled into the lungs. The user breathes in the mist through a mouthpiece or facemask.
Nebulizers vary in size and shape, but can be a bit bulky and noisy and may need to be plugged in.
A child doesn't have to "do" anything to receive the medicine except stay in one place and accept the
mouthpiece or facemask. It usually takes about 5 or 10 minutes to give medication by nebulizer, and
sometimes longer. Nebulizers can be less effective if a child is crying during use, since less medicine
will be inhaled.
Practice, Practice
Be sure the doctor shows you how the nebulizer or inhaler works so that you can teach your child how
to use it correctly. Improper usage may result in less medicine getting into your child's lungs.
Reviewing the instructions that come with the inhaler and practicing at home can help, too.
If you have any questions about the device or if you're concerned that your child isn't getting the
proper dose of medication, talk to your doctor.
Reviewed by: Elana Pearl Ben-Joseph, MD
Date reviewed: January 2014
Originally reviewed by: Nicole A. Green, MD

Role of Inhaled Corticosteroids in The Management of Acute Asthma

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Role of Inhaled Corticosteroids in The Management of Acute Asthma

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The role of inhaled corticosteroids

in the management of acute asthma

ERS Journals Ltd

Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to 2-agonists in

Belda J, Margarit G, Martinez C, et al. Anti-inflammatory effects of high-dose inhaled

Wedde-Beer K, Hu C, Rodriguez MM, Piedimonte G. Leukotrienes mediate neurogenic

Published online November 30, 2007.

Expert Review of Clinical Immunology

Inhaled Corticosteroids as Rescue Medication in Acute

Abstract and Introduction

Selected Clinical Evidence on the Use of Inhaled CS in

Omission of relevant studies [11,12]

Non distinction between genomic and nongenomic effects

Pooled analysis of studies with different doses and timing of administration

Defining the Biological Bases of CS Actions: The

mechanisms of action of CS on the inflammatory process are complex (Figure 1).

nongenomic pathways or airway blood-flow responses in the observed clinical or

Analysis of the Clinical Evidence in Agreement With the

Expert Commentary & Five-year View

Correlate (directly) with baseline airway blood flow

More powerful with budesonide or fluticasone than with beclometasone

Can improve 2-adrenergic bronchodilation

These vascular effects of inhaled CS on the airways could be expected to have

Sidebar: Key Issues

Role of inhaled steroids in acute asthma exacerbations

Dr. Julian Marsden (biography and disclosures)

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P SammarelliMay 12, 2012 at 11:05 pmPermalink

Excellent reminder for me!

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Narayanappa DayanandaJune 27, 2012 at 11:45 amPermalink

v.27(4); Oct-Dec 2010

Lung India. 2010 Oct-Dec; 27(4): 230235.

Nebulized corticosteroids in the management of acute exacerbation of COPD

ACUTE EXACERBATION OF COPD

PATHOPHYSIOLOGICAL CONSEQUENCES OF AECOPD

TREATMENT OF ACUTE EXACERBATION OF COPD WITH INHALED

23. Devidayal, Singhi S, Kumar L, Jayshree M. Efficacy of nebulized budesonide

ALLERGY & IMMUNOLOGY 10.08.20100 COMMENTS

Asthma Attacks Not Helped

discharge from the emergency department, no significant differences were

Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine,

ARB Therapy May Slow

This article is a collaboration between MedPage Today and:

MONTREAL -- A subset of patients with chronic obstructive pulmonary

Lambert and colleagues disclosed no relevant relationships with industry.