THE LANCET

Treatment of acute asthma

Brian J Lipworth

The drug treatment for acute severe asthma has changed inhaled l3-agonists, and is easy for the patient to use
little over the past two decades, comprising primarily of during an acute attack. 5 mg nebulised salbutamol driven
bronchodilators, corticosteroids, and oxygen. Most deaths by 6 IJmin oxygen has been shown to be a safe and
from acute severe asthma are potentially preventable and effective treatment when administered by trained
this requires recognition of severity of the attack and ambulance crew to patients with acute “severe asthma
delivery of optimum acute therapy, both in the during transfer to hospital.5 The potential concern
community and in hospital. regarding inadvertent carbon dioxide retention with high-
International and national guidelines have provided flow oxygen in patients with unsuspected chronic
evidence-based consensus statements on the management obstructive pulmonary disease is reduced by an age cut
of acute asthma in children and adults in general practice off of 50 years, along with diagnostic information from
and hospital settings.‘J Audit studies in the UK have the patient or general practitioner. Conventional open-
shown that many recommendations from previous vent jet nebulisers are, however, relatively inefficient
national guidelines have not been adhered to in either the devices with much of the nominal dose being wasted
community or hospital, and this suggests that wider during exhalation along with the residual volume at the
dissemination of the guidelines and improved education is end of nebulisation. Drug delivery to the lung depends on
required.3,4 the performance of the nebuliser chamber and an
As the international and national guidelines contain adequate flow rate from the compressor source. When 17
detailed algorithms for pathways of management in acute commercially available jet nebulisers were evaluated under
asthma exacerbations, it is not the intention to review the optimum operating conditions they showed an eight-fold
contents of these published reports here. A summary flow variation in the respirable dose delivered.6 The
chart for the treatment of acute severe asthma is shown in performance of a nebuliser may be further compounded
figure 1, based upon the key points from the international’ by variations in flow rate from a compressor which needs
and UK” management guidelines. The agenda for this to be, although rarely is, regularly maintained.
brief overview is to critically appraise some of the more A large-volume spacer device with a metered dose
contentious aspects of drug treatment in acute asthma, inhaler is an alternative means of delivery, which allows
but not to deal with initial assessment, follow-up, and tidal rebreathing with a mask or mouthpiece, and
patient education. On a more general point, it is improves delivery of respirable particles. Two studies in
important to appreciate that interpretation of many acute severe asthma have shown an equivalent
studies in acute asthma is limited by their small sample bronchodilator response from salbutamol when given via
size, making them vulnerable to statistical type IT error, a holding chamber or a nebuliser, when the holding
although this may be overcome by meta-analysis where chamber used a six-fold lower nominal dose.7,8 Studies in
appropriate. acute asthma in children have shown a similar response to
terbutaline given by a nebuliser or by large-volume spacer
Bronchodilator therapy on a microgram equivalent or half microgram equivalent
The purpose of bronchodilator therapy in acute asthma is nominal basis.9J”
to reverse any bronchial smooth muscle spasm, in order to The delivery of salbutamol from large-volume spacer
buy time until the anti-inflammatory effect of the holding chambers may be impaired by multiple actuations
corticosteroid begins to work after 6-12 hours. In view of or inhalation delay,” suggesting that repeated cycles of
the severity of airflow obstruction, it is imperative to two puffs (200 ug) with a deep tidal breathing method
achieve a maximum or near maximum response with should be employed in acute asthma. General
minimum systemic adverse effects. High doses of inhaled practitioners should have a supply of large-volume plastic
P,-adrenoceptor agonists such as salbutamol are widely spacers which have been prewashed in detergent and drip-
accepted as first-line bronchodilator therapy, although the dried to reduce static charge. Use of a spacer in this way
role of the nebuliser for delivery has come under with up to ten sequential puff cycles of salbutamol (200
increasing scrutiny. The place of additional bronchodilator ug each time) will in most circumstances be equally or
therapy with inhaled anticholinergics and the use of more effective than an inadequately serviced compressor
intravenous salbutamol or aminophylline are debated. in conjunction with a low-performance nebuliser.
Improved lung delivery from a spacer might conceivably
inhaled p;agonist delivery increase systemic absorption, although this is likely to be
The nebuliser, administered by mask or mouthpiece and offset by reduced lung bioavailability due to reduced small
driven by an air compressor or more preferably by high- airway calibre in acute asthma, as well as down-regulation
flow oxygen, is the mainstay for delivering high doses of and associated desensitisation of extrapulmonary p,-
adrenoceptors. Further studies are required to look at
Lancet 1997; 350 (suppl II): 18-23 spacer use in patients with acute severe asthma.
Departments of Clinical Pharmacology and Respiratory Medicine, The main disadvantages of a spacer are that it precludes
Ninewells Hospital and Medical School, University of Dundee, concomitant use of an oxygen mask (but not nasal
Dundee DDI 9SY, UK (B J Lipworth MD) cannula) and requires patient cooperation and closer

