Sympathomimetics in acute severe asthma: ... parenteral, nebulizer or spacer? A Noseda, J.C.

REVIEW
Sympathomimetics in acute severe asthma: inhaled or
parenteral, nebulizer or spacer?
A. Noseda, J.C. Yemault
.-tJJsom:une·r1cs in acute severe asthma: inhaled or parenteral. nebulizer
Noseda, J.C. YerMult.
(t I! accepted today that all patient$ with acute asthma
trea ted with a sympathomimetic, Irrespective or previous tbershort review addresses the question of the opllmal mode or
n or these drugs In acute severe asthma. lnh~tled sympa thure a:s errectlve as StLbcutru\.eous adrenaline, ur Intravenous
or terbutallne, and, I&S they produce fewer slde-errects, are
amroendeG as the best mode or adm.lnlstratlon. However, seJrwlth a ready to use subcutaneous preparation may be lndl·
In those patients prone to very abrupt altack.r;. The conventional
of Inhalation thera py In acute asthma Is nebull"tutlon, but equally
broncbodUatatlon may be obtaJned with metered-dose Inhalers
with valved spacers. Tachypnoeic patients unable to perform
...,,,.,"'"""'"' Inhalation manoeuvre can use one-way valve Inhalation
wll h repeated Udal ~reath& Finally, sequential or even contlnulat.lon techniques have recently been advocated, portJcularly In
wi th Impending respiratory fa ilure.
Rupir 1., 1989, 2, 377-382.
asl.hma remains a mnuer of concem as it may
ing even in young people. Syrnpat.hcs are considered as l.he ftrSL choice bronchodilhe Boston group has dcmonst.mted lheir
to inLTavenous (i.v.) aminophylline. In an
publication (1980) lhese investigators [ I} reported
young aslhmalics (under 45 y.rs or age) presenting
the ward of a general hospital, a mean improvement
forced expiratory volume in one second (FEV,)
one hour of 80-90% of lhe initial value after
isoproterenol or subcutaneous adrenaline, to be
IIIIIJJI:IH:O with +25% after i.v. aminophyltine despite
of a loading dose as high as 5.6 mg·kg·• body
In a second step lhey showed that inhaled isoJIIIuwn:no• alone was as effective as combination tller(inhalcd isoproterenol plus i.v. aminophyUine) even
those patients wilh the most severe baseline obSLruc(FEV1<0.8 I) as well as in lhose admiued to hosPilal with low (< 10 Jl&·m·1) serum theophylline levels
[2). These results were further confirmed in a subseQuent study 131, as well as by another group 14) ll~ing
ll'lelaprmerenol as lhe inhaled beta-mimetic. Moreover,
lhe latter investigators demonstrated thal i.v. aminophylline increased the frequency of side-effects (tremor,
lllxiety, palpitations) without additional benefit in terms
Of bronchodilatation.
Although the use of i.v. aminophylline is still recomlllendcd [5] in patients wilh insufficient response to
Oest Dept. H6pital Erasme, and Pulmonary Divi·
sion, Dept. of Intemal Medicine, Hopilal Brugmann,
Brussels, Bclgiwn.
CorTCspondence: O.est Dept. Hopilal Erasme, Route
de Leooik, 81070, Brussels, Belgium.
Keywords: Acute asthma; nebulization; spacer device; sympathomimetics.
Received: May, 1988; accepted for publication November 23, 1988.
first-line therapy it has recently been shown [6) that
i.v. aminophylline given after a eumulative dose of 2.4
mg nebulized fenoterol produces a clinically significnnt
(>0.2 t) additional improvement in FEV1 in only a
minority of patients (4 out of l8). Prelimmary results
wilh i.v. enprofyUine, a new xanthine derivative more
potent on a molar basis t.han theophylline, suggest Lhat
it may compare favourably wilh an inhaled sympalhomjmeLic in the initial management of acute asthma [71,
but lhis needs to be confirmed.
