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Cardiopulmonary Responses to Exercise in Chronic Airflow Obstruction
clinical Clinicll investigations inllllillliins Cardiopulmonary Responses to Exercise in Cardiopulmonary Responses to Exercise
Chronic Airflow Airflow Obstruction* Obstruction* Chronic Effects Effects of of Inhaled Inhaled Atropine Atropine Sulfate Sulfate Stephen Stephen E. E. Brown, Brown, M.D., M.D., FC.C.P.; F.C.C.p.; Richard Richard S. Prager, M.D.; M.D.; Richard Richard A. A Shinto, Shinto, M.D.; M.D.; Claudia Claudia E. E. Fischer, M.D.; M.D.; David W. Stansbury, Stansbury, M.D.; M.D.; and and Richard Richard WW. Light, M.D., M.D., F.C.C.? F.C.C.P. David W.
The The purpose purpose of of this this study study was was to to evaluate evaluate the the effects effects of of inhaled inhaled atropine atropine sulfate sulfate on on the the exercise exercise capacity capacity and and cardiocardiopulmonary pulmonary responses responses to to exercise exercise inin patients patients with with chronic chronic airflow airftow obstruction obstruction (CAO). (CAO~ Eighteen Eighteen patients patients underwent underwent duplicate (15 watts/mm) watts/min) maximal mavmal cycle cycle ergomeergomeduplicate incremental incremental (15 ter 60 minutes ter exercise exercise tests tests 60 minutes after after either either inhaled inhaled atropine atropine (0.075 (0.075 mg/kg) mglkg) or or placebo, placebo, in in double double blind blind randomized randomized fashion fashion on on consecutive consecutive days. days. Bronchodilator Bronchodilator medications medications were Spirograms were were withheld withheld before before each each study. study. Spirograms were obtained obtained before before and and 60 60 minutes minutes after after each each aerosol aerosol treatment. treatment. AtroAtropine 1.37 ±± 0.49 pine increased increased the the FEy, FEV. by by 25 25 percent, percent, from from 1.37 0.49 to to 1.71±0.52 1.71±0.52 LL (p
Nlost ost patients with chronic airflow obstruction M (CAO) have limited exercise tolerance and compatients
(CAO)
have
with
limited
chronic
exercise
airflow
tolerance
obstruction
and com-
plain generally accepted accepted plain of of exertional exertional dyspnea. dyspnea. ItIt isis generally that these patients limited that the the exercise exercise tolerance tolerance ofof these patients isis limited predominantly of ventilatory ventilatory mechanmechanpredominantly by by impairment impairment of
the the ventilation ventilation at at exhaustion exhaustion (VEmax) (VEma) increased increased signifisigni&candy cantly (from (from 52.3±11.5 52.3 ± 1l.5 to to 55.9±10.0 55.9 ± 10.0 Lfmin, Umin, P<0.05) P
These These individuals individuals had had no no known known left left ventricular ventricular disease, disease, glaucoma, glaucoma, prostatic prostatic
hypertrophy, hypertrophy, or or other other disorders disorders which which would would preclude preclude
maximal maximal exercise exercise testing. testing. Characteristics Characteristics ofofthese these patients patients (receiving (receiving
bronchodilator therapy) therapy) were were defined de6ned on on aa preliminary preliminary screening screening day day bronchodilator as as follows: tollows: age, age, 62±6 62±6 yrs; yrs; wt, wt, 76.1±15.2 76.l±15.2 kg; kg; FEy,, FEV.. 1.56±0.41 l.56±O.41 L; L; FVC, FVC, 3.24±0.87 3.24±0.S7 L; L; FEV,/FVC, FEV/FYC, 0.48±0.08; 0.4B±0.08; TLC, TLC, 124±20% 124±2O% prepre-
ics.’4 Although bronchodilators bronchodilators have have become become aa mainmainics. l -4 Although
dicted; BY, 218±72% 2l8±72'11 predicted; predicted; and and dicted; FRC, FRC, 191±41% 191±41'll predicted; predicted; RV,
stay CAO, few studies have few studies have assessed assessed stay inin the the treatment treatment ofofCAO,
Dco, Dco, 58 58 ±± 22% 22'11 predicted. predicted.
