role of inhaled corticosteroids in the management of acute asthma

The role of inhaled corticosteroids in the management of acute asthmaB. 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 2 million 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 β-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 β-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 (MgSO4) 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 β-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) 0.18–0.58). 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 0.29–1.09). 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, double-

dummy, randomized controlled trial with concealed allocation, 39 adults with acute

asthma received either high-dose fluticasone (4,000 μg·day−1) or prednisone (30

mg·day−1) for 4 days. The patients were followed with induced sputum and blood

inflammatory markers at baseline, 2, 6 and 24 h. 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

60 yrs. 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 6 yrs, 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 0.52–1.09).

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

References

1. ↵

Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma - United States, 1960–

1995. MMWR CDC Surveill Summ 1998;47:1–28.

Medline

2. ↵

Louis R, Lau LCK, Bron AO, Roldaan AC, Radermecker M, Djukanovic R. The relationship between

airways inflammation and asthma severity. Am J Respir Crit Care Med 2000;161:9–16.

CrossRef Medline Web of Science

3. ↵

Weiss KB, Sullivan SD. The health economics of asthma and rhinitis. I. Assessing the economic

impact. J Allergy Clin Immun 2001;107:3–8.


4. ↵

Serra-Batlles J, Plaza V, Morejon E, Comella A, Brugues J. Costs of asthma according to the degree

of severity. Eur Respir J 1998;12:1322–1326.

Abstract

5. ↵

Krahn MD, Berka C, Langlois P, Detsky AS. Direct and indirect costs of asthma in

Canada. CMAJ1996;154:821–831.

Abstract

6. ↵

Tsuyuki RT, Sin DD, Sharpe HM, et al. Management of asthma among community-based primary

care physicians. J Asthma 2005;42:163–167.

Medline Web of Science

7. ↵

Chapman KR, Ernst P, Grenville A, Dewland P, Zimmerman S. Control of asthma in Canada: failure

to achieve guideline targets. Can Respir J 2001; 8, Suppl. A. 35A–40A.

8. ↵

Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for Asthma -

United States, 1980–1999. MMWR Surveill Summ 2002;51:1–13.

Medline

9. ↵

Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for β-agonist

treatment of acute asthma. Cochrane Database of Syst Rev. 2006;2:CD000052

10. ↵

Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in the emergency

management of acute asthma exacerbation: a meta-analysis of randomized clinical trials. Ann

Emerg Med 1999;34:8–18.


11. ↵

Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department

treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst

Rev. 2001;1:CD002178

12. ↵

Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA Jr. Magnesium sulfate for treating

exacerbations of acute asthma in the emergency department. Cochrane Database Syst

Rev2000;1:CD001490

13. ↵

Ram FSF, Wellington SR, Rowe BH, Wedzicha JA. Non-invasive positive pressure ventilation for

treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane

Database Syst Rev2005;1:CD004360

14. ↵

Blitz M, Blitz S, Beasely R, et al. Inhaled magnesium sulfate in the treatment of acute

asthma. Cochrane Database Syst Rev 2005;4:CD003898

15. ↵

Rodrigo G, Pollack C, Rodrigo C, Rowe BH. Heliox for nonintubated acute asthma

patients. Cochrane Database Syst Rev 2006;4:CD002884

16. ↵

Travers A, Jones A, Camargo CA Jr, Rowe BH. Intravenous β2-agonists for acute asthma in the

emergency department. Cochrane Database Syst Rev 2001;1:CD002988

17. ↵

Parameswaran K, Belda J, Rowe BH. Addition of intravenous aminophylline to β2-agonists in

adults with acute asthma. Cochrane Database Syst Rev 2000;4:CD002742

18. ↵

Graham VAL, Lasserson T, Rowe BH. Antibiotics for acute asthma. Cochrane Database Syst

Rev2001;2:CD002741

19. ↵

Chan L, O'Malley BW. Steroid hormone action: recent advances. Ann Intern Med 1978;89:694–

701.


