a randomized comparison of atropine and metaproterenol inhalational therapies for refractory status...

$: A randomized comparison of atropine and metaproterenol inhalational therapies for refractory status asthmaticus$
ORIGINAL CONTRIBUTION asthma; atropine, asthma; metaproterenol, asthma

A Randomized Comparison of Atropine and Metaproterenol Inhalational Therapies for Refractory Status Asthmaticus

Study objective: To compare the forced expiratory volume in one second (FEV~) response to inhaled anticholinergic with the response to ~-adrenergic solutions in adults with refractory status asthmaticus.

Design: After the decision was made to hospitalize, 40 patients were prospectively randomized in a double-blind trial to receive either atropine sulfate or metaproterenoI by nebulizer.

Setting: A county teaching hospital emergency department. Type of participants: Adults requiring hospitalization for refractory sta-

tus asthmaticus. Interventions: Standard therapies for acute bronchospasm, followed by

either 1.5 mg atropine or I5 mg metaproterenol by nebulizer. Measurements and main results: The two groups were similar on entry

into the study, including mean FEV l measurements (0. 70 L atropine~0.60 L metaproterenol, P > .05). Compared with baseline, the FEV 1 improvement for the metaproterenol group was statistically significant (+0.18 L, P = .05; +31%, P < .05), whereas the improvement with atropine did not reach significance (+ 0.09 L or +10%, P > .05). Comparing the two groups, statistically significant differences favoring metaproterenol were found in the percent improvement in the FEVI (+10% atropine~+31% metaproterenol, P < .05) and in the percentage of patients experiencing at least a 15% decrease in their FEV 1 below baseline (35% atropine/IO% metaproterenol, P < .05). No patient suffered adverse side effects.

Conclusion: For the majority of adults with refractory status asthmaticus, an additional ~-adrenergic inhalation treatment results in greater FEV 1 improvement than that resulting from the addition of an atropine inhalation. [Young GP, Freitas P: A randomized comparison of atropine and metaproterenol inhalational therapies for refractory status asthmaticus. Ann Emerg Med May 199i;20:513-519.]

I N T R O D U C T I O N The role of anticholinergic agents in the emergency therapy of acute

bronchospasm remains unresolved. Through inhibi t ion of muscar in ic cholinergic receptors in the respiratory tract, atropine sulfate appears to have more of a bronchodilatory effect on large airways than do ~-adrenergic agents, the standard inhalational agents for the relief of bronchospasm, which have greater effect on smaller airways. 1 In certain patient subgroups, such as patients with chronic obstructive pulmonary disease (COPD 1 or asthmatic patients who inadvertently receive B-blocker therapy, anticholinergic agents may be as effective or more effective than ~-adrenergics. 1-3

In asthmatic patients, the effect of atropine sulfate and its anticholinergic derivative ipratropium bromide may be additive to that of the S-adrenergics.~ -3 In the treatment of acute asthma, combination therapy may be more effective than either individual therapy for many reasons, including 1) the maximal response to bronchodilator therapy in patients who are rel- atively resistant to the effects of ~-agonists is increased; ~-7 2) the duration of effect is increased;i, 8 or 31 lower doses of both agents may be used for the same effect, decreasing the frequency and severity of side effects.i, 9

In the long-term therapy of stable outpatients with COPD, ipratropium bromide (Atrovent ®, Boehringer, Ingelheim, Ridgefie]d, Connecticut) in-

Gary P Young, MD, FACER FACP* Portland, Oregon Paul Freitas, MD, FACEPt Oakland, California

From the Department of Emergency Medicine, Portland Veterans Affairs Medical Center, Portland, Oregon;* and the Department of Emergency Medicine, Highland General Hospital, Oakland, California.I-

Received for publication February 27, 1990. Revision received November 26, 1990. Accepted for publication December 14, 1990.

Presented at the Society for Academic Emergency Medicine Annual Meeting in San Diego, May 1989.

Address for reprints: Gary P Young, MD, Portland VAMC, Emergency Department, PO Box 1034, Portland, Oregon 97207.