Tile Boston group has alSP shown that patients
pretrcated wilh sympathomimetics respond in the emergency room to a nebulizcd sympathomimetic as well
as patients who have not used such drugs (8]. This
evidence, that all the young adult patients wilh acute
asthma may be successfuUy treated wilh sympalhomimetics irrespccti ve of their medication history, is
very important as it had been speculated in tlle late
Sixties that tachyphylaxis resulling from regular
inhalation of sympalhomimetics could exacerbate llll
episode of acute astJ1ma by inducing resistance to
catccholamincs [91. Since then, many pharmacological
studies [10-121 have provided strong evidence thlll
tuchyphyla,;is is not clinical ly relevant in asthma 1131.
1t is now accepted thnt when sympathomimeljcs delivered from a metered-dose inhaler (MDI) fail to provide
relief to a patient with acute asthma, this fa iltLrc should
not be ascribed 10 phannacological resistance, but in
378
A. NOSEDA,
some patients to an inadequate mode of adminisltation
and in others to severe inflammation of the airways. In
the former patients, sympathomimetics do work when
either an adequate mode of aerosol delivery or the parenteral route is used [8], while in the latter. steroid therapy is required to improve airway obs11uction [ 14]. In
summary the evidence is now that all patients with
acute asthma should be treated with a bc~-adrencrgic
agent, irrespective of previous therapy. The present
short review addresses the question of the best mode
of administration of these agents, aerosol versus parenteral, nebulizcr versus metered-dose inhaler (MDI) plus
spacer.
Route: aerosol or systemic?
Whcrca~ sevcml pharmacological studies have shown
that in stable asthmatics the inhaled route provides the
most effective bronchodilauuion and the fewest sideeffects [15], it has been questioned whether an inhaled
drug would be able to reach its site of action in
pati.e nts with severe airway obstruction.
Efficacy
Several groups have compared the cflicacy of inhaled
versus subcutaneous or intravenous sympathomimelics
in acute asthma. Compared to subcutaneous adrenuline,
.inhaled isoproterenol or terbul.aline were constantly
found to be as effective Jl, 16] or more effective [3,
171. When i.v. salbuUtmol or tcrbutaline were administered, the results varied from a slight superiority of
pnrenteral therapy [ 18, 19) to equal effectiveness of
both regimens [20-22). or slight (23} or more mnrkcd
[24 I superiority of inhaled therapy. Compilation of
method data available from rivc recent studies suggests
these differences in results to be at least partJy related
tO the inltaled to i.v. dose ratio (R) used and the mode
of adminisltation of i.v. tlterapy. A condnuous i.v.
infusion of rather high doses (R=5) favours superiori ty
of i.v. therapy [ 19), single i.v. bolus of lower doses
(R=lO, ll.l nnd 16.7) favours the cquaJ effectiveness
[20-22) or even (R=30) superiority of inhaled therapy
124j.
Side-effects
a) Cardiovascular. fn acute asthma studies, an ihcrcasc
in heart rate has often been reported after parcnteml
sympathomimetic therapy [17, 19, 21, 231 while
baseline tachycardia is reduced after nebulized fcn otcrol
r25l, salbutamol (22, 26) or terbuwline [17, 2 1, 271.
Cardiac arrhythmias induced by bet.a1-mimctics have
only been reported in isolated instances r28J but
prolonged elcctrocardiogr<tphic monitoring has rarely
been performed. In n prospective Study. severe arrhyLhmias during combined continuous i .v. infusion of tcrbutaline and aminophylline were found to involve a
J.C. YERNAULT
minority (24%) of patients and to resolve "l"lllll'lflt'1,._
in all. ca~es [29]. E~e~ated serum ~P~-MB leveta
may md1cate subchmcal myocardial mjury have
reported in children with acute severe asthma
with i.v. isoproterenol [30).
