Acute Care 1988-89;14-15:208-228

Status asthmaticus

Adrian J. Williams a, Silverio Santiago a, Earle B. Weissb, Myron Steinsa Medical and Research Services, West Los Angeles VA Medical Center, Los Angeles, Calif . ;bAnaesthesia Research Laboratory, Brigham and Women's Hospital, Boston, Mass ., USA

Key Words . Asthma • Acute asthma - Severe asthma • Clinical featuresPathophysiology and treatment

Introduction

Status asthmaticus, or acute severeasthma [ 1 ], is a potentially life-threateningepisode of severe asthma failing to respondto usually effective or increasing amounts ofinhaled [32-adrenergic agonists and theophyl-line preparations . Such an acute episode ofasthma is often preceded by inadequate con-trol of symptoms over the preceding weekswith more rapid deterioration 24 h imme-diately before presentation [2, 3] . The diag-nosis implies the need for immediate hospi-talization, frequently with intensive care,and treatment with additional adequatedoses of (32-adrenergic therapy along withparenteral corticosteroids .

Although asthma was long said to be anonlethal disease (as Osler's dictum 'asth-matic patients pant into old age' reflects),recent experience has reminded us that thisis not so. The `epidemic' of fatal asthma inthe middle to late 1960s is recurring now .Death rates reached a nadir in 1977 andhave since increased steadily, almost dou-

©1989 S. Karger AG, Basel0254-0819/89/0154-0208$2 .75/0

bling from 0.6 per 100,000 in 1977 to 1 .4 per100,000 in 1984 [4] . There are even moredramatic age-related features, with thisdeath rate being almost tripled in those overage 85 . Similar or more striking increases inasthma mortality are found in Canada, theUnited Kingdom, Australia, and New Zeal-and [5, 6]. The implications are clear .Prompt, appropriate therapy for acute se-vere asthma is important, certainly shortensmorbidity, and can save lives .

Pathophysiology of Severe Asthma

The clinician's definition of asthma asreversible airway obstruction is a useful onethat helps identify patients at risk, but it isinsufficient as the sole framework on whichto base treatment. Physiologists have helpedus understand that asthma is a problem ofbronchial hyperreactivity to a variety ofstimuli [7] . Evidence shows that the degreeof hyperreactivity correlates somewhat withthe severity of disease and that it is favorably

Status asthmaticus

influenced by reduced exposure to stimuliand by regular effective treatment [8] . Ccurrently pathologists have contributed sig-nificantly to our understanding of airwayhyperreactivity by emphasizing that in addi-

ases in bronchial smooth musclemass and mucus-secreting apparatus, thereare submucosal edema and vascular changes,desquamation of the epithelium, and promi-nent infiltration with eosinophils, granulo-cytes, and lymphocytes . The pathologic deft-

of asthma as chronic eosinophilicitis [9, 10] summarizes this new un-

derstanding of asthma as a disease of inflam-ith resulting important implica-

s for treatment .The cellular constituents of this inflam-

matory response are increasingly the focus ofresearch into mechanisms of airways reactiv-ity and obstruction [I I]. Vast numbers ofeosinophils can be found in sputum or bron-choalveolar lavage material [2-13] . Frigasand Gleich [14] have shown large amountsof eosinophil-derived major basic protein inmucus plugs obtained from the airways of

patients with chronic asthma . Major basic

protein and other mediators/inflammatoryproducts are highly toxic to the airway epi-thelium and to other cells . Mast cells can alsobe present in increased numbers [ 13] andmay be relevant to the inflammatory re-sponse. A variety of triggers of mast cell acti-vation, immunologic (allergens, lympho-kines) and nonimmunologic (peptides suchas substance P) are known [ 15] . The resul-tant generation of various vasoactive-spas-mogenic mediators - for example, hista-mine, leukotriene C4, platelet activating fac-tor, eosinophilic chemotactic factor, andneutrophilic chemotactic factor [16, 17] -

goes a long way to explain the developmentof acute asthma and status asthmaticus. The

209

role of these mediatand late response to allergens is, holess certain [ 18] .

In addition to these biologically actsubstances, neurogenic regulation of bron-chial tone, particularly parasympathetic, andsecretions play significant roles in the gene-sis of airway obstruction [ 18]. Stimulation ofairway neural receptors with histamine orother irritants causes afferent actuation ofneural pathways and efferent reflexes includ-

ooth muscle spasm and glandular andCholinergic activity main-

tains normal airways in a mildly constrictedstate. The influence of baseline bronchomo-tor tone on clinical disease has importantimplications. A normal diurnal variation inflow rates is easily appreciated by measure-ment of peak flow [ 19] . This is the result ofunderlying diurnal variations in circulatinghistamine and corticosteroid levels with alesser effect from sympathomimetics [18] .Because resistance to laminar airflow is iversely proportional to the 4th power of theradius, small reductions in airway caliberdue to edema, inflammation, and secretionsmake nocturnal dipping more pronouncedand even symptomatic.

During severe asthma attacks, marked al-terations of cardiopulmonary function occurincluding reduced airflow rates, air trapping,and ventilation perfusion imbalance leadingto arterial hypoxemia and possibly hypercar-bia. Large changes in intrathoracic pressurewith increased work of breathing and altera-

n cardiac preload and afterload [20]may occur. Increases in residual volume(RV) and functional residual capacity (FRC)are characteristic . Approximately 50% of pa-tients also exhibit an elevation in total lungcapacity. The elevation of FRC may also berelated to progressive airway closure because

e ej

2 1 0

100

90

80

70

60

50

a° a a° asa a

a

a

as ~m~

oAaA

a

a

a p~

A

aa °g a p1a°a a as a a0 a aaaaa ° a

a a°a

naaa

°aa a

10

20

30

40

50Pred . FEV1, %

aa

G O

a

a a

a6

a° as

70

during the acute event, the RV often exceeds

the patient's normal FRC . Tachypnea ac-

companying the episode may be an added

adverse factor, but the precise mechanisms

leading to hyperinflation are poorly under-

stood. One major cause is an increase in the

tonic activity of the inspiratory muscles .

