Treatment of nocturnal asthma with pulsed-release albuterol.

R M Bogin and R D Ballard Chest 1992;102;362-366 DOI 10.1378/chest.102.2.362 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/102/2/362

CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright 1992 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692

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Treatmentof Nocturnal Asthma with Pulsed-ReleaseAlbuterol*

Robert M. Bogin, M.D. , F.C.C.P;t and Robert D. Ballard, M.D4
The treatment of nocturnal asthma remains a challenge. We investigated the use of a pulsed-released albuterol in ten patients with nocturnal symptoms of asthma. In a randomized, double-blind, placebo-controlled, crossover designed study, we tested the use of 8 mg of pulsed-release albuterol sulfate (Proventil Repetabs) vs placebo. The pulsed-release albuterol significantly blunted the overnight drop in FEy,, improved peak flow readings in the morning, and decreased subjective awakenings from sleep. We con dude that pulsed-released albuterol is an effective thera peutic option in patients with nocturnal asthma.
(Chest 1992; 102:362-66)

he nocturnal

@vorsening of asthiiia

is a coniii@on

would be expected
worsening of a single ofasthma. bedtime

to l)etter
Therefore, dose

control

the nocturnal
the uSe albuterol

phenomenon' that ren@aiiis a therapeutic chal lenge. A comn@only used approach has been the evening use of sustained-release theophylline This
regimen results the in maximal nocturnal theophylline period concentra bron tiOflS during of increased

we evaluated

of pulsed-release

sulfate (Proventil Repetabs) to control symptoms and improve airflow in asthmatic subjects with nocturnal worsening. We also sought to determine the effects of
pulsed-release albuterol on sleep architecture in these

cho)co)nstriction and is therefore helpfiul in iuariy asth matic I)atiellts; however, the use of theophylline has well-known drawbacks. Therapeutic serum levels must he established, and many drugs giveti concomitantly may affect theophylline metabolism. Side effects of
tremor, jitteriness, and nausea may occur even at

Patients.
MATERIALS Subjects Teui adult patients (ages, 18 to 65 years) with a documented
history of asthma per the ATS definition2l were recruited from the

ANt) METhoDs

therapeutic serum levels. Theophylline

shown to adversely

has alSo)been

affect sleep (@t1ality.@

Other therapies have also l)een used with variable sttccess.9@ An alternative approach has been the evening use of oral @3-adrenergic agents. St,stained release preparations of albuterol@' and buan'' have been demonstrated to improve nocturnal asthma
111many 1)atielltS. The unavailability ofsuch sustained

release preparations in this country has previously forced 1)hySiCiaflSto use rapidly-acting formulations Although this has been well tolerated by most patients, the briefer duration of action has left many patients without effective bronchodilation during the critical
early morning hours.

outpatient po)ptllatiofl. The@' were not receiving steroids, crornolvn, or oral @3-adrenergicagonist tl)eraI)@AflOI@ had they tused such unedicatu)n during the @re@i@iis three months. These patients therefore had mild to moderate disease and were treated with sustained-release theophvlliuie and inhaled @3-adrenergic agonists onl@@ Nevertheless, the patients repo)rted nocturnal or early morning s@nuptoins of bronchoo.Mnstriction and demonstrated decreases in either peak expiratory How rate (PEFR) or FE@I of at least 20 I)erce@t in the morning compared to l)C(ltiflle. Subjects were excluded from the study if they had a history of
significant heart disease; other pulmonary disease, incll,(ling

chro,,ic (durations action of from5 to 8 h)forthispt@@p@se.

airflow limitation (chronic bronchitis; ev@physenia; hronchi ectasis); an acute upper respiratory infection or sinusitis; current oi@ recent (less than three na)nths) cigarette tusage; clinical instability
in tlw opinion of the physicianinvestigator; pregnancy or delivery

within OI)t' @ear; r nocturnal o

LXp(rl?)U'fltal I@otocol

or irregular

work shifts.