the these drugs drugs on on exercise exercise performance performance inin the effects effects ofof these
this studies have this patient patient group. group. Results Results of of previous previous studies have
Pulnwnary Pulmon4ry Function Function Tests Tests
a
seal
Spirometric 12 LL dry Spirometric measurements measurements were were made made with with a 12 dry rolling rolling seal
been con8icting.5-8 We We are are unaware unaware of of any any previous previous been conflicting.9 studies inhaled studies which which have have reported reported the the effects effects ofof inhaled
spirometer spirometer (CPI (CPI 221). 221). Lung Lung volumes volumes were were measured measured by by body body
atropine atropine on on cycle cycle ergometer ergometer exercise exercise performance performance inin
was was measured measured by by the the single-breath single-breath method. method. The The normal normal values values ofof
these was toto these patients. patients. The The purpose purpose ofofthe the present present study study was determine with aeroaerodetermine whether whether increasing increasing the the FEY, FEV1 with
voluntary voluntary ventilation ventilation was was performed perfOrmed for tor ten ten seconds seconds and and extrapoextrapo-
solized solized atropine atropine sulfate sulfate would would alter alter the the cardiopulmocardiopulmonary nary responses responses toto exercise exercise and/or and/or improve improve maximum maximum exercise CAO patients. patients. exercise performance performance inin CAO
plethysmography. plethysmography. The The diffusing diffusing capacity capacity ofof the the lung lung for tor CO CO (Dco) (Dco)
Knudson Knudson etet al’#{176} allO and and Cotes Cotes and and Hall” Hallu were were utilized. utilized. Maximum Maximum lated lated toto L/min, Umin, BTPS. BTPS.
Study Study Design Design Testing Testing was was performed perfOrmed inin aa randomized randomized double double blind blind crossover crossover fashion. each study, study, theophylline theophylline was was withheld withheld for tor 12 12 hours hours tashion. Prior Prior toto each
MATERIALS MATERIALS AND AND METHODS METHODS Patient lbtient Population PopultJtion Eighteen Eighteen subjects subjects with with moderate moderate toto severe severe CAO CAO were were evaluated. evaluated.
and and inhaled inhaled beta-adrenergic beta-adrenergic agents agents were were held held for tor six six hours. hours. Patients Patients gave gave their their written written informed infOrmed consent. consent. AA baseline baseline spirogram spirogram was was
performed was administered. perfOrmed and and the the aerosol aerosol treatment beatment was administered. On On one one study study day, day, the the aerosol aerosol treatment beatment consisted consisted ofof atropine atropine sulfate sulfide (0.075 (0.075 mg/kg) mWkg) administered administered inin aa concentration concentration ofofl1 mg/mI mglml via via an an aerosol aerosol T” 'T'
*From *From the the Department Department ofofMedicine, Medicine, Veterans Veterans Administration Administration MediMedi-
cal cal Center, Center, Long Long Beach, Beach, and and the the University University ofof California, California, Irvine. Irvine. This This study study was was supported supported by by the the VA VA Research Research Service. Service. Manuscript Manuscript received received May May 27; 27; revision revision accepted accepted July July 23. 23. Reprint lIeprint requests: requests: Dr Dr. Brown, Brown, VA VA Medical Medical Center, Center; liP, 111p, 5901 5901 East East 7th 7th Street, Street, Long Long Beach Beach 90822 908J2
medication medication nebulizer. nebulizer. Nebulization Nebulization was was continuous continuous and and was was not not timed occur only only during during inspiration. inspiration. On On the the other other day, day, an an equal equal timed toto occur volume volume ofof saline saline (placebo) (Placebo) was was used. used. One One hour hour following tollowing treatment, treatment, spirograms spirograms were were repeated. repeated. Thereafter, Thereafter, exercise exercise testing testing was was carried carried out. out.
CHEST II 89 89 IIl 1 II JANUARY, JANUARY, 1888 CHEST 1986
77
After
Table Table 1-Spirograms l-Spirograma Before Before and and After Atropine Atropine and and Placebo Placebo (n18, (n=18, mean±SD)* mean±SD)*
Table =18, Table 3-Maximum 3-Mtaimum Exercise E:rerciae Data Data (n(n=18,
Placebo Placebo
Atropine Atropine
1.35± 0.48 1.35±0.48
1.39± 0.44 1.39±0.44
60 60 mm min Postaerosol Postaerosol
Placebo Placebo
Atropine Atropine
1.37±0.49 0.49 1.71±0.52* 1.37± 1. 71± 0.52· FVC,L 2.89±0.74 2.89±0.74 2.98±0.69 2.98±0.69 3.07±0.81 3.07±0.81 3.65±0.89* 3.65±0.89· FYC, L 58.4±18.4# 51.2± 10.9 Mvv, L/min Umin 51.2± 10.9 58.4± 18.4# MV\ FEY1, FEV" LL
p
placebo and and atropine. atropine. placebo
YE, VE,
Llmin BTPS Umin BTPS VT, L BTPS VT, L BTPS Fb, breaths/min Fb, breaths/mm Io,, L/min STPD Vo., Umin STPD Veo., Vco,, Umin L/min STPD STPD rr VE/VO, VElVo. VE/VCO, VElVco.