This activity results in a higher lung volume

with a greater tissue radial traction force onthe airway favoring its patency. Neverthe-

less, a mechanical disadvantage may ensuewhen breathing occurs at such markedly ele-vated lung volumes. Concurrently, this phe-

nomenon may also be responsible for thedevelopment of severe dyspnea that patientswith advanced asthma experience. For ex-

ample, Permutt [21 ] has pointed out that an

increase in the FRC of 2 .5 liters leads to an

11-fold rise in the inspiratory work ofbreathing, thereby contributing to the sensa-tion of clinical dyspnea. The increased inspi-

ratory muscle force needed to overcome the

larger elastic recoil of the lungs and thorax at

Williams/Santiago/Weiss/Stein

Fig. 1. Percent predicted FEV,versus arterial oxygen tension inacute asthma. Reprinted with per-mission from Weiss et al . [87] .

these high volum s also explains the sterno-

cleidomastoid muscle retraction observed in

severe asthma. That the diaphragm may also

be actively involved in maintaining an in-

creased lung volume, has been reported by

Muller et al. [22] during experimental hista-

mine-induced hyperinflation.

This advanced airway obstruction leadsto gross maldistribution of inspired air, with

adverse consequences on V/Q relationshipsand hence on arterial blood gases and pH .

Dangerous levels of hypoxemia, occasionallydeveloping with alarming speed, may ensue .

This hypoxemia may initially be unasso-ciated with carbon dioxide retention. Thedegree of arterial hypoxemia roughly corre-

lates with the severity of airway obstruction,

and significant hypoxemia (Pa02 < 60mm Hg) is generally seen when the FEV 1 is

less than 1 .0 liter . For example, in 101 pa-tients, McFadden and Lyons [23] found a

mean FEV 1 of 59, 39 and 18 % of predicted

and a mean Pa02 of 83, 71, and 63 Torr,

Status asthmaticus

Fig . 2 . Minute (VE) and alveolar(VA) ventilation versus percent pre-dicted FEV, in acute asthma . Re-printed with permission fromMcFadden and Lyons [23] .

Fig . 3 . Percent predicted Fversus arterial carbon dioxide ten-sion in acute asthma . The normalrange of PaCO2 is shown by theshaded area. Reprinted with per-mission from Weiss et al . [87] .

respectively . In another series, a Pa02 of< 60 Torr was common with a FEV 1 of< 0.5 liter or 30% of predicted (fig . 1) .

The V/Q inhomogeneity producing hyp-oxemia is usually accompanied by hypocap-nia initially . With progressive airway com-promise, though, effective alveolar ventila-tion falls (fig. 2) and hypercapnia super-

211

venes. The relationship between PaCO2 andFEV1 is not linear. When the FEV 1 exceeds0.75 liter or 30% of predicted, hypercapniais rarely seen. As the FEV1 falls below theselevels, hypercapnia is observed with increas-ing frequency (fig . 3). These observationsstress the limited value of ventilatory func-tion tests in differentiating various levels of

2 1 2

Table 1. Arterial blood gas and pH in asthmas

a Schema of general range values only,b On therapeutic oxygen.

gas exchange in persons with severe asthma.While the absolute incidence of such hyper-

capnia may be as low as 10% or a high as50%, depending on the reported patient se-

ries, prompt identification of this hypoventi-latory stage is required because of its poten-

tially high mortality rate (see below) .No one single pattern of Pa02, PaCO2, or

pH is characteristic of status asthmaticus ;

rather, evolving stages of severity can bearbitrarily categorized (table 1) . Significant

advances in the management of status asth-

maticus have emerged with the use of serialarterial blood gas and pH profiles .

Such profiles serve as the most reliable

basis for assessing asthma severity . Hypox-

emia with mild hypocapnia and respiratoryalkalemia (due to hyperventilation from

hypoxia, anxiety, metabolic stress) charac-terizes the least severe gas exchange distur-

bance, or stage I (table 1) . Here, V/Q abnor-malities are insufficient to yield ventilatory

failure, and respiratory work remains effec-

tive in eliminating carbon dioxide . Oxygen

and a sound therapeutic program generally

supports such patients. In stage II, which

reflects a more severe airway obstructive

level of status asthmaticus advanced hypox-

emia with augmented hyperventilation is ob-

Williams/Santiago/Weiss/Stein

served; these patients are typically ta-

chypneic and dyspneic with frank respira-

tory distress. Many of these patients respondto proper bronchodilator therapy and other

supportive measures. Regrettably, other pa-

tients may remain refractory to such therapyand continue to progress to graver stages ofgas exchange impairment in association with

pharmacologic resistance .

Stage III is a critical point in the evolu-

tion of airway obstruction . It also serves as a

clinically reliable index of progressive respi-

ratory failure heralding frank ventilatory in-stability and respiratory acidosis [24] . The

salient feature is the finding of normal val-ues for arterial PCO2 and pH despite the

patient's obvious cotinued clinical deteriora-

tion. This normalization of PaCO2-pH rela-

tionships reflects progressive failure of effec-tive alveolar ventilation and is in fact a state

of relative hypoventilation. This is the cross-

over phase (fig. 4). It is stressed to alert phy-sicians to the evolution of hypoventilation

(stage IV) from hyperventilating stages I and

II. Because stage IV, with overt alveolar hy-

poventilation and respiratory acidosis, is

most critical in terms of morbidity or even

survival and can develop with alarming ra-

pidity, the crossover phase is a major clinical

Stage Pa02, Torr PaCO2, Torr pH FEV, Dyspnea

I Mild attack or chronic stable normal or mild 35-42 7.40 > 2 .0 +65-80 --

II Mild-moderate attack 55-65 <35

> 7.45 -1-2 ++III Crossover 45-55 (or normalb) ~ 40

= 7.40 __ I ...IV Severe

< 45 (or normals) >45

< 7.35 < I ...+

Status asthmaticus

Fig . 4 . An example of cross-over

stage III . PaCO2 and pH in a 46-year-old woman in status asthmat-

icus. Note initial hypocapnia and

respiratory alkalosis progressing tonormal PaCO2-pH relationships as

a prelude to frank respiratory aci-

dosis despite full medical therapy.Pa02 on supplemental oxygen at

the cross-over point was 80 Torr.

The vertical arrow indicates institu-tion of intubation and ventilatorysupport. The patient fully recov-ered. Note the rapid developmentof acidosis; it can occur in an hour .Reprinted with permission from

Weiss and Faling [24] .

oncern. At this . point, serial ar-terial blood gas observations are mandatory

ddition to intensification of therapeuticmodalities. Stage IV patients with advancedhypoxemia complicated by hypercapnia andrespiratory acidosis may exhibit limited re-sponses to bronchodilator drugs and otherconservative measures . While some patientspresenting in stage IV may be successfullymanaged conservatively, as dictated by theindividual clinical conditions, other patientsrequire intubation and mechanical ventila-

if they are exhausted, obtunded,sor have critical Pa02, PaCO 2 or pH values(see below) .