Albuterol sulfate has recently become available in this country in a pulsed-release formulation (Proventil Repetabs). The sequential pulsed release of this formulation is designed to extend the duration of
action up to 12 h. Such an extended duration of action

Serium theoph@'lline was adjusted reginien at three-day

levels

were

obtained to attain

at 8 sro prior to entry a level in the range of

into the stt,d@@ level was less than lOp.g/dl, theoph@lline dosage Ifa
intervals

10@iWdl 20p.g/dl. Each subject was also maintained on a stable to

ofiuihaled albuterol four times daily beverages
8 iag of

@unless dditional a for the duration

pt@lsedrelease

doses of the

were neede(l acutely for increasing asthmatic symptoms. All patients *Ffl)n, the Departments of Medici,ie, National Jewish Center for lmmtinolog@ and Respirator@ Medicine aiid the University of Colorado health Sciem.es Center, and I)eiiver W'terans Adminis tratu)n Medical Center, Denver. tAssistant Professor of Medicine and Staff Physician, I)epartnwiit of Medicine, Natio,,al Jewish Center for Immunology and Respi ratorv Medicine. lAssistant Professor of Medicine and Stall Physician, l)eiiver \A M('(liCa] Center. St@pported e,itirelv h@fuiuls from Schering (orporat iou. Manuscript receiv('(l Marcl@5; revision acct'f)ted October :31. Reprint requests: I)r Begin, National Jewish Center, 1.5(K)jackson Street, Denver 80206 362
dlS() al)staifle(l
IBedicatiOn

from caffeinated
placels) or

sttitl@. At entry
(either

into the pr@t@col, each subject

was given
alhuterol

sulfate IProventil Repetabsl assigned randomly and in a (10111)10 l)lin(l fitshion) to 1)0 taken onto' dail@@ 10 ,sifor a total of ten at , (la\s. I)uring this time. subjects nlaintaine(1 a svmptoni log auid recorded at least thrice daily PEFRs. On the tenth studs day; each
SIIl)jOCtu,nder'we,,t a nocturnal sleep study and sVaS monitore(l using

all techniques descrilx-d in the section, Study echniques. T Following the initial sleep stu,d@ each slll)ject was crossed oser to the alternative nedication in the protocol . After an additional ten
Treatmentof NocturnalAsthma (Bogin, Ballard)

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days of maintaining a symptom log and monitoring thrice daily PEFRS, each subject again underwent a sleep study as outlined subsequenfly. Study Techniques Sleep studies were routinely started by 11 PMand terminated at 6 AM During each sleep study, parameters 1 to 4 in the following . list were monitored and recorded: 1. Sleep Staging. Sleep was staged per the standard criteria of Rechtschaffen and Kales,u using continuous recordings of electro oculographic, electromyographic, and electroencephalographic ac

Table 1Spirometric Data*

LAlbuterolPlaceboBedtimeFEV12.620.322.730.26MorningFEV12.310.231.840.23tBed Measurement,

19MorningFVC3.620.363.850. FVC3.330.232.990.27tBedtime FEy orning FEV10.31 m 18tBedtime FVC orning FVC0.290.87t m

170.89 0.

0.

tivities. These activities were recorded using a 16-channel chart

recorder (Grass Instruments model 78D).

*Data are means SE. tp<0.005 for morning vs bedtime FEV1 or FVC. @p<0.05 for placebo vs albuterol.

2. Oxygen aturation. S Allsubjects weremonitoredsing u anear

oximeter (BIOX III). The SaO, was continually recorded throughout each study using the chart recorder.