Vol350. Ocrober . 1997 ~1118

 THE LANCET

i Pulse >IlO/min, respiratory rate >25/min j PaCO, >6kPa (45 mm Hg) 1

PEF ~60% predicted or best : [ PaO, <8kPa (60 mm Hg) j
j SaO, ~92% if. pH ~7.35 j
.. .,. . ..,. _ . _. “~. .^*-.-&
i Unable to complete sentences
.-. . . . _ --,
I Mf4Mxiiening features
i,~“-~I -_. ~.~.~-~-~
i Silent chest, cyanosis, feeble respiratory effort i
; Bradycardia or hypotension
i Exhaustion, confusion, or coma
PEF ~30% predicted or best
r.. -. ~. .._” . . - .” . _ Cr_ ._.^-_._“.“____llr

Initial treatment
“____ . ... 1 . .. -- ...I.- “. --.- 1 x
j { ‘&ygen’(at least 60% FiO,) Initial response $ Admit to hospital for I
! i Nebulised salbutamol (in 0,) +/- nebulised ipratropium’ within 1 h 1 further observation and 1
1j i5 Oral corticosteroid treatment
s .-.1-._“-.~ _.,.x.__i^l _. .. r .._.‘.... ,. .I a. ~, ..“.,~ _“,..” .F.,___ ii
Life-threatening features
or
Poor initial treatment response after 30 min
1
(repeat severity markers)

Add in
_. , I _,
Repeated nebulised salbutamol every 30 min
: Nebulised ipratropium
iv corticosteroid
Consider iv salbutamol or aminophylline
Chest radiograph to’exciude pne&n&horax
I Monitor serum K with high dose &-agonist
_I ., .

1 Poor response within 1 h

(repeat severity markers)
1

Admit to intensive care for possible intubation and

mechanical ventilation
..”
:““.
Figure 1: Guidelines for hospital treatment of acute severe asthma
Adapted from international and UK guidelines.‘,* Usual recommended doses In adults for acute severe asthma: nebulised salbutamol 5 mg, nebulised
ipratropium 0.5 mg; oral prednisolone 50 mg, intravenous (iv) hydrocortisone 200 mg; iv salbutamol 4 pg/kg, iv aminophylline 5 mg/kg (both as
infusions over 20 min).