Metabolic acidosis due to lactic acid ac-cumulation may occur in some patients withacute severe asthma. The lactic acidosis isbelieved to be due to a continued overpro-duction of lactic acid by the respiratory mus-cles and diminished hepatic removal of lac-tate [25] . Alterations in cardiac functionmay also lead to diminished peripheral per-

7.

H FIC02

60

,pH

50-

40-poCross-over

s~int40

. \ /k

30 -1

20-

12 noon 7p, 10 P- 11 P-1

2

3

4Days

ith resulting anaerobic metabolism .Lactic acidosis results in a low pH and in-creased anion gap and is indicative of asevere state of asthma likely to produce se-vere ventilatory difficulties .

Clinical and Laborato

Clinical ConsiderationsImportant historic features sug

patients at risk for acute severe asthma in-clude previous hospitalization for acute se-vere asthma, prior need for corticosteroidsor dependency on them, failure of usuallyeffective therapy, a history of severe asthma,or short-lived relief with drugs. The salientclinical features include singificant dyspnea,wheezing, cough, pulsus paradoxus, andvere decreases in airflow rates . Theseings may evolve gradually or precipitofollowing a variety of inciting causes such asallergic provocation, infection, nonspecific

2 1 4

RelapsedHospitalized patientspatients

0FEV1, titers

Successfullydischargedpatients

3

Fig . 5 . This graph depicts the estimated frequencydistribution of post-treatment forced expiratory vol-ume in one second (FEV,) in three groups of patients :those who have been hospitalized, those who were ini-tially discharged but suffered relapse, and those whowere successfully discharged . The vertical bar (FEV 1= 2.1 liters) represents the value below which hospi-talization has been recommended . Even though themean FEV 1 differs from group to group, the wideoverlap makes it difficult to place a person in oneparticular group .

For example, a patient who has an FEV, of 2 litersafter treatment could be placed either in the group ofsuccessfully discharged patients or the group of dis-charged but relapsed patients . The colored area repre-sents those patients who did well after hospital dis-charge but who, according to the proposed guidelines,would be hospitalized : in this example, one third ofall recommended admissions were unnecessary .

This ambiguity emphasizes the problem of ap-plying population-derived criteria to individual pa-tients . Thus, relying on results of pulmonary functiontests as the sole means of determining patient dispo-sition is inadequate . Adapted from Nowak et al . [75]with permission,

alant-irritant exposure, trigger mecha-nisms or drug sensitivity due to inappropri-rate therapy or inappropriate drug schedulesthereby further potentiating the process .Anxiety, tachypnea, sinus tachycardia,monosyllabic speech, diaphoresis, accessoryrespiratory muscle use with sternocleido-mastoid muscle retraction, and mentalchanges are typically present. Disturbances

Williams/Santiago/Weiss/Stein

of consciousness, systemic hypotension, car-diac arrhythmias, and obvious cyanosisimply severe or refractory asthma ; yet theirabsence does not indicate the lack of anadvanced obstructive state . Cough is com-mon. It may be productive of mucoid orpurulent-appearing sputum or may be appar-ently irritative and unproductive . An inabil-ity to raise secretions is ominous, indicatingpossible widespread bronchiolar inspissa-tion of tenacious secretions . If a relativelysilent chest is auscultated, then such wide-spread secretions must be inferred . Inspira-tory wheezing is also significant because itreflects a more severe obstructive processthan that associated with mere expiratoryprolongation or wheezing with good inspira-tory air entry . However, wheezing, as a ma-jor physical sign relates poorly to the ade-quacy of ventilation in severe asthma . Plug-ging of peripheral airways can be extensiveand remain undetected until alveolar venti-lation is severely limited; hence, physical ex-amination of the chest may be misleading inassessing the actual severity of the episode .Pulsus paradoxus is an easily monitoredclinical index reflecting asthmatic severity .Rebuck and Read [26] found that a pulsusparadoxus of >10 mmHg often indicatedan FEV 1 of 1 .25 liter or more . This physicalsign has been shown to reflect lung hyperin-flation combined with wide fluctuations inintrapulmonary pressure. While regarded asan index of considerable disease severity,Shim and Williams [27] observed that pulsusparadoxus is often present with mild asthmaonly and at times absent with severe obstruc-tion .

Criteria for AdmissionSince status asthmaticus is the most criti-

cal clinical expression of bronchial asthma

Status asthmaticus

and because its advanced gas exchange de-fects are life-threatening, this diagnosis im-plies the need for immediate hospitalizationwith full supportive measures. Assessment ofresponse to either P-adrenergic agonists ortheophylline or both during the first 2 h of

ent facilitates establishment of thediagnosis and the need for admission. Afavorable response includes both subjecticlinical features and objecti(FEVI or peak expiratory flow rates PEFR) .Because these observations may vary widely

patient, strict criteria for appro-e therapeutic trial or response cannot be

provided (fig . 5). An arterial blood gas andpH determination may also be required tovalidate the clinical and spirometric im-provement .

Table 2 lists cdeciding to hospitalize or discharge patientswith acute asthma [28] . However, more re-cent publications did not find indexes usefuland suggested close observation and tailor-ing of decisions to individual patients [29,30] .

clue of chest raestablish the presence or absence of spe-

cific precipitating causes of status asthmat-icus such as pneumonia or complicationssuch as pneumothorax, pneumomediasti-num, or atelectasis with mucoid impaction .Although advanced hyperinflation is seen, it

ible. It is also associated with preser-vation of the symmetrical pulmonary vascu-lar pattern throughout the lungs in contrastto destructive pulmonary emphysema.

With infection, leukocytosis with itore bands may be observed ; dehydration,intercurrent corticosteroid use, or metabolicstress may influence these values . Blood eo-

Table 2 . Indications for hospitalizing awith severe asthma

Possible indicationsPrior hospitalizations for asthmaDependence on glucocorticosteroidsExcessive use of/dependence on metered-dose

inhalersProlonged duration or gradual worseni

symptomsay inflammation (dyspnea, wheeze, cough,

chest tightness, tachycardia, tachypnea, hyper-inflation)

Return to emergency department (ED) after initialtreatment

Signs of severe asthma (such as pulsus paradoxusgreater than 18 mm Hg, or use of accessorymuscles for respiration)

Failure to respond to therapy within 2-6 h in the ED

Definite indicationsSigns of respiratory failure (such as cyanosis,

arterial oxygen, tension less than 55 mm Hg,diaphoresis, hypercapnia, altered mental status,fatigue)