42/513 Annals of Emergency Medicine 20:5 May 199

INHALATIONAL THERAPIES Young & Freitas

haled by metered-dose inhaler has been accepted as a primary therapeutic agent.1 However, the relative role of anticholinergic agents, both atropine sulfate and ipratropium bromide, in the emergency department treatment of status asthmaticus is still open to question. There are at least three major reasons for the lack of relevant clinical data to answer this question: 1) The nebulizer solution form of ipratropium bromide is not generally available f rom the manufacturer because its preserva- tives, benzalkonium chloride and ethylenediaminetetra-acetic acid, are each capable of eliciting a paradoxi- cal b ronchocons t r i c t ion in some asthmatic patients, which has been observed to occur with the manufacturer's isotonic ipratropium bromide nebulizer solut ion; 1° 2) the only available anticholinergic agent in solution for nebulized treatments is atropine sulfate, which, despite its widespread availability in EDs for use in patients with cardiac bradyar- rhythmias, has been the focus of lit- tle controlled clinical research in patients with status asthmaticus;Lll-13 and 3) there are m a n y effec t ive [~-adrenergic bronchodilating agents available for the ED management of status asthmaticus.~-sA ~-13

To clarify the relative efficacy of inhaled nebulized atropine sulfate for patients with acute asthma, we performed a double-blind, prospective comparison of inhaled atropine sulfate and inhaled metaproterenol, a [~-adrenergic agent, in the treatment of a group of adult patients refractory to standard ED therapies for status asthmaticus. We attempted to answer two questions regarding the ED treatment of adults with status asthmaticus. First, does atropine sulfate add any benefit to that already received from B-adrenergics, steroids, and theophylline, as measured by the forced expiratory volume in one second (FEV1)? Second, is the improvement in the FEV~ with the addition of an inhaled atropine sulfate treatment superior to the improvement resulting from another S-adrenergic treatment ?

Our twin study hypotheses were that the inhalation of an anticholinergic agent (atropine sulfate) would result ~n a significant improvement in the FEV~ for patients with status asthmaticus refractory to standard ED therapies and that the inhalation

of an anticholinergic agent (atropine sulfate) would result in a greater improvement in the FEV 1 than that from another inhalation treatment of a [~-adrenergic agent (metaproterenol).

MATERIALS A N D METHODS The experimental design was a

prospective, randomized, controlled, double-blind, interventional clinical trial in wh ich pat ients in s tatus asthmaticus received the same therapy for acute bronchospasm, except for the addition of a final inhalational treatment consisting of nebulized solutions of either atropine sulfate (1.5 mg) or metaproterenol (15 rag) to pat ients forming two unmatched, independent study groups. The patient population comprised adult pa t ien ts present ing to our coun ty teaching hospi ta l ED for treatment of status asthmaticus who failed to improve sufficiently with standard therapy for acute bronchospasm and who were determined by the treating physicians to require admission to the hospital.

Status asthmaticus was defined as acute respiratory insufficiency due to clinically obvious bronchospasm in a patient with a previous history of asthma as defined by episodic wheez- ing or dyspnea that rapidly reverses with treatment and is separated by asymptomatic periodsA 4

Exclusion criteria were established to ensure patient safety (ie, no patients with unstable cardiovascular disease, such as unstable vital signs or unstable angina or arrhythmias requiring treatment; no patients with narrow-angle glaucoma; and no preg- nant or breast-feeding women); to ensure that extraneous treatment vari- ables were eliminated by requiring c o m p l i a n c e wi th a s t andard ized t reatment protocol (see below) for acute bronchospasm (ie, strict adher- ence to the time intervals established for each therapeutic and diagnostic step in the study design and no patients receiving atropine sulfate inhalation therapy or other anticholinergic agents before ent ry into the study); to ensure that patients with status asthmaticus accompanied by another complicating disease process that could have an exacerbating effect, such as long-term steroid depen- dency or acute pneumonia, were excluded; and to ensure that patients with causes of acute respiratory in-

sufficiency other than asthma were not entered into the study (ie, pulmonary, upper airway, or cardiac).