supervision by the doctor administering the treatment. showed a greater than 10% increase in FEVl after the
Furthermore, there is a perception by many patients that second inhalation, compared with 13 out of 29 patients
a nebuliser represents high-technology therapy compared who showed less than a 10% change in FEV, at the same
with the simpler plastic spacer, which many asthmatics time point with the Nebuhaler. This is in keeping with the
will already be using for their inhaled corticosteroid observation that in acute asthma 98% of patients were
therapy. In patients with more severe asthma and able to generate sufficient inspiratory flow through a
respiratory failure, continuous administration of Turbuhaler, allowing a therapeutic dose of terbutaline to
P,-agonists may be easier via a nebuliser, particularly be delivered to the airways.‘” These findings are therefore
when anxiety impairs patient cooperation. It has been reassuring for patients using dry-powder inhaler devices,
shown that routine substitution of metered-dose aerosol although in the presence of tachypnoea the use of tidal
in conjunction with a spacer (Aerochamber) instead of breathing with a nebuliser or large-volume spacer would
nebulised P,-agonist therapy resulted in projected annual be preferable.
savings in one hospital amounting to US@33 OOO.‘* Full or partial ,$-agonists
How do portable dry-powder inhalers perform when There has been controversy about the possible harmful
given as repeated puffs by patients before the doctor’s effects of inhaled fenoterol (a full agonist) compared with
arrival? In a study of 62 patients with acute severe airflow salbutamol (a weaker partial agonist). In particular, case-
obstruction, delivery of terbutaline given by dry-powder control studies from New Zealand suggested a putative
inhaler (Turbuhaler) or metered-dose inhaler plus large- association between fenoterol use and asthma deaths,
volume spacer (Nebuhaler) was evaluated with two which was attributed to its greater cardiac toxicity in
sequential 2.5 mg doses given 15 minutes apart.” A 39% conjunction with effects of hypoxaemia.” However, a
and 57% increase in forced expiratory volume at 1 second more detailed analysis of risk factors suggests that the
(FEVJ with the Turbuhaler compared with a 16% and association between fenoterol and severe life-threatening
23% improvement with the Nebuhaler was seen for the asthma is explained by preferential prescribing to patients
two doses. 32 out of 33 patients with the Turbuhaler with more severe disease.16