Secondary pulmonary complications (such aspneumonia, lobar consolidation, pneumothorax,pneumomediastinum)

otal eosinophilcounts (TEC), are often useful in diagnosingan allergic exacerbation; values as high as1,000-1,500 cells/mm 3 may be observed incomparison with a normal value of 3501MM 3 . Nonetheless, such extremes dospecifically imply the diagnosis of statusasthmaticus, nor is the diagnosis excluded bynormal counts. Glucocorticoid-induced eosi-nopenia (< 100 cells/mm3) may be viewed asan index of steroidal biologic efficacy . Sucheosinopenia may parallelclinical and pulmonary functisons with steroid-resistant asthma who haveaccelerated plasma cortisol clearances tend

215

2 1 6

to have higher TECs and require greater cor-ticosteroid doses to achieve eosinopenia andclinical remission . In one series, TECs fell75% in steroid-responsive patients but only36% in steroid-resistant asthmatics after40 mg i .v. cortisol [32] . Hence, if a statusasthmaticus patient has eosinophilia, the ti-tration of corticosteroid doses to clinical re-solution may be facilitated by serial mea-surements of TEC . Significant tissue hyp-oxia may be reflected in a transient elevationof hepatic enzymes, serum glutamic-oxalo-acetic transaminase or serum glutamic-py-ruvic transaminase. Rhabdomyolysis withrenal failure is an unusual complication ofstatus asthmaticus ; these are believed to re-sult from hypoxia, vigorous respiratory mus-cle contraction, and dehydration [33] . Elec-trocardiographic changes, often reflectingthe severity of asthma, are generally revers-ible: P pulmonale (2t 2.5 mV), right axis de-

right bundle branch block, prema-ture ventricular ectopic beats, ST-segmentand T-wave changes are described [34] . Gelbet al. [35] reported the association of P pul-monale with hypercarbia in 4915 of caseswhere the PaCO2 was > 45 Torr and the pHwas ~ 7.37. In the presence of P pulmonale,the P wave and QRS axes were 79 ± 8 and80 ± 20°, respectively. These changes corre-lated strongly with the extent of airway ob-struction and were reversible . Sinus tachy-cardia, the most common rhythm pattern,does not necessarily correlate with the sever-ity of the illness and is often influenced bychronotropic drug administration . In olderpatients, the stress of hypoxia during statusasthmaticus may provoke frank cardiac isch-emia or infarction . We have personally wit-nessed cases of acute myocardial infarctionin middle-aged patients who received adren-aline as emergency room therapy for acute,

Williams/Santiago/Weiss/Stein

refractory asthma. Cardiovascular functionstudied during severe, acute asthma in chil-dren disclosed a mean stroke volume andcardiac output of 89 and 131 % of restingconvalescent values, bearing no correlationwith PEFR or blood gas measurements[36] .

Expectorated sputum may reflect certainpathologic dynamics of intra-airway secre-tions. Noninfected mucoid sputum with eo-sinophils or purulent material with bacteriaoffer possible clues to the precipitatingevent. In the early phases of status asthmat-icus sputum volumes are often scant pre-sumably because of inspissation and no hy-posecretion. Such sputum is viscous andopalescent, adhering tenaciously to oral mu-cosa or sputum cups . Gross inspection re-veals fine, threadlike mucinous strandscomposed of glycoprotein, cellular debris,and epithelial cells often admixed with larg-er, coiled whorls - Curschmann's spirals -containing eosinophils. Brown expectora-tion may indicate aspergilli . Because it re-flects allergic and inflammatory elements,sputum cytology is useful in determiningdiagnosis and therapy . The Creola body, acluster of columnar bronchial epithelial cellswith intact cilia, implies severe asthma, asintense submucosal edematous reactions arerequired for cellular dehiscence from thebasement membrane. Sputum eosinophils,or their crystalloid derivates called Charcot-Leyden crystals, reflect both intrinsic aller-gic elements and immunogenic mast-cellmediator release of eosinophilic chemotac-tic factor. In addition, the principal protein-aceous constituent of the eosinophil granule,the major basic protein, constituting 50% ofthe cytoplasmic granules, is discharged dur-ing the degranulation processes . Major basicprotein results in respiratory epithelial dam-

Status asthmaticus

age with desquamation and overt cytotoxici-

ty. Frigas et al. [37] described elevated con-centrations of major basic protein in spu-tum of patients with acute asthma, reverting

therapeutic improvement in the clini-

cal state . Chodosh [38] and Reid [39] re-viewed the cytologic, rheologic and bio-

chemical changes of sputum in status asth-

maticus .

Role of Infection in Status Asthmaticus

There is little to implicate bacterial infec-s a major cause of status asthmaticus

[40, 41 ] . While bacterial infections may beimportant in the progressive deterioration

and acute exacerbation of chronic bronchi-

tis, data is lacking to implicate acute or

chronic low-grade bacterial infections in ex-

acerbation of status asthmaticus. Neverthe-

less, there is a consensus that viral infec-

tions, particularly rhinoviruses, can induce

airway hyperreactivity that can be persistent

and very severe [40] . Furthermore, viral in-fections may be a trigger mechanism that

induces hyperreactivity to other inciting

agents [42] . If corroborative evidence of bac-terial infection (pneumonitis of bacterial ori-gin, exacerbation of chronic bronchitis, pu-

rulent mucus) is absent, antibiotics shouldnot be administered .

Specific TreatmentIn the treatment of asthma, empiricism

has predominated [43] because factors pro-ducing airway obstruction in asthma include

(1) bronchial smooth muscle contraction,(2) mucus plugging, (3) mucosal edema,

(4) thickening of basement membranes, (5)

cellular infiltration, and (6) vascular conges-tion . Simple relaxation of constricted

smooth muscle is rarely a sufficient thera-

peutic regime .