3. Cardiac Rate and Rhythm. Cardiac activity was recorded

continually throughout each study from a standard chest electrode

usingthe chartrecorder.
4. Spirometry. Spirometry (Collins Eagle II) was performed at bedtime, time of awakening in the morning, and at any at the
nocturnal awakening due to symptoms of increasing bronchocon striction. Each reported measurement consisted of the best (highest FEy1) of three consecutive efforts. 5. Symptom Scoring. During the study, each subject was also required to maintain a daily symptom log. These symptoms included

the following:general daytime asthmasymptoms;nighttime wheez

ing, coughing, and tremor; sleep quality; and nocturnal awakenings with asthma. The symptoms were scored as follows: 0 no symptom or occurrence; 1 mild or occasional; and 2 = severe or frequent; while sleep quality was scored as 0= good, 1 = slightly disturbed, and 2 = frequent awakenings. This log included PEFR measure ments made before and after the bronchodilator at least three times

study. These data were analyzed by paired t-tests. Variables that were measured daily were summarized by averaging the measure ments for the last three days in each period. This effectively emphasized the longer term effect of treatment and reduced the possibility ofa carryover effect between periods. All other variables were measured at the end of each treatment period. The variables of cough and tremor were not analyzed, since almost all of their values were zero. All variables (and summary variables) were analyzed using the methods described in Jones and Kenward.'@'In particular, the model was a repeated-measures analysis of variance which included terms for period, carryover, and treatment effects. This allowed for separate tests of significance for systematic differences over time, different residual treatment effects between the two treatment sequences, and differences between the placebo and albuterol treatments, respectively. RESULTS

daily: upon morning awakening, midafternoon, at bedtime, and at

any nocturnal awakening associated with symptoms of bronchocon striction and necessitating treatment. The PEFRs were measured

with a peak flowmeter (mini-Wright). Data Analysis Total sleep time, sleep efficiency, sleep latency, sleep stage
distribution, total number of arousals (awakenings lasting less than 15 s), total number of awakenings (awakenings lasting more than 15 s), total number of sleep stage changes, mean oxygen saturation, and mean heart rate were calculated from each nocturnal sleep

Eight men and two women were recruited into the study. The mean age ofthe ten subjects was 31.4 2.4 years. The mean AM theophylline level was 12.9p.g/dl 0.8p.g/dl. All subjects completed the pro tocol. The results of spirometry are shown in Table 1.
When using placebo, subjects experienced a signifi cant overnight drop in FEY,; this effect was blocked

by using pulsed-release
The change in morning

albuterol
FEy,

sulfate (p<O.O5).
to

and FVC compared

F
Jo
FIGURE 1. Overnight drop in FEVI (in liters) in ten

subjects while using placebo and pulsed-release albu terol sulfate (Proventil Repetabs). Mean FEV, change is represented by dashed line.

Treatment
CHEST 1 102 I 2 1 AUGUST. 1992 363

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Table 2Diary Recordings*

RecordingAlbuterolPlacebo)Daily Diary symptoms0.63 140.68 0. 0.18Nighttime wheezing0.330.090.730.1StSleep quality0.42 120.57 0. 0.14No. ofawakenings per night0.27 0.130.55 16tExtrapuffsofinhaleratnight0.300.100.650.24 0.

Table 4Sleep Parameters

ParameterAlbuterolPlaceboTotal sleep, mm299 9Percent efficiency75 5792Latency, 3Percent mm19 awake20 4172Percentstagel151163Percent
24323

416

*Data are means SE. tp<0.05 for placebo vs albuterol.

stage 249 2@04Percentstage33131Percentstage41121PercentREM122122Heart

evening values was also moderated by the pulsed release albuterol (p<O.005 for both FEY, and FVC). Figure 1 demonstrates that the overnight drop in
FEY, was significantly lower when the subjects used

rate, beats per mm73 2662*Sa02,percent930.6920.9No. ofawakenings10 1131No. 9No. of stage changes59 ofarousals9292 *p = 0.005 for placebo vs albuterol.