~1119 Vol350. October. 1997

THE LANCET

Studies in stable asthmatics have shown that when continuous nebulised salbutamol in patients with more
fenoterol and salbutamol are administered on a severe airflow obstruction.27J8
microgram equivalent basis (from 100 ug to 4000 ug), The pharmacokinetic profile for high-dose nebulised
there is no difference in bronchodilator potency, whereas salbutamol shows that rapid absorption occurs from the
systemic potency for B2-adrenoceptor responses is greater lung reaching a peak concentration within 10 minutes of
with fenoterol.” In adequately oxygenated patients with inhalation.“’ It is therefore conceivable that appreciable
acute severe asthma and dose titration of fenoterol (up to systemic concentrations may in part contribute to the
3200 pg) or salbutamol (up to 1600 ug) given via a spacer bronchodilator effect. There is, however, considerable
(Aerochamber) with face mask, there was no evidence of interindividual variability in lung bioavailability of
clinically significant cardiac arrhythmias, despite the fact salbutamol when given by the nebulised route in acute
that the two-fold higher dose of fenoterol produced asthma, and a more predictable pharmacokinetic profile is
greater systemic B,-mediated effectsI In particular, with achieved with the intravenous route.30,31
respect to changes in QTc interval, less than 5% of Two large multicentre studies in acute severe asthma
patients had moderate prolongation (1525%) and none have compared treatment with either intravenous or
showed severe prolongation (>25%). nebulised salbutamo1.32’33 The intravenous salbutamol
Another property of a partial agonist such as regimens were administered either as a 10 minute bolus of
salbutamol is that it would be predicted from first 5 ugikg a1one,32 or as a 60 minute infusion of 500 ug in
principles to behave as a competitive antagonist at conjunction with hydrocortisone 200 mg.13 Both studies
B,-adrenoceptors in the presence of raised adrenergic showed a better bronchodilator response with the inhaled
tone, as has been demonstrated under experimental route. Higher plasma salbutamol concentrations were
conditions in healthy volunteers.‘” However, this found with the inhaled route in one study” and the
phenomenon is clinically unimportant in acute severe intravenous route in the other,33 and in both cases higher
asthma and there is no role for routinely using a higher levels were associated with greater systemic B,-mediated
efficacy agonist such as fenoterol instead of salbutamol. effects.
Salmeterol, which is a weaker agonist than salbutamol, The more relevant question-whether intravenous
also shows the same Bz-adrenoceptor antagonist effect in salbutamol improves the initial bronchodilator response
healthy vo1unteers.Z0 However, prior treatment with single when given in addition to nebulised salbutamol and
doses of salmeterol in stable asthmatic patients does not intravenous corticosteroid-has been addressed in two
appear to impair the bronchodilator response to repeated studies.‘4,35 In acute asthmatic adults, Cheong et al found
puffs of either salbutamol or fenoteroLZ’~** that intravenous salbutamol 12 ugimin over 4 hours after
an initial 5 mg dose of nebulised salbutamol and
intravenous hydrocortisone, resulted in a greater
Anticholinergics
improvement in peak flow than three successive nebulised
The rationale for the use of anticholinergic therapy is the
5 mg doses given over 2 hours, although tachycardia was
presence of increased airway vagal tone which may not be
more prominent in the intravenous gr0up.l” In a study of
overcome by treatment with high doses of inhaled
acute severe asthmatic children, a 10 minute single
&-agonists alone. More recent studies have tended to
intravenous infusion of salbutamol (15 ugikg) or saline
reveal conflicting results on the benefit of adding was given in the first 2 hours in addition to optimum
nebulised ipratropium to nebulised salbutamo1.23-26 The frequent nebulised salbutamol and intravenous
variability in results probably relates to the criteria for
hydrocortisone, with follow-up for 24 hours.35 The
patient selection, the small numbers of subjects in some recovery time to cessation of 30 minute administration of
studies, the dose and frequency of administered nebulised nebulised salbutamol was 4 hours for the intravenous
salbutamol, and the use of concomitant systemic group compared with 11.1 hours in controls, with
corticosteroid therapy. Although mean improvements in intravenous salbutamol also being associated with a lower
FEV, with ipratropium tend to be small, it is likely that dependency on medical oxygen and with discharge from
larger increases may occur in certain individuals with an the emergency department 9.7 hours earlier than the
exaggerated degree of cholinergic tone who may also have control group. Systemic Bz-mediated effects on plasma
impaired B,-adrenoceptor responsiveness. On the basis glucose and potassium did not differ between the two
that high-dose nebulised ipratropium bromide has few groups, although there was a higher proportion of tremor
systemic adverse effects, its use is advocated for patients at 2 hours in those who received intravenous salbutamol.
with life-threatening features or for those who do not Studies with intravenous aminophylline have also
respond to initial high-dose inhaled Bz-agonists, as revealed conflicting results as to whether there is
suggested by the recommended guidelines. improvement over and above the response to high-dose
inhaled B,-agonist and systemic corticosteroid.3”39 As with
Intravenous bronchodilator therapy other studies of second-line bronchodilator agents, the
The available drugs for intravenous bronchodilator variability and results can be explained by methodological
therapy are the Bz-agonists and theophyllines. For differences between studies. The acute therapeutic
salbutamol, the main disadvantage of the parenteral route bronchodilator response to intravenous aminophylline is
of administration is systemic B,-mediated adverse effects, dependent on achieving adequate blood concentrations
which are usually greater than those associated with the which requires monitoring, and its use is associated with
inhaled route. Nonetheless, it is conceivable in acute drug interactions and more frequent adverse effects than
severe asthma that greatly reduced peripheral airway other second-line agents such as nebulised ipratropium.
calibre would result in poor lung delivery when given by There is, therefore, no rationale for deviating from the
the inhaled route of administration. This effect can be recommended guidelines in terms of reserving the use of
partly offset by increasing the dose and frequency of the intravenous bronchodilator therapy as second-line
inhaled bronchodilator, as has been shown in studies of treatment except in life-threatening cases.