Bronchodilator drugs are the mainstay of

the emergency treatment of asthma, and re-cent objective data have allowed for guide-lines for the effective management of status

asthmaticus. Bronchodilator drugs are clas-

sified as : (1) sympathomimetic, acting on 0-adrenergic receptors, the mainstay of acute

treatment; (2) anticholinergic, blocking para-

sympathetic effects, a useful additional ther-

apy; and (3) methylxanthines, a second line

of defense .(1) (3-Adrenergic Agonist Drugs . The ef-

fects of the sympathomimetic drugs depend

on which receptors they stimulate . These

fects include vasoconstriction (a) ; cardiac

stimulation (PI) ; bronchodilatation, skeletal

muscle tremors, hyperglycemia, and hypo-kalemia 02). Epinephrine was shown to be

effective subcutaneously in 1903, and in

1910 Barger and Dale [44] proved its inhala-

tion to be helpful, an interesting observation

the effects on mucosal edema now rec-ognized as an important part of airway ob-

struction .There are now a number of drugs with

clinical effects almost entirely resulting from

P2-receptor stimulation. Albuterol is onesuch drug. Inhalation is the preferred routeof administration [43, 45] . It is now appre-

ciated that prior unsuccessful use of self-administered (3-adrenergic agents does notimply resistance to the drug . Doses of 5-10 mg of albuterol taken by nebulizer (hand-

held or compressed-air nebulizer) may begiven every 3-4 h or more frequently in theacute phase. Multiple puffs from a metered-

dose inhaler especially via a spacer device

such as the InspirEase (Key Pharamceuti-

cals, Kenilworth, N.J .) can be substituted fornebulizer therapy, thereby decreasing thedose of drug required to effect relief and

thereby diminishing side effects . In the rare

217

Status asthmaticus

age with desquamation and overt cytotoxici-ty. Frigas et al . [37] described elevated con-centrations of major basic protein in spu-tum of patients with acute asthma, revertingwith therapeutic improvement in the clini-cal state . Chodosh [38] and Reid [39] re-viewed the cytologic, rheologic and bio-chemical changes of sputum in status asth-maticus .

Role ofInfection in Status AsthmaticusThere is little to implicate bacterial infec-

tions as a major cause of status asthmaticus[40, 41] . While bacterial infections may beimportant in the progressive deteriorationand acute exacerbation of chronic bronchi-tis, data is lacking to implicate acute orchronic low-grade bacterial infections in ex-acerbation of status asthmaticus. Neverthe-less, there is a consensus that viral infec-tions, particularly rhinoviruses, can induceairway hyperreactivity that can be persistentand very severe [40] . Furthermore, viral in-fections may be a trigger mechanism thatinduces hyperreactivity to other incitingagents [42] . If corroborative evidence of bac-terial infection (pneumonitis of bacterial ori-gin, exacerbation of chronic bronchitis, pu-rulent mucus) is absent, antibiotics shouldnot be administered.

Specific TreatmentIn the treatment of asthma, empiricism

has predominated [43] because factors pro-ducing airway obstruction in asthma include(1) bronchial smooth muscle contraction,(2) mucus plugging, (3) mucosal edema,(4) thickening of basement membranes, (5)cellular infiltration, and (6) vascular conges-tion. Simple relaxation of constrictedsmooth muscle is rarely a sufficient thera-peutic regime .

217

Bronchodilator drugs are the mainstay ofthe emergency treatment of asthma, and re-cent objective data have allowed for guide-lines for the effective management of statusasthmaticus. Bronchodilator drugs are clas-sified as: (1) sympathomimetic, acting on (3-adrenergic receptors, the mainstay of acutetreatment; (2) anticholinergic, blocking para-sympathetic effects, a useful additional ther-apy; and (3) methylxanthines, a second lineof defense .

(1) /3-Adrenergic Agonist Drugs. The ef-fects of the sympathomimetic drugs dependon which receptors they stimulate . These ef-fects include vasoconstriction (a) ; cardiacstimulation (PI) ; bronchodilatation, skeletalmuscle tremors, hyperglycemia, and hypo-kalemia (R2) . Epinephrine was shown to beeffective subcutaneously in 1903, and in1910 Barger and Dale [44] proved its inhala-tion to be helpful, an interesting observationgiven the effects on mucosal edema now rec-ognized as an important part of airway ob-struction .

There are now a number of drugs withclinical effects almost entirely resulting fromP2-receptor stimulation. Albuterol is onesuch drug. Inhalation is the preferred routeof administration [43, 45] . It is now appre-ciated that prior unsuccessful use of self-administered [3-adrenergic agents does notimply resistance to the drug . Doses of 5-10 mg of albuterol taken by nebulizer (hand-held or compressed-air nebulizer) may begiven every 3-4 h or more frequently in theacute phase. Multiple puffs from a metered-dose inhaler especially via a spacer devicesuch as the InspirEase (Key Pharamceuti-cals, Kenilworth, N.J .) can be substituted fornebulizer therapy, thereby decreasing thedose of drug required to effect relief andthereby diminishing side effects . In the rare

218

treme breathlessness makesnebulizer therapy too difficult, parenteraltherapy with 0 .3 ml of 1 :1,000 epinephrinemay be given subcutaneously in patients un-der 40 years of age, 0 .25 mg subcutaneousterbutaline may be administered to older pa-tients or those with hypertension or cardiacdisease, or both. In this setting attempts ataerosol therapy may also be undertaken withintermittent positive pressure breathing .Levy [46] recently reviewed the role of thiscontroversial therapy in acute asthma, point-ing out limited beneficial effects .

(2) Anticholinergic Drugs . Bronchocon-striction from stimulation of cholinergicnerves plays a significant role in proximal

narrowing. In chronic obstructiveary disease, ipratropium bromi

the nonabsorbable quaternary isopropyl de-rivative of atropine, has been shown by Re-buck et al. [47] to be an equally effectivebronchodilator as fenoterol and by Gross[48] to be superior to fenoterol . In asthma ithas been used as an additional bronchodila-

ith varying degrees of success [47, 49,50]. In another three studies, it was con-cluded that the addition of ipratropium bro-mide results in further rise in PEFR com-pared with a [3-agonist alone [51 a, b, c] . Inaddition, O'Driscoll et al. [52] showed a dm-

401h advantage over abluterol therapyalone. The exact role of ipratropium bro-mide in asthma has yet to be determined but

resistant cases should be considered asplemental therapy [47] .(3) Methylxanthines (Theophylline) . Apart

from its action as a bronchodilator, theoph-ylline is a central nervous system stimulantand abolishes periodic respiration . It pro-duces a mild diuresis because of a self-limit-

effect on the renal tubules, and it has anunpredictable effect on the pulmonary circu-

c

Williams/Santiago/Weiss/Stein

)n, generally producing vasodilatation inpoorly ventilated regions of the lung . Theeffectiveness of theophylline as a bronchodi-lator is attributed to its ability to relax bron-chial smooth muscle, but its basic mecha-

as not been clearly established. It iswidely described as an inhibitor of cyclicnucleotide phosphodiesterase thus increas-ing intracellular cyclic adenosine monophos-phate (cAMP) . In fact, it is only a mild dies-terase inhibitor, while potent inhibitors suchas papaverine do not show any bronchodila-tor activity. Also theophylline-induced relax-ation of contracted smooth muscle in iso-lated organ preparations did not result insufficient alteration in either cAMP or cyclicguanosine monophosphate (cGMP) [53] .Other possible mechanisms of action includeadenosine receptor antagonism [54] . It hasalso been suggested that the theophylline ef-fect is indirect, perhaps through inhibition ofmast-cell histamine release [55] or reversalof diaphragm muscle fatigue [56] .