20. ↵

Edmonds ML, Camargo CA Jr, Pollack CV, Rowe BH. Early use of inhaled corticosteroids in the

emergency department treatment of acute asthma. Cochrane Database of Syst

Rev 2003;3:CD002308

21. ↵

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

fluticasone versusoral prednisone in asthma exacerbations. Eur Respir J 2007; 30: 1143–1149

22. ↵

Rowe BH, Bota GW, Fabris L, Therrien SA, Milner RA, Jacono J. Inhaled budesonide in addition to

oral corticosteroids to prevent relapse following discharge from the emergency department: a

randomized controlled trial. JAMA 1999;281:2119–2126.


23. ↵

Pizzichini E, Pizzichini MM, Efthimiadis A, et al. Indices of airway inflammation in induced sputum:

reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care

Med 1996;154:308–317.


24. ↵

Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum

cell counts: effect on exacerbations. Eur Respir J 2006;27:483–494.

Abstract/FREE Full Text

25. ↵

Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and

identification using induced sputum. Respirology 2006;11:54–61.


26. ↵

Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts:

a randomised controlled trial. Lancet 2002;360:1715–1721.


27. ↵

Klassen TP, Feldman ME, Watters LK, Sutcliffe T, Rowe PC. Nebulized budesonide for children with

mild-to-moderate croup. N Engl J Med 1994;331:285–289.


28. ↵

Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing

relapses following acute exacerbations of asthma. Cochrane Database Syst

Rev 2001;1:CD000195

29. ↵

Edmonds ML, Camargo CA Jr, Brenner B, Rowe BH. Inhaled steroids in acute asthma following

emergency department discharge. Cochrane Database of Syst Rev 2000;3:CD002316

30. ↵

Rowe BH, Wong E, Blitz S, et al. Adding long-acting β-agonists to inhaled corticosteroids after

discharge from the emergency department for acute asthma: a randomized controlled trial. Acad

Emerg Med 2007; (In Press)

31. ↵

Persson CC. The role of microvascular permeability in the pathogenesis of asthma. Eur Journal

Respir Dis Suppl 1986;144:S190–S216.

32. ↵

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

inflammation in lungs of young rats infected with respiratory syncytial virus. Am J

Physiol 2002;282:L1143–L1150.

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 AsthmaGustavo 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

http://www.medscape.com/viewpublication/21539

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 (β-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 [11,13]

Pooled analysis of studies with different doses and timing of administration [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,[20,21] and the responses are much more rapid (seconds or minutes). Membrane

receptor inactivation has been shown to induce rapid effects on a variety of second-

messenger systems.[16] In addition, CS could bind to other receptors, ion channels,

enzymes or transporters.

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 µg) or

budesonide (400 µg) 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 µg 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 µg 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 30-

min 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 β2-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.

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 β2-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 µg every 15 min, and 800 µg every 30 min,

respectively. The use of 400 µg every 30 min of budesonide via a MDI and spacer

was also effective, and greater doses (fluticasone 500 µg 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 β2-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

1. Rodrigo GJ, Rodrigo C, Nannini LJ. Fatal or near-fatal asthma: clinical entity or incorrect management? Arch. Bronconeumol. 40, 24-33 (2004).

2. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults. A review. Chest 125, 1091-2002 (2004).3. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of adult acute asthma

treatment: an evidence-based evaluation. Chest 121, 1977-1987 (1999).4. 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).5. Barnes PJ, Adcock IM. How do corticosteroids work in asthma? Ann. Intern. Med. 139, 359-370

(2003).6. 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).

7. Pansegrouw DF. Acute resistant asthma caused by excessive β-2-adrenoceptor agonist inhalation and reversed by inhalation of beclomethasone. South Afr. Med. J. 82, 179-182 (1992).

8. Scarfone RJ, Loiselle JM, Wiley JF, Decker JM, Henretig FM, Joffe MG. Nebulized dexamethasone versus oral prednisone in the emergency department of asthmatic children. Ann. Emerg. Med. 26, 480-486 (1995).

9. 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 steroids.Endocrinology 30, 437-453 (1942).