Vol350 * October - 1997 SII20

 THE LANCET

airway concentration of corticosteroid with the inhaled

route, this may be negated by poor peripheral aerosol
delivery due to severe airway narrowing in an acute
attack. There are concerns that high-dose inhaled
corticosteroid might be inappropriately administered to
patients with acute asthma in whom the severity of the
attack has been underestimated. One possible
compromise might be to use high-dose systemic
corticosteroid in the first 24 to 48 hours, followed by
high-dose inhaled corticosteroid, providing that the
patient has responded adequately to initial therapy in
terms of a peak expiratory flow (PEF) above 60% of
predicted or best. However, the optimum duration of
systemic corticosteroid therapy and when to institute
inhaled corticosteroids remain unclear.
Preliminary data have shown that following initial
treatment with oral prednisolone and high-dose inhaled
/3,-agonist, recovery of lung function is similar after
7 days of follow-up treatment with budesonide 3200 ng
per day to a tapering dose of prednisolone from 40 mg to
5 mg daily.47 In another study, inhaled fluticasone
propionate 2000 ug per day was as effective as a 16-day
reducing course of oral prednisolone in patients with a
Figure 2: Acute bronchodilator response (FEV,) to cumulative mild exacerbation of asthma (PEF greater than 60%
doses of inhaled formoterol following pretreatment with regular predicted or best) who did not require hospital
formoterol 24 pg twice daily (FM) or placebo (PL) given for 4
admission.48 These data should not be extrapolated to
weeks
acute severe asthma (PEF less than 60% of predicted or
Repeated puffs of formoterol (12-108 ug, shown as shaded dose-ramp)
were given 1 hour after bolus administration of either systemic best), where the benefits of systemic corticosteroid far
corticosteroid (S) or placebo. The data are shown as change from outweigh any small potential risk of short-term systemic
baseline (A) in FEVI plotted against time after the first administered adverse effects.
puff of formoterol (time 0 represents 1 hour after placebo or steroid
administration). This shows that prior treatment with formoterol alone These types of studies looking at earlier sequential oral
(FM) induces bronchodilator subsensitivity, as a rightward shift in the and inhaled corticosteroid therapy in less severe acute
dose-response curve, compared with placebo alone (PL), which is asthma exacerbations have primarily been driven by the
acutely reversed after 1 hour of systemic corticosteroid administration
(FM+S). Adapted from Tan et al, Am J Respir Crit Care Med 1997,“’ with pharmaceutical industry. It is, therefore, important to bear
permission of the American Lung Association. in mind the relative drug costs, as for example in the
above study,“” where there was a 34-fold difference in
Corticosteroid therapy price for 2 weeks’ treatment with inhaled daily fluticasone
Systemic corticosteroids propionate 2000 ,ug (Flixotide, Allen and Hanbury’s, UK)
The rationale for the administration of systemic compared with daily oral prednisolone 25 mg (non-
corticosteroids in acute asthma is to reverse the proprietary).49 It should also be pointed out that high
inflammatory component which will not be ameliorated doses of inhaled corticosteroids may be associated with
by bronchodilator therapy. The efficacy of systemic systemic adverse effects,5o although these are unlikely to
corticosteroids is borne out by clinical experience and be of clinical relevance in the short-term. Thus, the
data from meta-analysis.4” Conventionally, corticosteroids common sense and safe approach to acute asthma is to
are administered systemically in acute asthma, although overtreat rather than undertreat, and as such all patients
there appears to be no gain in most patients for should receive systemic corticosteroid therapy as
intravenous over oral administration.4’a42 Although there is recommended by the guidelines.
evidence of a dose-response effect, there is little advantage
with doses of prednisolone greater than 50 mg daily in Facilitatory effects of corticosteroids on
adults.43,44 Dispersable prednisolone may be used as an P;adrenoceptors
alternative for patients who cannot swallow tablets whilst The acute bronchodilator response to repeated puffs
intravenous hydrocortisone or methylprednisolone should of inhaled P,-agonist may be attenuated in patients
be used for patients who are vomiting or in cases with life- receiving regular long-acting Pz-agonists such as
threatening features. In terms of disease control it has also salmeterol and formoterol. This occurs as a consequence
been shown that tapering a short pulse of oral of down-regulation and associated desensitisation of
corticosteroids is unnecessary after acute asthma Pz-adrenoceptors, due to receptor occupancy for 24
exacerbations provided that patients are also protected by hoursS1 Although studies in stable asthmatics have shown
concomitant inhaled corticosteroid therapy.45,46 However, only a small reduction in mean bronchodilator response,
the dose of prednisolone should be individually titrated there is considerable interindividual variability in
against the severity and recovery rate of the acute attack, susceptibility to desensitisation which appears to be
as part of a personalised self-management plan. associated with the Gly 16 polymorphism of the
PZ-adrenoceptor.52 Doctors and patients alike should
Inhaled corticosteroids therefore be alert to the possibility that higher doses of
Can the anti-inflammatory effect of oral corticosteroids be salbutamol might be required in an acute attack for
achieved by high doses of inhaled corticosteroid in acute patients receiving regular long-acting P,-agonists. In-vitro
asthma? Although one might expect a much higher local studies show that corticosteroids prevent Pz-agonist-