O.-Pulse, mllbeat 0,-Pulse, mI/beat
Fc, Fc, beats/mm beats/min
VE
VE max, max, L/min Umin BTPS BTPS VT VT max, max, LL BTPS BTPS
Fb, Fb, breaths/mm breaths/min
Va. max, max, Limin Umin STPD STPD STPD Vco. max, max, L/min Umin STPD
VO, rr
VElVo. VE/VCO, VElVco. VE/VO,
Table 2-Resting 2-Re3ting Data Data (n (n =18, mean ± SD) Table 18, mean ± SD)
Fc, Fc, beats/mm beats/min
Workload, watts Workload, watts
0,-Pulse, O.-Pulse, mI/beat mllbeat
Placebo Placebo
Atropine Atropine
79±18 79±18
88±19 p<0.025 88±19 p
14.7±3.0 14.7±3.0 0.63±0.12 0.63±0.12 20±3 20±3 0.327±0.065 0.327±0.065 0.265±0.049 0.265±0.049 0.81±0.06 0.81±0.06 45.2±4.9 45.2±4.9 55.8±6.1 55.8±6.1 4.27±0.96 4.27±0.96
Maximal Exerci8e Tests Maximal Exercise Tests
Exercise testing was on cycle Exercise testing was perfurmed performed on an an electrically-braked electrically-braked cycle previously described by this ergometer in similar to ergometer in a a manner manner similar to that that previously described by this laboratory. resting measurements, patients pedaled at laboratory.”2 UI Following Following resting measurements, patients pedaled at fOr one one minute; minute; the the workload was "0" watts watts (unloaded (unloaded cycling) cycling) for workload was subsequently increased by until subsequently increased by 15 15 watts watts each each minute minute until the the patient patient became exhausted. Expired volume (YE) was measured with (VE) was measured with aa became exhausted. Expired volume turbine. Analysis of the mixed expired fractions of oxygen oxygen (FEO,) turbine. Analysis of the mixed expired fractions of (FEO.) was with gas gas analyzers. and dioxide (FECO.) and carbon carbon dioxide (FECO,) was perfurmed performed with analyzers. fOr measurements were Standard calculations Standard calculations for metabolic metabolic measurements were utilized.13 utilized.0
Statistical Analysis Statistical Analysis Data were were analyzed analyzed at rest rest and and at at maximum maximum exercise following Data at exercise fOllowing placebo and In comparisons fOr meaplacebo and atropine. atropine. In addition, addition, comparisons for selected selected measurements were also also made made at at equivalent equivalent work loads, loads, corresponding surements were work corresponding
95±28 95±2B 126± 12 126±12 52.3± 11.5 52.3±1l.5 1.45± 0.36 1.45±0.36 34±6 34±6 1.36±0.30 l.36±O.30 1.22±0.36 l.22±O.36 0.97±0.12 0.97±0.12 40.5± 8.3 40.5±8.3 42.4±8.6 42.4±8.6 10.98±2.62 10.98±2.62
SD) SD)
Atropine Atropine
Placebo Placebo
Preaerosol Preaerosol
mean mean ±±
101± 19 101±19 131±23 131±23 55.9±10.0 55.9±10.0
p<0.05 p
1.52± 0.27 1.52±0.27 35±6 35±6 1.33±0.21 1.33±O.21 1.36±0.27 1.36±O.27 1.02±0.09 1.02±0.09 43.9±6.4 43.9±6.4 p
to approximately 25 100 to approximately 25 percent, percent, 50 50 percent, percent, 75 75 percent, percent, and and 100 percent of the work load. were analyzed percent of the placebo placebo maximum maximum work load. Data Data were analyzed using Student’s paired t-test. A value of p
Resting Data Resting Data
The The preaerosol preaerosol FEV! FEY, values values on on the the placebo placebo and and atropine days did did not not differ differ significantly significantly (Table 1). 1). The (Thble The atropine days FEY, increased 25 percent percent (to 1. 1.71± 71± 0.52 0.52 FEV! increased by by aa mean mean of of25 (to L) following following atropine (p<0. 001), but but was was not not altered altered by L) atropine (p<0.001), by placebo (Table 1). 1). Additional Additional resting data are are summasumma(Thble resting data placebo rized in in Table increased the cardiac cardiac fre'Thble 2.2. Atropine Atropine increased the frerized quency (Fc) from from 79 79 ± ± 18 18 to to 88 88 ± ± 19 19 beats beats per per minute minute quency (Fc) (p
Group mean mean data data at at exhaustion exhaustion are summarized summarized in Group are in Table 3. 3. The The "Emax ‘Emax increased by 7 7 percent percent following 'Thble increased by following V02 AT AT REST REST AND AND DURING DURING EXERCISE EXERCISE VOt
1.4
1.2
1.0
.,..