Although theophylline is an effectivebronchodilator in certain clinical situationssuch as nocturnal asthma [57], the far morepotent P2-agonists make theophylline ofquestionable value in acute severe asthma[58], especially because of its narrow thera-peutic window, potential for side effects, and

toxicity . The common cardiac dys-ia of multifocal atrial tachycardia

s in one study causally linked, at times,with theophylline blood levels at therapeuticconcentrations [59] .

The initial intravenous loading dose oftheophylline depends on drug history . Forthose not receiving aminophylline, Mitenkoand Ogilvie recommended a loading dose of5.6 mg/kg aminophylline infused dilutedover 30 min, followed by a maintenance in-fusion of 0 .9 mg/kg/h [60] . However, Hen-

50% and the mai

0

e

o

ive hes

ecu

o

0

eof toxicity .

onally, thes va

atient

rapy

g 9 ato b

e trea.ttm ,entt

e

o their effects

~.cu.te

irateu F'< ._

effects of the-d

hose with

c

use of as-

mor:

e

on

c eitial

ous loading

` osteroids producropria

ced by 25-

sthma

o '0.2-0.5 mg/e

o

i

o

esue

e

u

e .or re-

e of l

ave- s

i

s

ing dose o

iluted in

s

ce I e s/o dextrose in water

infused

en 8 _ and

riod of 30 min to reduce vulnerabil--

e

ewer'

y

Recom- o s ofd

t

oIn acute sever

d be c

e

ration

a

ndicate

a

ducing a plasma corns:tt

food levels .

that at least e

Is that obtained b , • mommaIts over age 6

er

1 cortex shoo .,,. 7

bs

n "I ,--l

e1

1

r~r

e

o0

d

has

`gym :C

F

ant ° .

olds an be se

.,

icians should be awaref patients may require higher doses o

ednisolone. In a report of severeasthma, Krause et al. [69] identified patientswho had required up to 500 mg methylpred-nisolone per day to induce remission andwho repeatedly required this large amount .

Reduction in oral prednisone dosage canbe dictated by an arbitrary scale until 20 mg/day is reached. This dosage should then bemaintained until the patient is examined af-ter discharge from the hospital . At this level,

eing is maintained and maximum pos-sible recovery allowed. Turner-Warwick [70]showed that among the various responses to -treatment of severe asthma, one was the slowreturn toward normal, taking more than 3-4weeks. If such recovery is not allowed, somepatients may risk permanent disability . No

feces of high-dose steroids (< 30 mg/day) are seen if used for less than I month .

inic or office follow-up, high-dose in-haled steroids can be introduced while oralsteroids are tapered. Other methods of predi

g a safe tapering schedule have includedmeasuring blood eosinophil levels, with a

after the eosinophil countreaches < 300/mm3, or frequent peak flow

ings to identify a leveling off of values,and with this presumed maximal recovery.

less, patients may regain their lungfunction very slowly and the `holding period'on 20 mg/day seems a desirable compro-mise .

er Therap s-

[8?]

ory component of ther in tearly stages and should be admi stered atlow flow rates even if e blood- gasresults are not yet available. This t spe-cially true if an aminophylline loading doseis to be administered because of the poten-tial for worsening V/Q relationships .

venous fluids are administered as aof the delivery of medications used, b

re is some controversy over the need fod 'on. In many patients with severe'

Gastrointes tmal nausea, vomiting, epigahematemesis, diarrhea

Central nervous headaches, irritability, rest ssness, insomnia, reflex hyperexctability, muscle twitching,' clonicand tonic generalized convulsions

Cardiovascular

palpitations, tachycardia, extra-systoles, flushing, vrhythmias, hypotensiotory failure

Respiratory

tachypnea

Renal potentiation of iuresis, alburia, increased excretion of renaltubular cells and red blood cells

other hyperglycemia, syndrome of in-appropriate antidiuretic hormonsecretion

mprovements in e live_ car acuteasthma have kept pace with pharmacologicadvances. Death from acute asthma is rare inintensive care or specialized units, and the

6

o erdiagnosis of status asthmaticus is an indica- theophylline. Reprinted with permissition for admission to such a unit . Oxygen is a et al . [87].

k

4

Normal loss -

osses during an attack

e

1,500

0

0400500

700

0

3

0

-I)

2,000

r ;,

cider

o

e .is com

fever, m

entilation .s

cis assume

a

o ds

about 10 %

in ease0

ulldc'!s

e

pro fou i

e

gsmucous me

e

slight

a

uo

abnormalnorm

i

stens".,',

oliguric

oli gurc

siighfl , increasedo

s

hvperna r :nma

0

tI

s

cre

markedi

r

s5I Stein

0

n

1 s

t

/2

moderate

Lv, fluff

o

V2

0 0

100-1Oral fluid in ke

ormal intake,

as uch as patient.g., 2-3 1/24 h

e

l

every 12 hsod'

ao 'ne monitonng

routs

0

a a

a

ase; NS = nor

s e' D5W

ee

r

i

0

ao

1

ien s, in heel ly, and in

i

e

yI

ation, intravenous fluff

e

a

°s

ophylline than for eestablishment of fluid balance.

r

J

s

r

d"I oowe

s

cl

cI

e

9

stmt.5 liters per d a

e

ypoten

e

p1

es. Zimen

out that crease

? ands

s

a may

con- viscous sec *o s. Suggesable 4). Se

placement

'

I

y

s'

0

e

o eut

evere

there are dangers' o

1

o

:nous acute pulmonary

< < emfluids

i

medications Thus, fluid repleti

:.auid deficit tiously inn these patients.

ea

indicated that measures to i

, } a

h

evere

rS

00 mI/h

I

pressure.

224

ance have little effect on inspissated sputum

already adherent to airways in acute asth-

matic persons. Humidification therapy is not

essential unless the patient is intubated . The

use of expectorants has likewise not been

shown to significantly enhance the clearance

of respiratory secretions. The role of fluid

replacement should be similar to that in anypatient with an acute illness effecting fluid

balance. For further information, the readeris referred to Ziment's excellent review of

hydration and fluid balance [71] .