srr2 1 Vol350. October - 1997

 THE LANCET

induced down-regulation and gene expression of 16 Garrett J, Lanes SF, Kolbe J, Rea HH. Risk of severe life threatening
pulmonary P2-adrenoceptors.53 Indeed it has been shown asthma and P-agonist type: an example of confounding by severity.
Thorax 1996; 51: 1093-99.
in stable asthmatics that intravenous hydrocortisone 200 17 Lipworth BJ, Newnham DM, Clark RA, Dhillon DP, Winter JH,
mg rapidly reverses bronchodilator desensitisation McDevitt DG. Comparison of the relative airways and systemic
induced by regular treatment with inhaled formoterol, potencies of inhaled fenoterol and salbutamol in asthmatic patients.
Thorax 1995; 50: 54-61.
and that this effect occurs within 1 hour of corticosteroid 18 Newhouse MT, Chapman KR, McCallum AL, et al. Cardiovascular
administratiorP (figure 2). Although there are no safety of high doses of inhaled fenoterol and albuterol in acute severe
comparable data in acute severe asthma, it is conceivable asthma. Chest 1996; 110: 595-603.
that P,-adrenoceptor down-regulation and desensitisation 19 Grove A, McFarlane LC, Lipworth BJ. Expr;ession of the
Pz-adrenoceptor partial agonist/antagonist activity of salbutamol in
would, if anything, be compounded by effects of excessive states of low and high adrenergic tone. Thorax 1995; 50: 134-38.
P,-agonist consumption. Thus corticosteroids may have a 20 Grove A, Lipworth BJ. Evaluation of the P,-adrenoceptor
dual effect in acute asthma with an early facilitatory effect agonist/antagonist activity of formoterol and salmeterol. Thorax 1996;
on airway Pz-adrenoceptor sensitivity and a later effect on 51: 54-58.
21 Smyth ET, I’avprd ID, Wang CS, Wisniewski AFZ, Williams J,
airway inflammation, which further emphasises the need Tattersfield AE. Interaction and dose equivalence of’salbutamol and
for corticosteroids to be administered as early as possible salmeterol in patients with asthma. BMJ 1993; 306: 54345.
during an acute asthma attack. 22 Grove A, Lipworth BJ. Effect of prior treatment with salmeterol and
formoterol on airway and systemic P,-responses to fenoterol. Thorax
1996; 51: 585-89.
Conclusions 23 O’Driscoll RB,Taylor RJ, Horsley MG, Chambers DK, Bernstein A.
The current international and national guidelines for the Nebulised salbutamol with and without ipratropium bromide in acute
treatment of acute asthma seem entirely appropriate in airflow obstruction. Lancet 1989; i: 1418-20.
recommending high-dose inhaled P,-agonist in 24 Schuh S, Johnson DW, Callahan S, Cally G, Levison H. Effects of
frequent nebulised ipratropium bromide added to frequent high dose
conjunction with systemic corticosteroid, and reserving albuterol therapy in severe childhood asthma. J Paediatr 1995; 126:
second-line therapy with ipratropium bromide or 63945.
intravenous bronchodilators for refractory or more severe 25 Karpel Jp, Schacter NE, Fanta C, et al. A comparison of ipratropium
cases. A greater awareness of the severity markers in acute and albuterol versus albuterol alone for the treatment of acute asthma.
Chest 1996; 110: 611-16.
asthma is also required, although when in doubt the safest 26 Fitzgerald MK, Grunfeld A, Parae I’D, et al. The clinical efficacy of
axiom is always to overtreat rather than undertreat to combination nebulised anticholinergic and adrenergic bronchodilators
prevent a potentially fatal attack. Further large-scale versus nebulised adrenergic bronchodilator alone in acute asthma.
Chest 1997; 111: 311-15.
studies are required to resolve issues such as the use of
27 Rudnitsky GS, Eberlein RS, Schoffstall JM, et al. Comparison of
large-volume spacers and the role of intravenous intermittent and continuously nebulised albuterol for treatment of
P,-agonists in acute severe asthma. asthma in an urban emergency department. Ann Emerg Med 1993; 22:
1842-46.
28 Shrestha M, Bidadi K, Gourlay S, Heys J. Continuous versus
References intermittent albuterol at high and low doses in the treatment of severe
1 Global initiative for asthma: global strategy for asthma management aCute asthma in adults. Chest 1996; 110: 42-47.
and prevention. Bethesda: NIH, NHLBI, Publication No 95-3659, 29 Newt&am DM, Lipworth BJ. Nebuliser performance,
1995. pharmacokinetics, airways and systemic effects of salbutamol given via