To ensure that the study population of asthmatic patients was homo- geneous, patients with the previous diagnosis of either chronic bronchitis or emphysema or a history of persis- tent cough and sputum production and/or chronic shortness of breath without symptom-free periods were excluded under the diagnosis of COPD. 14

Interventions and Measurements Failure of the bronchospasm to im-

prove and the need for admission for treatment of status asthmaticus were defined by clinical decision making on the part of the treating physicians and by a pulmonary function test (FEV 1 less than 2.0 L) after administration of the standardized ED treatment protocol for acute bronchospasm. The standardized therapy for bronchospasm consisted of 1) three inhalations of metaproterenol (15 mg) at 30-minute intervals beginning at the time of presentation to the ED, 2) one IV dose of solumedrol (125 mg) on presentation to the ED, and 3) the at tainment of a therapeutic serum theophylline concentration with an appropriate loading close of IV amino- phylline.

Serum theophylline concentration was measured on presentation to the ED in each patient, with a star labo- ratory result turnaround time of 30 minutes. As soon as the theophylline level was received, a dosage of 1 mg/ kg IV aminophyll ine was administered over 30 minutes for every 2-~g/ mL increase in the theophylline level necessary to ensure a therapeutic theophylline level above 10 ~g/mL. If at this point the treating physicians determined that the patient required admission to the hospital for further intensive asthma therapy, consent was obtained and the patient was entered into our study.

The two patient samples entered into the study were unmatched and independent. Treatment allocation was randomized by having the study solut ions of a t ropine sulfate and metaproterenol prepared by the hospital pharmacy and labeled using a random-numbers table. There was no difference in the amount of solution or in any other observable charac- teristic of either study solution. Both the physicians and patients were

20:5 May 1991 Annals of Emergency Medicine 514/43


TABLE 1. Changes in FEV 1 at one hour after inhalation therapy

Pretherapy Post-therapy Change % Change P Atropine 0.70 _+ 0,12 L 0.79 _+ 0.12 L +0.09 L +10.3 > ,05

Metaproterenol 0,60 +- 0.07 L 0.78 _+ 0.09 L +0,18 L +30.7 < .05

P > .05 > .95 < .05 < .05

bl inded to the s tudy so lu t ion admin- i s te red . P a t i e n t s i n h a l e d n e b u l i z e d s o l u t i o n s of e i t h e r 15 m g m e t a - p r o t e r e n o l ( t he s t a n d a r d m e t a - protereno] dose reported in the acute a s t h m a l i t e r a t u r e ) 11 or 1.5 m g atropine sulfate (based on a dose calcu- la t ion of 0.025 mg/kg in a 60- to 70- kg patient).1,15 M e t a p r o t e r e n o l was c h o s e n b e c a u s e i t is t he s t a n d a r d f3-adrenergic agent used in our ED. The use of the metapro te renol con- t ro l group a l l owed for c o m p a r i s o n wi th atropine sulfate in l ieu of a sa- l ine placebo control group or a crossover design.

Sp i romet ry (FEV1) was per formed after the admin is t ra t ion of the standard t r ea tment protocol and just before admin is t ra t ion of the nebul ized s tudy so lu t ions (a t ropine sulfa te or me tapro te reno l ) and again one hour after the admin is t ra t ion of the s tudy drug because the peak ac t ion of in- h a l e d a t r o p i n e s u l f a t e is app rox i - m a t e l y one hour . 1 T h e two FEV 1 m e a s u r e m e n t s were t aken w i t h the same spi rometer (Jones Standard Pul- monor, Reynolds and Reynolds, May- wood, Illinois) in every s tudy pat ient in the upr igh t position~ the bes t of two FEV1 de te rmina t ions was used at each checkpoint . The FEV 1 measure- m e n t was used because i t is more ac- c u r a t e and r e p r o d u c i b l e t h a n the PEFR. 16 P r e d i c t e d n o r m a l FEV 1 values were those of Knudson et al. 17

In a d d i t i o n to the two p re t r ea t - m e n t and pos t - t rea tment FEV 1 measurements , the s tudy data suppl ied by the t rea t ing phys ic ians inc luded reasons for inc lus ion into the study, inc lud ing d i f fe ren t ia t ion of a s t h m a from COPD, t imes of the s tandard t r ea tmen t protocol therapies admin- i s te red before en t ry in to the s tudy, basel ine theophyl l ine level and dose of any IV a m i n o p h y l l i n e a d m i n i s - tered, checkoff l is t of specific reasons for no t exc lud ing the p a t i e n t f rom the study, s tudy drug number, treat- men t compl ica t ions and side effects (especia l ly ca rd iac leg, t achyca rd ia ] and p u l m o n a r y [eg, s y m p t o m a t i c worsening]), and any comments .