Monitoring potassium [72] and phos-phate levels [73] with replacements when

needed may also be important. Recent re-ports have indicated that hypokalemia and

hypohosphatemia may be related to 0-adren-

ergic therapy and can impede recovery fromrespiratory failure.

The frequency of arterial blood gas moni-

toring is dictated by individual circum-stances. As McFadden and Lyons [23]showed, there is a clear linear relationship

between Pa0 2 and FEV I so that even mild

hypoxemia implies very severe airway ob-struction (fig. 1). This is usually associatedwith increased alveolar ventilation and a low

PaCO2. In this setting oxygenation can befollowed by pulse oximetry to reduce the

need for frequent arterial blood gas measure-

ment. Hypercapnia, however, is an ominousfinding, but even a normal PaCO2 may indi-cate that the patient is in transition of venti-

latory adequacy between the low value of a

moderate attack and a high PaCO2 that

might herald a fatal attack. Although fre-

quent blood gas monitoring may be essen-

tial, studies by Raffin [74] and Nowak et al .

[75] showed that ABG results correlate

poorly with the severity of airway obstruc-

tion and that ABGs need not always be done

when the FEV1 is > 1 .0 liter .

Williams/Santiago/Weiss/Stein

Assisted mechanical ventilation is occa-

sionally required . In the 1970s, a progressivedecline in the need for mechanical ventila-

tion was reported [76], reflecting improved

management (and more aggressive use of ste-

roids), but in concert with the increasing

mortality observed since 1977 the number of

patients requiring such treatment has risen .

In our institution (Wadsworth VA Medical

Center) the number of asthmatic patients

requiring mechanical ventilatory support(0% in 1976) [76] had risen (to 6% in 1981)

without a change in personnel or protocols .Indications for considering intubation

and assisted ventilation include clinical ex-haustion or hypotension and tachycardia, a

rising PaCO2 despite maximal conventionalinhalation therapy, and a poor or delayed

response to corticosteroids . Muscular paral-ysis with succinylcholine chloride or pancu-

ronium bromide may be used to facilitateintubation and mechanical ventilation but

are not usually required . Conventional seda-

tion with morphine sulphate or diazepam

allows time for ventilation to be established

and controlled. Severe airway obstructionmay lead to high and problematic inspira-

tory pressures, but these can be minimizedby further use of inhaled (32-agonists [77] . Ahigh complication rate is associated with

ventilator therapy in these very ill patients .Hypotension has been reported in 31 %, ba-

rotrauma or pneumothorax in 18%, pulmo-nary collapse in 9%, gastrointestinal bleed-

ing in 9 %, and respiratory infection in 31 % .

Mortality in status asthmaticus patients on

ventilators has varied from 0 to 35% [78] . If

adequate alveolar ventilation is not achieved

by these methods, muscular-paralysis with

pancuronium bromide generally allows in-

creased ventilation despite underlying air-

way obstruction ; this provides time for corti-

ate the under0

Severalstudies have shown beneficial es when ventilator therapy and bicarbon-

ate infusions are combined to relieve respiatory and metabolic acidosis [79, 80] . Re-cently, continuous positive airway pressure(CPAP) with bicarbonate infusion [81] hasbeen advocated to decrease the need for me-chanical ventilation . It is believed that

oves lung mechanics and reducesatory muscle work. Further studies ad, though, before these therapies can

be prescribed for status asthmaticus .Darioli and Perret [82] have described

the use of low-pressure mechanical ventila-tion to improve hypoxemia with moderate

ection of hypercapnia in 34 episodes ofvere asthma. Hypercapnia is improvedh subsequent relief of airway obstruction.

There were no deaths in this study .c easures described as useful

is asthma (methotrexate [83], goldimmunotherapy) are not indicated foris with acute severe asthmaath due to Asthma. When an

cpatient dies, there may be a tendency toblame the patient, the family or the medicacare team, or both . This is particularly truewhen death occurs in younger asthmatics.Robin and Lewiston [85] recently describedunexplained rapid death despitetherapy in 4 young asthmatic pat nts .

ecent study described a larger seriesin which careful review of clinical records ledo the conclusion that mortality could n

e been prevented in 54% of patients whoom asthma [86] . Nevertheless, there is

a strong consensus that a carefully preplanned program of education and care can pre-

t death in the vast majority of patientswhose asthma tends to be severe .

or Disch rge. At the tim, patients should be stable and placed

on an effective regimen of only inhaloral medications or both. An educat 0

program on self-treatment of asthma shouu ated for patients, and for appro-

priate family members when feasible. Possi-ble causes of acute asthma, its complicatingfactors, or both should be researched, includ-ing for example allergic and occupationalhazards, viral infections, gastroesophageal<reflux with aspiration, sinusitis, aspirin, sul-fite or yellow dye sensitivity, [3-adrenergicinhibitors, psychologic problems, nocturnalexacerbations, and so forth. An early ap-pointment for continuous outpatient follow-up is mandatory, as post-hospitalization re-lapses are frequent events that should beminimized or eliminated by careful medicalcare.

I Clark TJH :

sthma n Clark TJH,S (eds) : Ast

Philadelphia, Saunders 1977, p367 .

2 Bellamy D, Collins JV: Ac

ma in adThorax 1979;34:36-41 .

3 Webb J, Clark TJH, Chilver SC: Tim courseresponse to obstruction . Thorax 1981 ;36:18-22 .

4 Sly RM: Mortality from asthma 1979-1984.Allergy Clin Immunol 1988 ;82:705-717 .

5 Barnes PJ : Asthma deaths: The continuing problem; in Sheppard M (ed): Advanced Medicine 24.London, Bailliere Tindall, 1988, pp 53-61 .

6 Jackson RT, Beaglehole R, Rea HH, SutherDC: Mortality from asthma : A new epidemicNew Zealand . Br Med J 1982;285:771-

7 Hargreave FE, Ryan G, ThomsonBronchial responsiveness to histamine or metha-choline in asthma: Measurement and clinical sig-nificance. J Allergy Clin Immunol 1981 ;68:347-355 .

8 ' on JR, Bur ey PG, Chinn S, Papacosta ATattersfield AE: The relation between change in

reactivity and chad medication in a cornpir Dis 1988;138:530-534.

ging face of asthma . Q1987;63:359-365 .

rnes PJ: New concepts in the pathogenesis ofbronchial hyperresponsiveness and asthma. J Alergy Clin Immunol 1989 ;83:1013-10Beasley R, Roche WR, Roberts JA, Holgate ST:Cellular events in the bronchi in mild asthma aafter bronchial provocation . Am Rev Respir Dis1989; 139 :806-817.

