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 Oest Dept. H6pital Erasme, and Pulmonary Divi· sion, Dept. of Intemal Medicine, Hopilal Brugmann, Brussels, Bclgiwn.

Noseda, J.C. YerMult. (t I! accepted today that all patient$ with acute asthma

treated with a sympathomimetic, Irrespective or previous tber­short review addresses the question of the opllmal mode or CorTCspondence: O.est Dept. Hopilal Erasme, Route

de Leooik, 81070, Brussels, Belgium. n or these drugs In acute severe asthma. lnh~tled sympath-ure 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, seJr­

Keywords: Acute asthma; nebulization; spacer de­vice; sympathomimetics.

wlth a ready to use subcutaneous preparation may be lndl· Received: May, 1988; accepted for publication No­vember 23, 1988. In those patients prone to very abrupt altack.r;. The conventional

of Inhalation therapy 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

wllh repeated Udal ~reath& Finally, sequential or even contlnu-lat.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.h-

cs 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 iso­

JIIIuwn: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 hos­

Pilal 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

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 FEV

1 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, J.C. YERNAULT

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.ents 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 superiori ty 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 fcnotcrol r25l, salbutamol (22, 26) or terbuwline [17, 21, 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

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 Pao

1 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 8

2-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 379

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-re-study 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 cvi­

spacer-aided delivery may be as effective ns f.'I••L.HLrun in patients with acute asthma using either Jltebuhulcr (27, 38, 391 or lhe fnspir Ease L40] de­

with 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.

problems, inhalation manoeuvre and ~Slti;n, fraction

Proper 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

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 , I.C. YERNAULT

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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382 A. NOSI!DA, I.C. YI!RNAULT

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! que soil le traitement r~u ant~r­iewement. 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

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.

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