The au thors rev iewed each s tudy pa t ien t ' s ED chart, admiss ion chart, and previous medica l records to de- t e rmine compl i ance w i t h i nc lus ion c r i te r ia , t r e a t m e n t p ro toco l s , FEV 1 m e a s u r e m e n t s and any c o m p l i c a - t ions resul t ing from the s tudy interventions.

Data Analysis Based on a review of the data anal-

y s i s p e r f o r m e d in t h e p r e v i o u s l y c i t e d c o n t r o l l e d t r i a l s of e i t h e r i p r a t r o p i u m b r o m i d e 2-8 or a t r o p i n e su l fa te 11-13 in p a t i e n t s w i t h acu te asthma, we compared mean basel ine FEV 1 measu remen t s wi th mean post- i n t e r v e n t i o n FEV 1 m e a s u r e m e n t s to compu te mean abso lu te increase in FEV1, mean percent change in FEV u change in FEV 1 as a pe r c e n t a ge of mean p red ic ted FEV1, percentage of pat ients in each group wi th a change in FEV 1 of at least 15%, and change in FEV 1 expressed as a percentage of t h e p r e d i c t e d m a x i m a l r e s p o n s e us ing the fo l lowing equat ion : 4 Per- centage response = (pos t - t r ea tmen t I~EV1 - i n i t i a l FEV1) + (pred ic ted FEV 1 - in i t ia l FEV1) x 100.

Stat is t ical analysis was performed comparing the two s tudy groups wi th basel ine and wi th each other using, when appropriate, X 2 test, Student ' s t test, Fisher 's exact test, and Median test.18 Di f fe rences were c ons ide r e d signif icant when P ~< .05; power and p -e r ro r a n a l y s e s were a lso ca l cu - lated. 19 The county H u m a n Subjects Resea rch C o m m i t t e e app roved the s tudy design and consent forms.

RESULTS Baseline Characteristics

Forty pat ients w i th acute bronchospasm resul t ing from status as thmat- icus were en te red in to our s tudy - 20 in the a t ropine sulfate group and 20 in the metapro te renol group. For the 17 m e n and three w o m e n in the a t r o p i n e su l fa te group, average age was 43 Years , and m e a n he igh t and weight were 5 ft, 8 in. and 68 kg, respec t ive ly . M e a n b a s e l i n e FEV 1 in the a t rop ine sulfa te group was 0.70

+ 0.12 L (18% of the mean predicted FEV 1 of 3.8 L). For the 12 men and e ight w o m e n in the m e t a p r o t e r e n o l group, average age was 44 years, and mean height and weight were 5 ft, 7 in. and 63 kg, r e s p e c t i v e l y . M e a n basel ine FEV 1 in the metapro te reno l group was 0.60 + 0.07 L (17% of mean predicted FEV 1 of 3.6 L).

Mean theophyl l ine concentra t ions measured at the t ime of ED presenta- t ion were 8.8 -+ 2.1 ~g/mL in the at- rop ine sulfa te group and 8.2 +_ 1.9 ~g/mL in the metapro te renol group. None of the differences in the above basel ine character is t ics and pa lame- ters were s ta t i s t ica l ly significant between the two groups of pat ients , in- c luding the facts tha t the a t rop ine su l f a t e g roup had m o r e m e n and fewer w o m e n than the metaproterenol group and tha t the me tapro te r - enol group had a lower mean FEV 1 at en t ry into the s tudy (comparison of m e a n base l ine FEV 1 m e a s u r e m e n t s of the two groups us ing x 2 tes t results in a P value of .75; Table 1).

Timing of Interventions The t ime course of the rapy f rom

p re sen t a t i on to the ED un t i l en t ry in to the s tudy was also s imi la r for each group. The first metapro te renol i n h a l a t i o n t r e a t m e n t and IV sol- u rnedro l were a d m i n i s t e r e d w i t h i n 30 minu tes after ED presenta t ion for each s tudy pat ient . The second and third metapro te renol nebul ized treat- men t s and any necessary IV amino- phyl l ine were admin is te red to all the s tudy pat ients w i th in two hours after presenta t ion to the ED.