b) 1/ypokalaemia. Sympathomimetic-induced
alacmia has been well documented wjth the p;weru~llll
route (3 1j. HAALBOOM et al. [32] have also
in stable asthmatics a moderate though
decrease in serum potassium level after "'"""' .._
dose.-; up to 1,200-2,400 ~g (6-12 puffs) fenotcroJ
a short period of 90 min; this protocol was thought
mlmick repeated inhalations such as patients with
asthma self-administer. The clinical significance or
observations has to be evaluated in future pro~:li..
trials.
c) 1/ypoxaemia. It is a current concept that oronctiOdli;:
lators may aggravate ventilation-perfusion
and exacerbate pre-existing hypoxaemia. However
group of 23 moderately hypoxaemic patients with '
asthma, the mean arterial oxygen tension (Pao~
mained unchanged after nebulized terbut.aJine and
improved after i.v. terbutaline (from 7.55 to 8.90 L.._,.. _,_
nevenheless, a clinically significant (0.67 and 1.33
decrease in Pao1 was seen in two individuals
inhalation [221. Although the possibility of t>ronoh1ocn.
lator-induced hypoxaemia has probably been
emphasized, oxygen therapy may be recommendecl
all patients with severe acute asthma.
Adrenaline or beta2 -mimetic?
From controlled studies comparing the efficacy and
side-effects of parenteral versus inhaled sympathoml·
metics in acute asthma, we conclude that both ....,,,_._,-...of administration are effective but that a higher efficacy
to side-effects ratio supports the use of the inhaled rou&e
as the first choice. If, however, the parenteral route is
chosen, which drug should be used? In a recent studJ
of 20 patients with acute asthma [33), 0.5 ma
terbutaline and 0.5 mg adrenaline given subcutaneouslY
produced equal bronchodilatation without serious
side-effects. The subcutaneous route is well adapted for
self-medication in those patients who are prone to vet'/
abrupt attacks of asthma and a high risk of ventilai?JY
arrest [34, 35). To be truly effective this acute Hdmanisltation requires "ready to use" preparations analogous
to those marketed in some countries for therapy oC
anaphylactoid reactions.
If the inhaled route is chosen, it has been speculated
Lhal nebulized adrenaline might be better than a ne~­
lizcd 82-selective agent, through a reduction irt bro~hJal
mucosal oedema via an a effect on bronchial artenole$
However, in n recent crossover study comparing I ma
nehulizcd adrenaline wilh 2.5 mg ncbulized salbutarnol•.
both drugs were found to be equipotent, but the. short
duration of action of adrenaline wilh a return ol lung
function to baseline value within 30 min was found 10
be a strong disadvantage [26]. Thus. it seems reasonable to conclude that, as in stable asthmatics [36], only-
SYMPATllOMIMBTICS IN ACUTE SEVIlRE ASTHMA
ac;ting specific
1.32-stimulants should be used for
therapy in acute asthma.
of inhaled sympalhomimetics used in acute
are largely empirical. Most investigators have
as hjgh as
2.5- 10 mg salbutamol or terbuby nebulizer without reported serious
Mrrcruru. et al. [25] pcrfonned a dose-restudy in patje.nts with acute asthma (as defined
fEV1<1.2 I) and found the dose required 10
a maximum bronchodilatation with nebulized
to range from 1-3 mg (4-12 drops of the
y available solution). There is obviously a
for further dose-response studies in patients with
asthma.
sympathomimetics: mode
or delivery?
therapy in acute asthma: general concepts
of aerosol delivery available include inhalafrom an MDI, nebulization and, for the last few
inhalation from an MDI combined with a spacer.
are inhalation devices fiued to the mouthpiece
ventionaJ MDI, including extension tubes, colbags and cone- or pear-shaped devices with a
VC
(37).