2 The British guidelines on asthma management: 1995 review and a novel delivery system (Ventstream). Thorax 1994; 49: 762-70:
position statement. Thorax 1997; 52 (suppl 1): Sl-21. 30 Schuh S, Parkin I’, Rajan A, et al. High versus low dose frequently
3 Neville RG, Hoskins G, Smith B, Clark RA. How general practitioners administered nebulised albuterol in children with severe acute asthma.
manage acute asthma attacks. Thorax 1997; 52: 153-56. Paedianics 1989; 83: 513-18.
4 Lipwortb BJ, Jackson CM, Ziyaie D, Winter JH, Dhillon DP, 31 Janson C. Plasma levels and effects of salbutamol after inhaled or iv
Clark RA. An audit of acute asthma admissions to a respiratory unit. administration for stable asthma. Eur RespirJ 1991; 4: 544-50.
Health Bull 1992; 50: 389-98. 32 Swedish Society of Chest Medicine. High dose inhaled versus
5 Ferguson RJ, Stewart CM, Wathen CG, Moffat R, Crompton GK. intravenous salbutamol combined with theophylline in severe acute
Effectiveness of nebulised salbutamol administered in ambulances to asthma. Eur RespivJ 1990; 3: 163-70.
patients with severe acute asthma. Thorax 1995; 50: 81-82. 33 Salmeron S, Brochard L, Ma1 H, et al. Nebulised versus intravenous
6 Loffert DT, IkIe D, Nelson HS. A comparison of commercial jet albuterol in hypercapnic acute asthma. Am J Respir Crit Care Med
nebulisers. Chest 1994; 106: 1788-93. 1994; 149: 1466-70.
7 Idris AH, McDermit MF, Raucci JC, Morrobel A, McGorray S, 34 Cheong B, Reynolds SR, Rajan G, Ward MJ. Intravenous P-agonist in
Hendels L. Emergency department treatment of severe asthma: severe acute asthma. BMJ 1988; 297: 448-50.
metered dose inhaler plus holding chamber is equivalent in 35 Browne GJ, Penna AS, Phung X, Soo M. Random&d vial of
effectiveness to nebuliser. Chest 1993; 103: 665-72. intravenous salbutamol in early management of acute severe asthma in
8 Colacone A, Afilalo M, Wokove N, Kreisman H. The comparison of children. Lancet 1997; 349: 301-05.
albuterol administered by metered dose inhaler and holding chamber 36 Murphy DG, McDermott MF, Rydman RJ, Sloan EP, Zalenski RJ.
or wet nebuliser in acute asthma. Chest 1993; 104: 835-41. Aminophylline in the treatment of acute asthma when P-adrenergics
9 Freelander M,Van Asperen PI? Nebuhaler versus nebuliser in children and steroids are provided. Arch Intern Med 1993; 153: 1784-88.
with acute asthma. BMJ 1984; 288: 1873-74. 37 Huang D, O’Brien RG, Harman E, et al. Does aminophylline benefit
10 Fuglasang G, I’edersen S. Comparison of nebuhaler and nebuliser adults admitted to the hospital in acute exacerbation of asthma. Ann
treatment of acute severe asthma in children. EurJ Respir Dis 1986; 69: Intern Med 1993; 119: 1155-60.
109-13. 38 DiGiulio G, Kercsmar C, Krug S, Alpert S, Marx C. Hospital
11 Clark DJ, Lipworth BJ. Effects of multiple actuations, delayed treatment of asthma: lack of benefit from theophylliie given in addition
inhalation and antistatic treatment on the lung bioavailability of to nebulised albuterol and intravenously administered corticosteroid. J
salbutamol via a spacer device. Thorax 1996; 51: 981-84. l’ediatr 1993; 122: 464-69.
12 Bowton DL, Goldsmith WM, Haponick EE Substitution of metered 39 Strauss ARE, Wertheim DL, Bonagura VR,Velacer DJ. Aminophylline
dose inhalers for hand held nebulisers: success and cost savings in a therapy does not improve outcome and increases adverse effects in
large acute care hospital. Chest 1992; 101: 305-08. children hospitalised with acute asthmatic exacerbations. Paediaaics
13 Tonnesen F, Laursen LC, EvaldT, Stahl E, IbsenTB. Bronchodilating 1994; 93: 205-10.
effective terbutaline powder in acute severe bronchial obstruction. 40 Rowe BH, Keller JL, Oxman AD. Effectiveness of steroid therapy in
Chest 1994; 105: 697-700. acute exacerbations of asthma: a meta-analysis. Am J Emevg Med 1992;
14 Brown PH, Ning ACWS, Greening Al’, McLean A, Crompton GK. 10: 301-10.
Peak inspiratory flow throughTurbuh&r in acute asthma. Eur RespirJ 41 Harrison BDW, StokesTC, Heart GJ,Vaughan DA, Ali MJ, Robinson
1995; 8: 1940-41. AA. Need for intravenous hydrocortisone in addition to oral
15 Crane J, Burgess C, Pearce NB, BlasleyY.The P-agonist controversy: a prednisolone in patients admitted to hospital with severe asthma
perspective. Eur Respir Rev 1993; 3: 475-82. without ventilatory failure. Lancet 1986; i: 181-84.

