Asthma remains a significant cause
of morbidity and mortality throughout
the world. Patients presenting
with near-fatal asthma provide a
unique population in which to
study the variables that contribute
to asthma-related mortality. By
identifying high-risk patients, using
objective and subjective measures
to detect severe exacerbations, and
initiating early medical intervention,
the morbidity and mortality of
asthma can be reduced.
In the May 2005 issue of The
Journal of Respiratory Diseases, we
reviewed the risk factors associated
with life-threatening asthma. In
this article, we will focus on management
Standard therapies for severe asthma
include ß-agonists, oxygen, and
corticosteroids (Table). ß-Agonists
remain first-line therapy for patients
with exacerbations of any degree
of severity (Figure 1).1 These
agents, with the exception of the
long-acting agents, induce bronchodilation
with a rapid onset of
action. Patients with life-threatening
asthma may have significant
bronchoconstriction, airway edema,
and inflammation, and may require
high doses or repeated doses
of ß-agonists before showing a sufficient
Numerous studies have indicated
that administration of ß-agonists
via metered-dose inhaler with
spacer is as effective as nebulized
treatments.2,3 Reports in the litera-ture suggest that continuous nebulization
may be beneficial in the
most severe asthma exacerbations.4
Levalbuterol, an isomer of racemic
albuterol, may play a role in
managing refractory asthma,5 particularly
in patients with ischemic
heart disease or severe tachycardia.
Levalbuterol is reported to have
fewer side effects, since the bronchodilatory
effects of albuterol result
from activity of the R-isomer,
while the side effects may result
from the S-isomer.5 In a subset of
patients with severe asthma, a
dose-dependent relationship existed
when higher doses of levalbuterol
Nebulized doses of levalbuterol
range from 0.63 to 1.25 mg in
adults, but a dose of 2.5 mg should
be considered in those with severe
asthma. One study demonstrated a
dose-response curve with doses
ranging from 0.31 to 2.5 mg in children
with severe exacerbations.6
Intravenous ß-agonists have not
been shown to be of more benefit
than inhaled ß-agonists in European
studies.7,8 Although most
patients respond to inhaled ß-agonists,
some may benefit from systemic
treatment. Appel and associates9
performed a randomized
controlled trial of patients with
acute asthma. In this double-blind
cross-over study, patients with a
peak expiratory flow rate (PEFR) of
less than 150 L/min received inhaled
metaproterenol or subcutaneous
epinephrine. At 120 minutes,
61% of those who received metaproterenol
had improved PEFR,
compared with 89% of those who
received epinephrine. Patients in
whom initial therapy failed had
symptoms for a significantly longer
duration before presentation, suggesting
that marked inflammation
and mucous plugging may result in
a suboptimal response to inhaled
medications.9 The results of this
study do not clearly define the role
of systemic ß-agonists in the treatment
of life-threatening asthma,
but they suggest that a trial of subcutaneous
ß-agonists should be
considered in patients who fail to
respond to inhaled medications.
Epinephrine can be administered
subcutaneously as 0.3 to 0.5
mg of a 1:1000 solution every 20
minutes to a maximum of 3 doses.
Terbutaline, 0.25 to 0.5 mg, should
be used in pregnant patients requiring
subcutaneous ß-agonist treatment.
Although there is some concern
about using systemic ß-agonists
in older patients, Cydulka and
associates10 showed that patients
older than 40 years had minimal
risk of side effects from subcutaneous
epinephrine if they had
no active angina and no history of
myocardial infarction in the previous
Corticosteroids should be administered
to all patients presenting to
the hospital with asthma unless
PEFR or forced expiratory volume
in 1 second (FEV1) is at least 80% of
predicted after 1 hour of treatment
(Figure 2). Systemic corticosteroids
decrease inflammation, increase
the number and sensitivity of
ß-receptors, and inhibit the migration
and function of eosinophils
A meta-analysis of 700 articles
with 30 randomized, controlled trials
demonstrated that corticosteroid
administration in the emergency
department (ED) reduced admission
rates and decreased relapse rates at 7 to 10 days.12 Oral therapy
was equivalent to intravenous therapy.
Corticosteroids were most effective
in patients with severe asthma
who were not receiving longterm
Because the maximum effect of
corticosteroids is not seen until 4 to
6 hours after administration, this
therapy should be instituted early
(within 1 hour of presentation).
The optimal dose remains controversial.
Haskell and associates13
randomized patients with severe
asthma to receive 125, 40, or 15 mg
of methylprednisolone every 6
hours. Medium and high doses
caused more significant improvement
than did low doses. The highdose
group had a more rapid improvement
in the first 24 to 36
hours of therapy.
We prefer using 125 mg of
methylprednisolone every 6 hours
for the first 24 to 48 hours in patients
admitted to the ICU. The
practice guidelines published by
the NIH recommend prednisone,
120 to 180 mg/d in 3 or 4 divided
doses (or the equivalent) for 48
hours, then 60 to 80 mg/d until
PEFR reaches 70% of predicted or
personal best.13 The guidelines also
state that no advantage has been
identified for higher doses or intravenous
administration if GI absorption
If patients have improvement on
this regimen, they may be switched
to oral prednisone, 60 to 80 mg (1
mg/kg) per day. Treatment should
be continued for 3 to 10 days, then discontinued without a taper
if the patient is receiving inhaled
corticosteroid therapy. Inhaled
corticosteroids should be
continued during systemic treatment
to avoid rebound bronchoconstriction
of systemic therapy.
Ipratropium has been shown to be
beneficial in managing acute bronchospasm
induced by ß-blockers
and monoamine oxidase inhibitors.
15 Patients with severe airway
obstruction (FEV1 of less than 50%
of predicted) also benefit from ipratropium
in combination with ßagonists.
In such patients, the combined
use of anticholinergics and ß-agonists
improves PEFR and FEV1
more than ß-agonists alone and significantly
decreases the risk of hospital
The onset of action of anticholinergics
in patients with acute exacerbations
of asthma is short, occurring
within 1 minute, with peak
effects within 20 minutes.15 Benefits
may persist for up to 48 hours.16
Anticholinergic therapy should be
continued until the patient stabilizes
but should not be added to the
patient's long-term asthma management
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