772

pulsed-release albuterol sulfate, when compared to placebo. Results from the patients' diaries are shown in Tables 2 and 3. Subjective improvement was noted in nighttime wheezing when taking the pulsed-release albuterol (p<O.O5); however, most notably, the sub jects reported awakening from sleep less frequently during the study period when using the pulsed-release albuterol. Other symptoms were unchanged by the drug, although there was a tendency towards fewer nighttime metered-dose inhaler puffs (p 0. 10). Peak
flow recordings (Table 3) demonstrated significant

decreased airflow in the morning, as compared to the

evening.24 This pattern of nocturnal bronchoconstric

improvement in peak flow readings taken before and after the bronchodilator in the morning, and before the bronchodilator in the evening when taking the pulsed-release albuterol.
The sleep study results are depicted in Table 4. No

tion contributes to the disruption of sleep in affected patients.' An increased evening dose of theophylline has been suggested as treatment for nocturnal asthma, and some of these preparations have been demonstrated to improve morning spirometry in mild asthma;35 however, this therapy may not be the treatment of choice in all patients. Serum levels must be checked
periodically to assure proper dosing ofthis drug. Once

daily dosing may not be adequate to control daytime symptoms in more severe asthma. Interaction with
other prescribed medications may occur and may

significant differences were noted in any of the sleep characteristics between drug and placebo. Not sur
prisingly, heart rate was significantly higher with

pulsed-release albuterol when compared to placebo (73 beats per minute with drug; 66 beats per minute with placebo).
DISCUSSION

result in toxic levels of theophylline. Many patients are unable to tolerate theophylline products, even if maintained within therapeutic levels, due to tremu lousness or GI upset. Finally, theophylline has been shown to adversely affect sleep quality.@@ A number of other drugs used in the treatment of asthma have been studied for use specifically in nocturnal asthma. Several authors have investigated
the use of ipratropium
al,12 Hughes,'3 and

Nocturnal

asthma

remains

a common

therapeutic

bromide.

Studies

by Cox et
a significant

challenge. Up to 75 percent of the patients with asthma have symptoms of nocturnal awakenings or
Table 3PeakFlow Measurements*
L/min.Flow Conditions of PeakPeakFloss; ReadingsAlbuterolPlaceboEvening before bronchodilator402 30tEvening after bronchodilator473 34Morning before bronchodilator370 23flMorning 29tMiddayafter bronchodilator463 before bronchodilator388 31Midday after bronchodilator473 *Data are means SE. tp<0.05 for placebo vs albuterol. 29373 29463 29334 28434 29371 28467 31

Catterall

et al'@ noted

but small improvement

peak flow when demonstrate

in overnight
was used

reductions

in

ipratropium

by asthmatic in nine

subjects at bedtime.

Coe and Barnes'5 were able to

in PEFR

a similar improvement

of 18 subjects using oxitropium at bedtime. Anticho linergics therefore seem to be somewhat effective in
improving nocturnal asthma in some patients. in patients with nocturnal

Horn et al16studied inhaled albuterol (salbutamol)

and beclomethasone

1: p<O.O5for morning beforebronchodilator evening vs before

bronchodilator. 364

asthma. These investigators'6 found that eight of 14 subjects showed improvement in overnight reductions in PEFR with the inhaled @3-adrenergicagonist alone, with further improvement occurring after addition of the inhaled steroid; however, spirometry, symptoms,
and sleep parameters were not measured.
Treatment of Nocturnal Asthma (Bogin, Ballard)

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Ketotifen, a newer antihistamine, has been shown to improve sleep quality in subjects with nocturnal asthma, but not to affect nocturnal Sa02 or morning
FEY, .

preparation for the treatment of nocturnal asthma. The release mechanism of this pulsed-release formu
lation essentially works as a tal)kt within a tablet (Fig

Morgan et al's investigated the use of nebulized cromolyn sodium (sodium cromoglycate) in patients with nocturnal asthma. These investigators'5 found that although the lowest nocturnal oxygen saturation was minimally improved in these patients (Sa02
dropped a maximum of 6 percent with the drug and 8