18. Klein K, Henk W. Clinical experimental studies on the influence of aldosterone on hemodynamics and blood coagulation. Z. Kreislaufforsch. 52, 40-53 (1963).

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, Rosário 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.

http://thischangedmypractice.com/bios/#jumarsde

http://thischangedmypractice.com/author/jumarsde/

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 μg/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; 281:2119–2126

http://jama.ama-assn.org/content/281/22/2119.full.pdf+html or with CPSBC

Please indicate how this article will change your practice:

Role of inhaled steroids in acute asthma exacerbations

I disagree with this approach

I will consider changing my practice, but need more information/time

I will likely change my practice

I will definitely change my practice (or I already do this)

https://www.cpsbc.ca/library/library-article-requests

http://jama.ama-assn.org/content/281/22/2119.full.pdf+html

http://www.thoracicmedicine.org/text.asp?2009/4/4/161/56006

http://www.thoracicmedicine.org/text.asp?2009/4/4/161/56006

http://www.bcguidelines.ca/guideline_asthma.html#recommendation3

View Results

Share this:

Read Later

Email

Print

Facebook

Share

Read More | 14 Comments

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.

http://thischangedmypractice.com/inhaled-steroids-in-asthma/comment-page-1/#comment-623



http://thischangedmypractice.com/inhaled-steroids-in-asthma/#comments

http://thischangedmypractice.com/inhaled-steroids-in-asthma/

http://thischangedmypractice.com/inhaled-steroids-in-asthma/

http://thischangedmypractice.com/inhaled-steroids-in-asthma/?share=facebook&nb=1

http://thischangedmypractice.com/inhaled-steroids-in-asthma/#print

http://thischangedmypractice.com/inhaled-steroids-in-asthma/?share=email&nb=1

http://thischangedmypractice.com/inhaled-steroids-in-asthma/?share=custom-1370472293&nb=1

http://thischangedmypractice.com/inhaled-steroids-in-asthma/#ViewPollResults

http://thischangedmypractice.com/accreditation?page-title=Role%20of%20inhaled%20steroids%20in%20acute%20asthma%20exacerbations&page-ID=2451#Role%20of%20inhaled%20steroids%20in%20acute%20asthma%20exacerbations

4. Shel GlazerMay 1, 2012 at 1:29 pmPermalink

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 we’ve 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)

14. Narayanappa DayanandaJune 27, 2012 at 11:45 amPermalink

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): 230–235.

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

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988175/#CIT1

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988175/



http://www.ncbi.nlm.nih.gov/pubmed/?term=Nadagouda%20S%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Gaude%20GS%5Bauth%5D

http://dx.doi.org/10.4103%2F0970-2113.71957

http://www.ncbi.nlm.nih.gov/pmc/issues/191835/

http://www.ncbi.nlm.nih.gov/pmc/journals/1151/

http://www.ncbi.nlm.nih.gov/pmc/journals/

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 patient’s 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,[9–11] 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 1.3–3.84) 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. Receptor–corticosteroid 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 ß2-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[9,16–18] 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 dose-response 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);


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988175/table/T0001/





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 9±2.3; prednisolone, 2.6±2.3; and placebo, 1.8±2.6. The decline in PaCO2 was significantly greater in the two active treatment groups than in the placebo group (-1 mm Hg±4, -1 mm Hg±5, and 1 mm Hg±6, 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 non-acidotic 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 µg 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 re-hospitalization 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:

REFERENCES

1. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932–46. [PubMed]

2. ™Global strategy for agnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2009. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2009. Global Initiative for Chronic Obstructive Lung Disease (GOLD)

3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349:1498–504. [PubMed]

4. Hattsville: U. S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2009. Third National Health and Nutrition Examination Survey (NHANES III) Public-Use Data Files.

5. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbation of COPD. Ann Intern Med. 1987;166:196–204. [PubMed]

6. Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD. Chest. 2000;117:1345–52. [PubMed]

7. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and COPD morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med. 1996;153:1530–5.[PubMed]

8. Kanner RE, Anthonisen NR, Connett JE. Lung Health Study Research Group. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: Results from the lung health study. Am J Respir Crit Care Med. 2001;164:358–64. [PubMed]

http://www.ncbi.nlm.nih.gov/pubmed/11500333








9. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: The ISOLDE trial. BMJ. 2000;320:1297–303. [PMC free article] [PubMed]

10. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild to moderate chronic obstructive pulmonary disease: A randomised controlled trial. Lancet.1999;353:1819–23. [PubMed]

11. Pauwells RA, Lofdahl CG, Pride NB, Postma DS, Laitinen LA, Ohlsson SV. European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): Hypothesis and design. Eur Respir J. 1992;5:1254–61. [PubMed]

12. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med.2000;161:1608–13. [PubMed]

13. Singh JM, Pada VA, Stanbrook MB, Chapman KR. Corticosteroid therapy for patients with acute exacerbation of chronic obstructive pulmonary disease. Arch Intern Med. 2002;162:2527–36. [PubMed]

14. Barnes PJ. Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci. 1998;94:557–72. [PubMed]

15. Gunen H, Mirici A, Meral M, Akgun M. Steroids in acute exacerbations of chronic obstructive pulmonary disease: Are nebulized and systemic forms comparable? Curr Opin Pulm Med. 2009;15:133–7.[PubMed]

16. Welte T. Inhaled corticosteroids in COPD and the risk of pneumonia. Lancet. 2009;374:668–70.[PubMed]

17. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000;343:1902–29. [PubMed]

18. Novak B. The role of corticosteroids in acute exacerbations of chronic obstructive pulmonary disease.Crit Care Nurse. 2002;22:80–1. [PubMed]

19. Yang IA, Fong K, Sim EH, Black PN, Lasserson TJ. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database System Rev. 2007;2:CD002991. [PubMed]

20. Gartlehner G, Hansen RA, Carson SS, Lohr KN. Efficacy and safety of inhaled corticosteroids in patients with COPD: A systematic review and meta-analysis of health outcomes. Ann Fam Med.2006;4:253–62. [PMC free article] [PubMed]

21. Mitchell CE, Alpers JH, Morton SM, Baggoley CJ, Croker WD, Walsh AJ, et al. Comparison of nebulized budesonide with oral prednisolone in the treatment of severe acute asthma. Eur Respir J.1995;8:S490.















22. Matthews EE, Curtis PD, McLain BI, Morris LS, Turbitt ML. Nebulized budesonide versus oral steroid in severe exacerbations of childhood asthma. Acta Paediatr. 1999;88:841–3. [PubMed]

23. Devidayal, Singhi S, Kumar L, Jayshree M. Efficacy of nebulized budesonide compared to oral prednisolone in acute bronchial asthma. Acta Paediatr. 1999;88:835–40. [PubMed]

24. Morice AH, Morris D, Lawson-Matthew P. A comparison of nebulized budesonide with oral prednisolone in the treatment of exacerbations of obstructive pulmonary disease. Clin Pharmacol Ther.1996;60:675–8. [PubMed]

25. Maltais F, Ostinelli J, Bourbeau J, Tonnel A, Jacquemet N, Haddon J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;165:698–703. [PubMed]

26. Mirici A, Meral M, Akgun M. Comparison of the efficacy of nebulised budesonide with parenteral corticosteroids in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Clin Drug Invest. 2003;23:55–62. [PubMed]

27. Gunen H, Hacievliyagil SS, Yetkin O, Gulbas G. The role of nebulised budesonide in the treatment of acute exacerbations of COPD. Eur Respir J. 2007;30:399–400. [PubMed]

28. Wei H, Xin Z. Practical Clin Med Mag. 2004. Nebulised budesonide in the treatment of acute exacerbations of chronic obstructive pulmonary disease; p. 3. [last cited on 2004]; Available from:http://www.scholar.ilib.cn/A-jslcyxzz200402003.htmlhttp://wwwscholarilibcn/A-jslcyxzz200402003html [last accessed on 2009 Oct 25]

29. Guozhong C, Wen X, Qi Z, Liang Z, Guozhong C, Huiwen XU, et al. Chinese General Medicine. 2005. The effect of inhaled budesonide in persons with acute exacerbations of chronic obstructive pulmonary disease; p. 3. [last cited on 2005]; Available from: http://www.scholar.ilib.cn/A-zgqkyx200520011.html [last accessed on 2009 Oct 25]

30. Marcus P. Budesonide inhalation suspension in adults with poorly controlled asthma or chronic obstructive pulmonary disease. J Appl Res. 2009;9:3–13.