recently MDls were thought to be ineffective
asthma. This idea was supported by RossrNo
[8] who showed that asthmatic out-patients deleon sympalhomimetics inhaled from MDls may
'IUCcessrully treated by sympathomimctics given by
in the emergency room. There is now cvispacer-aided delivery may be as effective ns
f.'I••L.HLru n in patients with acute asthma using either
Jltebuhulcr (27, 38, 391 or lhe fnspir Ease L40] dewith a tcrbulaline dose of 4 mg in adults [271,
of 1.25-2.5 mg [38] or 0. I mg·kg-1 [39J in chilThis could be important. As patients with severe
treated during a hospital stay with a ncbulizer
bute their improved status to this particulnr
~·""o"'au,m 141, 42], there has subsequently been an
patient request for nebulization maintenance
home. However, some concern has been
about the uncontrolled domiciliary use of
IIOUII7Pr~ [43) and the potential shon-tcrm (28] and
~s·u::rm (44) cardjac consequences from chronic use
lllOderate to high doses of sympa!homimetics.
~Slti;n,
Proper
problems, inhalation manoeuvre and
fraction
use of an MDI requires adequate "hand("actuation-inhalation") co-ordination. Up to
of stable asthmatics have been found 10 be "bad
(45), a proportion that may eveo increase
acute exacerbations. Optimal use of an MDI
379
also requires a slow, deep inspiration manoeuvre, followed by a ten second breath holding [46]; in these
optimal conditions lhe fraction of the metered dose
which reaches the respiratory tract may be 1ncreased up
to 11.2% [47]. This figure compares favourably with the
lung deposition obtained by nebulization which is also
influenced by many technical factors and is often found
to be around 10% [48, 49).
Spacers added to MDis may enhance lung deposition
through decreasing impaction in the oropharynx and
decreasing the size of particles following evaporation of
the solvent [37]. Deposition fractions around 15% have
indeed been reported with the Nebuhaler (50] and
Inspir Ease [471 devices. With these devices, which
contain the spray momentarily before it is inhaled, the
co-ordination between firing the MDI and inhaling is
no longer required. However, a slow deep inspiration
combined with brealh holding remains necessary, which
limits the use of spacers in patients with tachypnoea
[51].
Recent studies [52, 53} in stable asthmatics suggest
that valved spacers can be used with tidal breathing, the
expired air being rejected into room air on each cycle.
In children inhaling terbutaline from a Nebuhaler
device, five normal breaths which are just sufficient to
move the valve compared favourably in terms or bronchodilatation with two deep inspirations from residual
volume, each held for 5 s (52}. In a crossover study
in adults, 200 ~g salbutamol inhaled with four breaths
from an Aerochamber was as effective as ~.5 mg given
by nebulizer. As the relative benefit of the two meth·
ods of administration was not influenced by the severity of baseline obstruction, it was concluded thlll spacers used with tidal breathing might be useful in the
treatment of acute aslhma [53].
Comparative studies
Traditionally, much higher doses are used via
nebulizers than via MDis. As lung deposition fraction
is of the same order of magrutude, equal doses should
be tested. In patients with stable asthma, studies comparing different modes of delivery in terms or bronchodilatation have shown either the MDI and ncbulizer
to be equipotent [36, 49), the MDI plus spacer and
nebulizer to be equall.y effective but both better than
lhe MDI alone (54J, or the MDI plus spacer to be more
effective than the nebulizer [55, 56].
In patients wilh acute aslhma only two studies comparing spacer and nebulizer delivery were performed
using equal doses in a crossover design [27, 39].
Tcrbutaline was used in both studies, at a dose of 4
mg in adults [27), 0.1 mg·kg-1 in children [39], and
bronchodilatation obtained with the MOl plus Nebuhaler
was found to be equivalent [27] or even greater (39)
lhan that obtained wilh the nebuJizcr. In two other studies [38, 40] patients with acute asthma were randomly
allocated to either spacer or ncbulizcr delivery, which
were found to be equally effective despite the use of
higher doses with the nebulizcr. In one study, asthmatic
380
A. NOSEDA ,
children used a Nebuhaler device with repeated breaths
for one minute to ensure complete inlake of the metered dose actuated in the spacer, which was two-fold
lower than the terbutaline dose given via the nebulizer
[38]. The other investigation involved adults, mec.aproterenol and an Inspir Ease device with a nebulizer to
spacer dose ratio as high as 7.5 [40). In the paediatric
studies [38, 39), it was concluded that the inability of
some children to produce sufficient flow rates to trigger the valve was the only limitation to spacer delivery in acute asthma. Further studies comparing spacer
and nebulizer delivery in patients with acute severe
obstruction arc required, but there is reasonable evidence that spacers have a place in the treatment of these
patients, particularly if a tidal breath technique can be
used; there is a need for manufacturers to investigate
spacers with a lower threshold for valve triggering.