Mean t ime f rom ED p resen ta t ion to t h e i n i t i a t i o n of t he n e b u l i z e d s t u d y t he r ap i e s was two hours for the a t rop ine sulfa te group and one hour and 50 m i n u t e s for the meta- p ro te reno l group. The t i m e in te rva l b e t w e e n the d e t e r m i n a t i o n of the pre in tervent ion and pos t in te rvent ion FEV 1 measurement s was also s imilar for each group (63 minu te s for the atropine sulfate group and 69 minu tes for the metapro te reno l group).

Measurements and Statistical Analysis

Mean pos t in te rvent ion FEV 1 in the a t r o p i n e su l fa te group was 0.79 + 0.12 L (21% of predicted FEV1) or a m e a n a b s o l u t e i n c r e a s e of 0.09 L ( + 10.3% f rom base l ine and + 2.4% of mean predicted FEV1). Mean post- i n t e r v e n t i o n FEV 1 in t h e m e t a -



0,20 W

0.10

(L)

1 AS

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MP

FIGURE 1. Change in FEV 1 at one hour. AS, atropine; MP, metaproter- e l lO] .

FIGURE 2. Percent change in FEVI at one hour. AS, atropine; MP, m e t a - proterenol.

FIGURE 3. N u m b e r of pat ients wi th 15% or greater change in FEV 1 at one hour. AS, a tropine; MP, m e t a p r o - tereno].

proterenol group was 0.78 + 0.09 L (22% of predicted FEV1) or a mean increase of 0.18 L (+30.7% from baseline and +5.0% of mean predicted FEV1; T a b l e 1). For t h e m e t a - proterenol pa t ien ts , a s t a t i s t i ca l l y significant change c o m p a r e d w i t h baseline was found for the following parameters (Table 1): mean absolute increase in FEV 1 (+0.18 L, P = .05, s igned-rank test), p e r c e n t a g e improvement in mean FEVt { +30.7%, P = .01, paired t test), and change in FEV1 as a percentage of mean predicted FEV 1 (+5.0%, P < .05). Com- pared with baseline, none of these parameters was stat ist ically significant for the atropine sulfate group of patients (P > .05; ~-error range, 0.25 to 0.35).

Comparing the two groups wi th each other, mean absolute increase in FEV~ for the me tapro te reno] group was twofold that of the atropine sulfate group (Figure 1), mean percentage increase in FEV~ for the metaproterenol group was threefold that of the atropine sulfate group (Figure 2), and change in FEVt as a percentage of mean predicted FEV~ for the metaproterenol group was twofold that of the atropine sulfate group. Data analysis revealed statistically significant differences between the two groups in favor of metaproterenol (Table 1) in mean absolute increase in FEVt

30

20

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(0.09 L atropine sulfate/0.18 L metaproterenol, P < .05, signed-rank test), in mean percentage increase in FEV 1 (10.3% atropine sulfate/30.7% metaproterenol, P < .05, X s test), and in change in FEV 1 as a percentage of m e a n pred ic ted FEV 1 ( + 2 . 4 % atropine su l fa te /+5 .0% metaproterenol, P < .05 by t test).

Of the 20 patients in the atropine sulfate group, a lmos t as m a n y patients experienced at least a 15% decrease in FEV 1 from baseline (seven pat ients , or 35%; range, - 1 5 % to - 3 6 % ) as improved their FEV 1 by at least 15% (eight pat ients , or 40%; from + 19% to + 598%). Thus, fewer than half of the atropine sulfate pa- t i en t s i m p r o v e d thei r FEV 1 by at least 15% (Table 2 and Figure 3). Of the 20 patients in the metaproterenol group, the majority (12, or 60%) improved their FEV 1 by at least 15% (range, + 15% to +205%), and only two pa t ien ts (10%) exper ienced at least a 15% decrease in their FEV 1 (from - 17% to -47%) .