12 De Monchy JG, Kauffman HF, Venge P, Ko terGM, Jensen HM, Sluiter HJ, De Vries K: Bron-choalveolar eosinophilia during allergen-inducedlate asthmatic reactions. Am Rev Respir Dis1985;131 :373-376 .

13 Wardlaw AJ, Dunnette S, Gleich GJ, CollinsKay AB: Eosinophils and mast cells in bronchoal-veolar lavage in subjects with mild asthma : Rela-tionship to bronchial hyperreactivity . Am RevRespir Dis 1988 ;137:62-69 .Frigas E, Gleich GJ : The

phil and thepathophysiology of asthma . J Allergy Clin Immunol 1986;77:527-537 .

nes PJ, Chung KF, Page CP : In atorymediators and asthma. Pharmacol Rev 1988;40 :49-84.

16 Cuss FM, DixonCN, Barnes PJ ; Effectplatelet-activating factor on pulmonary function .Lancet 1986;ii:189-192.

17 Barnes PJ, Chung KF, Page CP : Platelet-activat-ing factor as a mediator of allergic disease . JAllergy Clin Immunol 1988 ;81 :919-934 .

approach to the treatasthma. N Engl J Med 1989 ;321 :1517-15

e -Warwick M : On observing patterns of air-truction. Br J Dis Chest 1977 ;71 :7386 .

is MH Jr, Schim CS: Clinical evaluation ofasthma , n Weiss EB, Segal MS, Stein M Bron-chial Asthma: Mechanisms and Therapeutics .Boston, Little . Brown, 1985, pp 310-317 .ermutt S : Physiologic changes in the acu

matic attack; in Austen KF, Lichtenst) : Asthma, Physiology, Immunopharmacology

and Treatment . New York; Academic Press, 1973,15 .

Muller N, Bryan AC, Zamel N : Tonic nsause of hyperin ation i

tamine-induc d sthma. J App! Physiol 1980 ;869-872 .

eiss/Stein

dtension in asthma.030,eiss EB, Faling LJ: C inC

during status asthma:

verpoint. Ann Allergy 1968 ;26:545-5

5 Appel- D, Rubenstein R, SchragerMH: Lactic acidosis in severe asthma1983;75:580-586 .Rebuck AS, Read J Asse s

nof severe asthma .. Am J Med 1971 ;51 :

7 Shim C, Williams MH Jr : Pulsus pa thma. Lancet 1978;i:530-531 ..

8

ik A, Gardnerpredicting relapse and need for hos italization ipatients with acute bronchial asthma . N EnglMed 1981 ;305:783-788 .ose CC, Murphy JG, Schwartz

of an index predicting the response owith acute asthma to intensive emergency dement treatment . N Engl J Med 1984;310:5

f

30 Centor RM, bpredict relapse in ac to asthma .

gI1984;310:577-580 .o

, o

R, Theodor , n sotal eosinophil counts i t

bro

sthma. N Engl J Me 9

!Ann

e

g9

0

nc

02

0

6

a

wtance in bron hial ast69:493-499 .

3 Chugh KS, Sing I , atrilysis and renal failure followinicus. Chest 1978;73:879-880.Siegler

Reversible

trocachanges i severe acute asthma. Thorax328-332.Gelb AF, Lyo

ai er RD, GlauserMorrissey R, Chefty K, Schiffman P: P pulmonalein status' asthmaticus. J Allergy Clin Imm1979;64:18-22 .

3 dmunds AT, Godfresponse during acute severe astment in children. Thorax 1981

7 Frigas E, Loegering DA, SolleyGleich GJ: Elevated levels of the Bost

basic protein in the sputum owith bronchial asthma. Mayo Clin Proc3

it ibbons e ocorticos oids on the (I-adrenergi receptors inbronchial smooth muscle . J Allergy

0;45:118-

an

a

; Hypophos-phatemia complicatin broncho

or therapyfor acute severe asthma . Arch Int Med 1989 ;1492367-2368 .

74 Raffin TA: Indicatysis. Ann Int Med 1986 ;105:390-395,o

a I vich M, Sarkar DD, etial blood gase

oing in acute bronchial asthma

comes. J Am Med Ass 1983 ;Santiago S, Klaustermeyer WB : Mortalit

s: A nine-year experience in a respi-ive care unit . J Asthma Res 1980 ; 17 :

5-79 .Hendel'

therapy: State of the art1988. J Resp Dis 1988 ;9:82-112 .

, Coakley J, Gordan IJ, AtherS • Acute severe asthma treated by mechani-ve a ' 10 years' experience from a dis-

trict general hospital. Thorax 1986 ;41 :459-463 .

1 : Steroids. Clin Chest Med (Resp Phar- 80macol) 1986;7:341-345 .

6

ause HA, Santiago SM, Kla t eyer WB: In-ravenously given methylpre

e in refrac-ry asthma. West J Med 1980;13 :106-110.

M: Clinical pati

of respon-sivene

o c rticosteroids in a(ed) : Cli

I Pharmacology a

egress. Cambridge, Blackwell, 1986, pp 347-

' ent I: Hydration, humidification, and muco-kinetic therapy ; in Weiss EB, Segal S, Stein

s : Bronchial Asthma : Mechanisms and Thera-'cs, ed 2. Boston, Little, Brown, 1985, pp-776 .

o'

Brown DS, Murphymia from

- receptor stimulation by circu

4epinep rine . N Engl J Med 1983 ;309:141

B

e

load gas a

0

Pro-'

e

s

I-

ss

E

onteat

s 'Thames Region . Br Med J [Clip

1:1255-1258 .

Segal MS, St

ie 'c

sed 2.

Receiv

4, 9Accepted • a

3

ivision W I IW

o VA Medical Centere

s Angeles, CA 90073 (USA)

e

s

t

Muranka M, Mivamthe treatment of bronchial asthstudy. Ann Allergy 1978 ;40:132-

N: Unexpectsudden death in young asthmatic s1989;96:790-793 .

efer JC, Runseo sodium bicarbonate in the tbronchial asthma . N Engl J Med 1965 ;272:12'1203 .Menitove SM, Goldringtor and bicarbonate strate

aticus. Am J Med 1983; 4togner SW, Norman JR: Face mask

n odium bicarbona n in acutesevere asthma and metabolic acidosis. Chest1989;96:943-944 .

'oli R, Perret C: Mechanic

oiled hypo-ventilation in status asthmaticus.

Rev RespirDis 1984 ;129:385-387 .

a

ensteiBailey GA, Olason I,the treatment of corticosteroid-depenma: A double-b

over study. N Engl J