Vol350 * October * 1997 3122

 THE LANCET

42 Rarto D, Alfaro C, Sipsey J, et al. Are intravenous corticosteroids 49 British National Formulary. London: British Medical Association and
required in status asthmaticus? JAMA 1988; 266: 527-29. Royal Pharmaceutical Society of Great Britain, 1997, no 33.
43 Webb JR. Dose of patients on oral corticosteroid treatment during 50 Lipworth BJ, Clark DJ. High-dose inhaled steroids in asthmatic
exacerbations of asthma. BMJ 1986; 292: 104547. children. Lancet 1996; 348: 820.
44 Bowler SD, Mitchel CA, Armstrong JG. Corticosteroids in acute severe 51 Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol
asthma: effectiveness of low doses. Thorax 1992; 47: 584-87. after twice daily salmeterol in asthmatic patients. Lancer 1995; 346:
45 O’Driscoll BR, Kalra S, Wilson M, Pickering CAC, Carroll KB, 201-06.
Woodcock AA. Double-blind trial of steroid tapering in acute asthma. 52 Tan KS, Hall II’, Dewar J, Dow E, Lipwortb BJ. Pz-adrenoccptor
Lancet 1993; 341: 324-27. polymorphism is associated with susceptibility to bronchodilator
46 Hatton MQF,Vatbenen AS, Allen MJ, Davies S, Cooke NJ. A desensitisation in moderately severe stable asthmatics. Lancet (in
comparison of abrupt stopping with tailing off oral corticosteroids in press).
acute asthma. Respir Med 1995; 89: 101-04. 53 Mak JCW, Nishikawa S, Shims&i H, Miyayasu I<, Barnes PJ.
47 Youngchaiyud l’, Maraneua N, Nana A, et al. Can inhaled steroids Protective effects of a glucocorticoid on down-regulation on
replace oral therapy after an acute asthma attack? Eur RespirJ 1996; pulmonary P,-adrenergic receptors in viva J Clin Invest 1995; 96:
9 (suppl23): 53s. 99-106.
48 Levy ML, Stevenson C, MalenT. Comparison of short courses of oral 54 Tan KS, Grove A, McLean A, GnosspeliusY, Hall Ii?, Lipwarth BJ.
prednisolone and fluticasone propionate in the treatment of adults with Systemic corticosteroid rapidly reverses bronchodilator subsensitivity
acute exacerbations of asthma in primary care. Thorczx 1996; 51: induced by formoterol in asthmatic patients. Am J Respir Crit Care Med
1087-92. 1997; 156: 28-35.

~123 Vol350 - October * 1997