Comparing the two groups with regard to patients with at least a 15% c h a n g e in FEV u t he re were 50% more patients in the metaproterenol group with such an increase in FEV 1 (12 versus eight in the atropine sulfate group, respectively), and there were more than threefold as many atropine sulfate patients wi th such a decrease in FEV 1 (seven versus two in the m e t a p r o t e r e n o l group, respec- t ively) . H o w e v e r , b e c a u s e of the smal l n u m b e r of pa t i en t s in this study (~-error, 0.25), there was not a stat ist ically significant difference in the percentage of patients experiencing at least a 15% increase in their FEV 1 compared wi th baseline (60% m e t a p r o t e r e n o l / 4 0 % a t rop ine sulfate, P > .05, X 2 test). But there was a statistically significant difference favoring metaproterenol in the percent-

12 I 11 10 9 8 7 - 6 - 5 - 4 - 3 - 2 - 1 - 0 1 - 2 - 3 - 4 - 5 - 6 - 7 -

MP

AS

age of patients experiencing at least a 15% decrease in their FEV 1 measurements f rom baseline (35% atropine sulfate/10% metaproterenol, P < .05, X 2 test).

Change in FEV 1 expressed as a percentage of the predicted maximal response (see equation in "Data Analy- sis") in the a t ropine sulfate group was half that in the metaproterenol group (2.9% vs 6.0%, respectively), which represents a stat ist ically signif icant difference between the two groups (P < .05, unpaired Student's t test). Subgroup analysis failed to reveal any statistically significant benefit from the inhalation of nebulized a t r o p i n e s u l f a t e s o l u t i o n a m o n g some of the atropine sulfate patients (ie, among men or women, patients younger or older than the mean age of the atropine sulfate patients, pa- t ients wi th baseline FEV 1 measure- men t s less than or more than the mean baseline FEV 1 of the atropine sulfate patients, or severity of illness stratif ication based on the baseline percent predicted FEV1). Overall, the s t u d y da ta i n d i c a t e t h a t a n o t h e r metaproterenol inhalation treatment is more effective than the addition of an atropine sulfate inhalation for patients with refractory bronchospasm resulting from status asthmaticus.

Participants The study was designed so that the

40 patients were entered randomly on ly after the t rea t ing e m e r g e n c y physicians determined that each patient required admission to the hospital for refractory bronchospasm re-

20:5 May 1991 Annals of E m e r g e n c y M e d i c i n e 516/45

tNHALATIONAL THERAPIES Young & Freitas

TABLE 2. Patients w i t h changes in FEV 1 of 15% or more

Atropine Metaproterenol

P

No. of FEV 1 by /> 15% FEV 1 by /> 15% Patients (N) (%) (N) (%)

20 8 (40) 7 (35) 20 12 (60) 2 (10)

> .05 < .05

sulting from status asthmaticus. Be- cause of phys ic ian d iscre t ion in declining to comply with the study protocol, the study population was not a consecutive sampling of all eligible status asthmaticus patients.

Of the 40 patients entered into the study, 39 were subsequently hospitalized after completing the study. Only one pat ient was discharged home after entry into the study. This patient was randomized into the atropine sulfate group, and his FEV 1 improved from 0.43 to 3.0 L (598%) within one hour after inhaling atropine (75% of his predicted FEV 1 of 4.0 L).

No patients refused entry into the study. None of the 40 patients was noted to have suffered any adverse effects resulting from inhalation of the two study solutions, and no patient was withdrawn from the study because of an adverse response. Specifi- cally, there were no significant differences in heart rate or blood pressure response, nor were there any arrhythmias associated with the adminis t ra t ion of either atropine or metaproterenol. The only patients excluded after entry into the study were those who had received nebulized atropine before entry into the study protocol (one patient from each study group); the absence of these patients in the study analysis does not result in any significant change in the statistical outcomes.

DISCUSSION Our prospective, randomized, con-

trolled, double-blind, interventional clinical trial compared the inhalation of a nebulized solution of an anticholinergic agent (atropine sulfate) in 20 adult patients with that of a [~-adrenergic agent (metaproterenol) in another unmatched, independent group of 20 adult patients with status asthmaticus refractory to standard ED t rea tment (ie, three 15-mg metaproterenol inhalation treatments, 125 mg IV solumedrol, and a therapeutic serum theophylline level above 10 t~g/mL). With this study design, we

attempted to answer two questions regarding the ED treatment of adults with status asthmaticus. First, does the inhalation of nebulized atropine sulfate result in an increase in the FEV 1 in addition to that already received from standard ED therapies for acute asthma? Second, is the improvement in the FEV 1 with the addition of an inhaled atropine sulfate treatment superior to the improvement resulting from another f}-adrenergic treatment?