2). An outer color coat surrounds COntains 2 mg of albuterol. These

a stIl)co)@ttsvhich two coats rapidly

percent with placebo), morning FE@', was unchanged by this medication. The timing of doses of oral corticosteroids was evaluated by Reinberg et al.'@ Their data indicated that morning dipping was improved but not eliminated when steroids were given at 8 AMand 3 tM . Soutar et a12 infused hydrocortisone into subjects with noctur
nal asthma. Although these investigators5 were aI)le

dissolve within the stomach and immediately release 2 mg of the drug. Beneath the drug's suhcoat is a barrier coat which is not soluble in the acid pH of the stomach. When the remaining portio)n ofthe tal)let enters the more basic environment of the small intestine (after about 6 h), the l)arrier coat dissolves, exposing the core tablet, which contains the remain ing 2 mg of albuterol . This core tablet then dissolves, releasing the remainder ofthe all)t,terol. Our study was designed to determine if a single l)edtime dose of 8 mg (two tablets) of pulsed-release
albtiterol
improving nocturnal

sulfate
airflow asthma,

(Proventil
limitation and to

Repetabs)
and evaluate

is effective
sleep any quality side

in
in

to prevent a nocturnal fall in plasma corticosteroid levels, they were unable to affect the overnight de
crease in PEFRs in five of their six subjects.

effects

produced

by 8 n-ig of this drug. Our data indicate

that

Previous

@J@@9.0) nocturnal of

asthma demon
dose ofa long

strated the efficacy ofa 16-mg bedtime

acting oral @3-adrenergicagonist preparation, with few

side effects. When a slow-release formulation of albt, terol (Ventolin Spandets) was compared to aminophyl

an 8-mg dose is very effective in improving the overnight increase in airflo@vlimitation, as measured l)y the overnight fall in FEy, and PEFR. The pulsed release alht@terol also improved the numl)er of night time awakenings due to asthma noted by the sul)jects. The pulsed-release formulation did not adversely af
feet sleep quality, and IR) increase in side effects @@as noted. The increase in heart rate of7 l)eats pe@ minute

line,'both drugs were found to significantly iniprove

morning peak flows, while albuterol evening peak flow Gastrointestinal phylline and for 19 percent Fairfax et al' also compared of those albuterol also improved the intolerance was a using albuterol. (Ventolin Span

problem for 23 percent of the subjects using amino

noted during the sleep studies is, we believe, unlikely to be clinically significant or disturbing to 1)atie1@ts. \Ve conclude that a single bedtime dose of 8 mg of
pulsedrelease all)uterol sulfate (Proventil Repetabs) and

dets) to nighttime

aminophylline

and noted

signifi

is effective
1)airlneh)t

in improving
hi 1)atiehlts

symptoms

and airflow im
asthma,

cantly higher mean peak expiratory flow rates on waking with both drugs; however, this albuterol prep

@vith tioctu rnal

aration is unavailable in this country. The introduction of an oral pulsed-release formulation of albuterol sulfate (Proventil Repetabs) to the United States has
provided the alternative of a long-acting albuterol

should be considered patients.

a therapeutic

option

in these

ACKNO\VLED(;MENT: \Ve thank Mr. J,no Pak for technical assistance, Nis. Jautet Blixler for secretarial su@)po)rt,and Ms. Lynn
Ackerson br statistical assistance.

TabletSubcoatCoretablet4 Proventil' Pepetabs' mg albuterol2

Color coat

mg albuterol2 Barrier coat

mg albuterol

1@' hour
Color coat dissolves. Subcoat dissolves releasing 2 mg albuterol

2nd@oth hours

7th

hour

Barrier coat

remains intact protecting coretablet.

Barrier coat dissolves. Coretablet dussolves releasing

2 mg albuterol

F, ;uto@ Nlechanisun of pulsedreleasealbuterol sulfate (Proventil Repetabs). 2.

CHEST I 102 I 2 I AUGUST. 1992 365

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366

Treatmentof NocturnalAsthma (Bogin, Ballard)

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Treatment of nocturnal asthma with pulsed-release albuterol. R M Bogin and R D Ballard Chest 1992;102; 362-366 DOI 10.1378/chest.102.2.362 This information is current as of August 22, 2010
Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/102/2/362 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.

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