31. Gaude GS, Nemagouda S. Clinical efficacy of nebulized budesonide with parental/oral steroids in patients with acute exacerbation of COPD: A prospective study in tertiary care hospital. Lung India.2009;26:S11–2.

ALLERGY & IMMUNOLOGY 10.08.20100 COMMENTS

http://www.medpagetoday.com/AllergyImmunology

http://www.scholar.ilib.cn/A-zgqkyx200520011.html

http://www.scholar.ilib.cn/A-zgqkyx200520011.html

http://www.scholar.ilib.cn/A-jslcyxzz200402003.html







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

http://www2.cochrane.org/reviews/en/ab002308.html

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 SourceCochrane 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




http://www.medpagetoday.com/reviewer.cfm?reviewerid=512

ARB Therapy May Slow Emphysema ProgressionDisease stabilization observed for up to 12 months

SAVE SAVED REGISTER TODAY

Earn Free CME Credits by reading the latest medical news in your specialty.

SIGN UP

http://www.medpagetoday.com/MeetingCoverage/CHEST/54386


by Charles Bankhead Staff Writer, MedPage Today

This article is a collaboration between MedPage Today® and:

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.

http://www.chestnet.org/Education/CHEST-Meetings/CHEST-2015


http://www.hopkinsmedicine.org/profiles/results/directory/profile/10000696/Allison-Lambert

mailto:[email protected]


"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

http://www.ncbi.nlm.nih.gov/pubmed?term=%22The+European+respiratory+journal%22%5BJour%5D+AND+2006%5Bpdat%5D+AND+Andreas%5Bfirst+author%5D&cmd=detailssearch

http://www.ncbi.nlm.nih.gov/pubmed?term=%22The+European+respiratory+journal%22%5BJour%5D+AND+2006%5Bpdat%5D+AND+Andreas%5Bfirst+author%5D&cmd=detailssearch

http://www.ncbi.nlm.nih.gov/pubmed?term=%22The+Journal+of+clinical+investigation%22%5BJour%5D+AND+2012%5Bpdat%5D+AND+Neptune%5Bauthor%5D&cmd=detailssearch

http://www.ncbi.nlm.nih.gov/pubmed?term=%22The+Journal+of+clinical+investigation%22%5BJour%5D+AND+2012%5Bpdat%5D+AND+Neptune%5Bauthor%5D&cmd=detailssearch

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Science+(New+York%2C+N.Y.)%22%5BJour%5D+AND+2006%5Bpdat%5D+AND+Neptune%5Bauthor%5D&cmd=detailssearch

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Science+(New+York%2C+N.Y.)%22%5BJour%5D+AND+2006%5Bpdat%5D+AND+Neptune%5Bauthor%5D&cmd=detailssearch

http://profiles.uthscsa.edu/?pid=profile&id=0V71EUFLD

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, proof-

of-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 lobe-

specific 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).

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Journal+of+the+American+College+of+Cardiology%22%5BJour%5D+AND+2006%5Bpdat%5D+AND+Mancini%5Bfirst+author%5D&cmd=detailssearch

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:

http://kidshealth.org/parent/asthma_center/words_know/controller.html

http://kidshealth.org/parent/asthma_center/words_know/rescue.html



http://www.medpagetoday.com/reviewer.cfm?reviewerid=755

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

http://kidshealth.org/parent/misc/reviewers.html#g

http://kidshealth.org/parent/misc/reviewers.html

role of inhaled corticosteroids in the management of acute asthma

Documents

asthma severity

treatment of acute asthma

acute exacerbations

control of chronic asthma

severe exacerbations

overall asthma costs5

frequency of exacerbations

inhaled agonists9