Based on the s tudy results, we were able to reach the following conclusions. First, the addi t ion of a fourth {3-adrenergic nebulized inhalation treatment results in a statistically significant improvement in mean FEV 1 (Table 1). Second, the addition of an atropine sulfate inhalation therapy does not result in a sta- t i s t ica l ly s ignif icant increase in mean FEV 1 after s tandard bronchodilator therapies have proved in- adequate for reversal of status asthmaticus. Third, the addition of a fourth f}-adrenergic treatment results in at least a 15% improvement in the FEV 1 in the majority of patients with status asthmaticus (compared with an atropine sulfate t reatment that does not; Figure 3).

Fourth, the addition of an atropine sulfate treatment results in significantly more patients experiencing at least a 15% decrease in the FEV 1 c o m p a r e d w i t h m e t a p r o t e r e n o l . Fifth, despite these overall negative results in the atropine sulfate group, an occasional pat ient with status asthmaticus may receive marked improvement in the FEV 1 after an atropine sulfate inhalation treatment (one of 20 atropine sulfate patients in this study). Finally, we found that the addition of an atropine sulfate inhalation is safe and well tolerated (none of the 20 patients in the atropine sulfate group experienced any adverse side effects).

Thus, our study hypotheses were not substantiated by the study results, which reveal that 1) the inhalation of a nebulized atropine, sulfate

treatment does not result in a statistically significant improvement in the FEV 1 for patients with status asthmaticus refractory to standard ED therapies, and 2) the inhalation of a nebulized atropine sulfate treatment does not result in a greater improvement in the FEV 1 compared with another inhalation treatment of a ~-adrenergic agent (metaproterenol).

A review of the recent literature regarding the use of nebulized atropine sulfate for the treatment of acute asthma reveals very few controlled clinical trials. A controlled comparison of atropine sulfate and metaproterenol was performed in 1986 by Karpel and coworkers. 11 In a double- blind, crossover comparison of 3.2 mg atropine sulfate administered twice (total dose, 6.4 mg) with metaproterenol in ED patients with acute severe asthma, they found that atropine sulfate did not produce clinically significant bronchodilation either alone or in combinat ion with metaprotereno]. However, they found that this large dose of atropine sulfate produced multiple adverse effects in all patients, although none was serious (eg, dry mouth, dizziness, headaches, blurred vision, and anxi- ety).

Two recent reports compared the inhalation of atropine sulfate with metaprotereno112 and isoetharine 13 in children with acute asthma. Guill and coworkers compared inhaled metaproterenol with atropine sulfate (at a dose of 0.05 to 0.1 mg/kg; maximum, 2 mg in 2 mL saline) in 44 epi- sodes of acute asthma occurring in 35 children aged 13 months to 13 years. ~2 Their results were also very similar to our own: Significant improvement was noted with the use of inhaled metaproterenol with or without combinat ion therapy with atropine sulfate, and the use of inhaled atropine sulfate alone resulted in significantly less improvement in the peak flow rate and significantly more treatment failures.

In a crossover design, Lew and coworkers adminis te red ei ther isoetharine alone or with atropine sulfate (0.05 mg/kg, up to 2 mg) to 17 children aged 7 to 15 years, lg Con- trary to our results and the results of the previously cited controlled trials, they found that combination therapy was superior in 11 cases (65%) and that isoetharine alone was superior



in four cases (23%). The different results in our study from the other status asthmaticus trials could be due, in part, to the use of isoetharine (compared with metaproterenol) and to the crossover study design; after the initial treatment interventions, four hours elapsed during the wash- out phase before the second crossover treatments were administered.

The fact that other reports found atropine sulfate to be an effective bronchodilator may be because some case series are noncon t ro l l ed reports, 20,2I some studies include both asthmatic and COPD patients, 4 and some studies report the use of atropine sulfate in stable, nonacute asthmatic populations. 15

In general, combining our study results with those of the few controlled studies of the use of inhaled atropine sulfate for acute asthma leads to the following conclusions. There may be a limited role for atropine sulfate in the ED management of patients with status asthmaticus, but inhalation therapy with the [~-adrenergic agents remains the first-line therapy. Com- bination therapy with the addition of atropine sulfa te to [3-adrenergic agents does not appear to be any more b e n e f i c i a l t h a n a n o t h e r ~-adrenergic inhalation treatment; in the majority of pat ients in status asthmaticus, any beneficial response from the administration of atropine sulfate appears to be less than that with the use of [3-adrenergic agents. While there may be some benefit to the use of atropine sulfate in some patients, the administration of atropine sulfate rarely results in a dra- matic response, and there is no clinical means by which to predict which patients will benefit from atropine sulfate, with the exception of asthmatic patients exposed to B-blockers. Finally, atropine sMfate inhalation therapy appears to be well tolerated in usual doses of 0.025 to 0.05 mg/ kg, up to 2 mg.