Sequential or continuous inhalation therapy
Finally, therapeutic regimens including sequential
inhalations have recently been advocated. An initial
dose of salbutamol by nebulizec folJowed by six consecutive doses at 20 min intervals may be used in children with severe acute asthma [57). NEWHOUSE and
Dowvtcn [42] have recommended the use in the emergency room of four puffs of the sympathomimetic of
choice via an MDI combined with a valved spacer, followed by one puff per minute until subjective, and if
available objective, benefit is achieved, or side-effects
such as tremor limit further drug administration. Similarly continuous nebulization has recently been
proposed. In a preliminary study on children with acute
asthma including 14 subjects with impending respiratory failure (mean arterial carbon dioxide tension
(Paco~ 5.90 kPa), continuous nebuliiation of 4 mg
terbutaline per hour was effective in improving clinical asthma score and Pacoz (mean 4.34 k:Pa after
continuous nebulization), weaning from continuous
nebulization being possible after 3-37 h [58).
Conclusion
From this short review of the use of beta-mimetic
drugs in the treatment of acute asthma we concJude that
in the vast majority of cases the inhaled route may be
preferred to the parenteral one and also that conventional nebulization can be replaced by MDis coupled
to some kind of spacer.
Aclurowfedg~ments:
The aulhors lhank R. Mahaux
for sccre1arial assurance.
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z.
382
A. NOSI!DA,
Les sympathicomimitiquu en crise d'ast~ aiglle: En hallO·
lation ou sysremiqu.e. ntbulization oli chontlKe d'e:xpan.rion A.
Noseda, J .C. Yerllllult.
R~UM~: U est acrucllcment bien etabli que tout p:sticnt
en crise d'asthme aigOe doit &re uait6 par un sympa·
thicomim~tique, que! q ue soil le traitement r~u ant~r­
iewement. Ceuc revue abordc le pmb~c du mode er
administration optimal de cc type de ~ieation en cas de
crise d'asthmc severe. Les sympathicomim~tiques en inhallltion. aussi cfficac:e.s que l'adrEoalin.e sous-cut.anl!e, le salbucamol ou la tetbutaline intra-veineusc, sont recommand~
comme le mode cfadministration de premier choix, dans la
mesurc oil !curs effets sccondaircs sont moindres. Toutcfois.
!'injection pdcoce d'un sympathicomim~ sous fonnc d'une
I.C. YI!RNAULT
pr6parotion sous-<:ul!ln~ prete il l'cmploi fleUt ctru
c!~ez les. p11tlcn~ A haut risqu? de. crise sur:sigut, Lo
d mlull11ll0n hllbatucl dans la erase d astlune aigul! esc 1
lisation. mais une bronchodihuation &juivalcntc
1
obtenue en utilisant un a6r0sol doseur eoupli A
d.'expansion munie d'une valve. Us patients UICI~.,..,..n._·
incapables d'ex6cuter une manoeuvns classique ~em
le contenu d'une chambre d'expansion munie d'une valv
directionnelle l l'aide de plusieurs cycles n:ISpinloitea :
ume courant Enfm. des techniques d'inhalation ~eq1ua11W"
voirc continue, one ~16 proposres r6ccmment, l'"'liCI~I~1l!IIIIOIIIii
pout lcs ~cients menaces d'insumsance respimoire ai&ul.
£UT Resprr 1., 1989. 2, 177-382.
J