Some commentary is necessary regarding our study design and results. First, our study comparing the use of an inhaled ~-adrenergic agent with the use of an anticholinergic agent was performed with nebulized atropine sulfate and not the isotonic ipratropium bromide nebulizer solution Atrovent ®, which was not available. Second, our study had insuffi- cient power (ie, less than the conven- tional power of 80%) to s h o w

statistically significant benefit from the administration of atropine sulfate in our study population. However, there was a sufficient number of status asthmaticus patients in our study to show a s tat is t ical ly significant benefit from a fourth nebulized inhalation treatment with metaproterenol.

Third, although subgroup analysis (ie, by sex, age, or severity of illness) failed to reveal any statistically significant benefit from the inhalation of nebulized atropine sulfate solution, some investigators have reported more benefit from the addi- t ion of an t icho l inerg ic agents to ~-adrenergic therapy in patients with more severe degrees of air-flow obstruction. 2,3 Fourth, the dose of atropine sulfate administered in the present study was on the more con- servative end of the accepted dosage range (0.025 to 0.05 mg/kg); there may be more response to higher doses of atropine sulfate. 15

Fifth, the 40 patients were entered randomly into the study only after the treating emergency physicians de te rmined that each pa t ien t required hospitalization for refractory bronchospasm resulting from status asthmaticus. It may be that the ad- m i n i s t r a t i o n of a n t i c h o l i n e r g i c agents sooner in the course of ED therapy might help some asthmatic patients avoid hospital admission.

Sixth, the study design allowed for physician discretion in entering patients into the trial, so the patient populat ion was not a consecut ive sampling of all eligible status asthmaticus patients. Nevertheless, there were only two patients excluded after entry into the study (one patient from each study group), and the absence of these pat ients f rom the study analysis did not result in any significant change in the statistical outcomes. Furthermore, there were no statistically significant differences between the metaproterenol and atropine sulfate groups with regard to baseline character is t ics , and the study protocol was sufficiently ad- hered to that there were no statistically significant differences in the time intervals elapsed between ED presentation and the administration of either the standard or study therapies.

Seventh, some of the patients in each group experienced a decrease in their FEV I after the study interven-

tion treatments, and of the 40 patients entered into the study, 39 were subsequently hospitalized after completing the study. Previously / Lewis and coworkers reported in children with acute asthma that the majority of their patients (69%) had a positive response in spirometric measurements to the first bronchodi lator treatment, but fewer patients had an objective response to successive treatments, and very few (12%) re- sponded to the fourth inhalation of isoetharine, z2 This might account for the minority of patients who did not respond to the fourth metaproterenol treatment and for the majority of patients in the atropine sulfate group who did not respond with an improvement in the FEV u particularly because the study patients were se- lected with refractory status asthmaticus.

CONCLUSION In a prospective, double-blind, ran-

domized, interventional clinical trial of adult patients with status asthmaticus refractory to standard ED therapies, we compared the efficacy of an initial inhaled atropine sulfate t r ea tmen t wi th a four th inhaled metaproterenol treatment. The re- suits showed that another [3-adrenergic t rea tment produces a statistically significant improvement in the FEV 1 at one hour compared with baseline and compared with an anticholinergic (atropine sulfate) treatment. No patients in either study group suffered any adverse outcomes.

We conclude that for the majority of adults in status asthmaticus refractory to standard ED therapies, an additional [3-adrenergic inhalat ion treatment results in more improvement than the addition of the cur- rently available anticholinergic agent in solution (atropine sulfate). Further study is necessary to delineate the role of higher doses of atropine sulfate earlier in the course of emergency therapy and of the anticholinergic agent ipratropium bromide in patients with status asthmaticus.

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