0...0a. C
0.8
f E
.
~
0.'
.~>9
__.. Placebo _Placebo
0.4 FIGURE ‘o, atat rest and at at comparable comparable levels of of work work FIGURE 1.1. VOl rest and levels fOllowing following placebo placebo (closed (closed circles circles and and solid solid line) line) and and (open circles and line). bars atropine atropine (open circles and broken broken line). Vertical Vertical bars represent 11 SE. is as of represent SE. Workload Workload is expressed expressed as aa fraction fraction of the placebo placebo maximum work load. load. VOl Vo, was was lower lower fOllowfollowthe maximum work ing at 0.50 0.75 ing atropine atropine at the the 0.25 0.25 (p<0.025), (p
8
fl_fl *t,opi,e ( : , - 0 Atropine
0.2
Rssl Re"
wallS o0 •• tt.
0.25 0.21
0.50 0.80
0.75 0.78
1.00 1.00
WL.IWLmaam•• WL/WL
Exercise in in Chronic Chronic Airflow Airflow Obstruction Obstruction (Brown et et a/) al) Exen:18e (BIOINI'I
atropine atropine (from (from 52.3±11.5 52.3±1l.5 toto 55.9±10.0 55.9±10.0 L/min, Umin, p
haustion were were not not significantly significantly altered altered with with atropine. atropine. haustion
DISCUSSION DISCUSSION
Atropine Atropine was was an an effective effective bronchodilator bronchodilator inin this this patient patient group, group, resulting resulting inin aa mean mean increase increase inin FEY, FEV! ofof 25 25 percent. percent. Similar Similar degrees degrees ofof improvement improvement have have previously previously been been reported reported inin other other patient patient groups groups with with
of the the drug. drug. !4-11 CAO using using varying varying doses doses of CAO The The major major finding finding ofof the the present present study study isis that that the the
Submaximal Submaximal Exercise Exercise
substantial airway substantial atropine-induced atropine-induced improvement improvement inin airway
The “0” watts The ‘‘2Vo. atat rest rest and and atat "0" watts decreased decreased insignifiinsignificantly "0" watts, watts, cantly with with atropine. atropine. At At all all workloads workloads above above “0”
in capacity. AlAlin the the group group mean mean maximum maximum exercise exercise capacity. though 18 study though nine nine ofof the the 18 study patients patients had had aa higher higher
the VOl was was significantly significantly lower lower following fOllowing atropine atropine (Fig (Fig the Yo, 1). Minute 1). Minute ventilation ventilation was was not not significantly significantly altered altered following (Fig 2). 2). There There was was aa trend trend for fOr aa larger larger following the the drug drug (Fig tidal (VT) and and aa lower lower respiratory respiratory frequency frequency tidal volume volume (YT) (Fr), significant. (Fr), but but these these differences differences were were not not significant. VENTILATION VENTILATION AT AT REST REST AND AND DURING DURING EXERCISE EXERCISE
80 80
50 50
mechanics significant improvement mechanics did did not not result result inin aa significant improvement
maximum fOllOwing atropine, atropine, maximum maximum maximum workload workload following workload was unchanged unchanged inin six six patients patients and and decreased decreased workload was in in three. three. Several for this this discrepancy discrepancy bebeSeveral possible possible reasons reasons for tween be tween mechanics mechanics and and exercise exercise performance performance must must be
considered. (1) (1) ItIt isis possible possible that that the the exercise exercise tolerance tolerance considered. of was limited limited predominantly predominantly by by factors factors of our our patients patients was other other than than ventilatory ventilatory mechanics. mechanics. This This appears appears unlikely 115 unlikely since since the the patients patients achieved achieved aa mean mean ofof 115 percent percent ofof the the FEV,-adjusted FEV!-adjusted predicted predicted ventilation ventilation atat exhaustion,> exhaustion,1I3 and and only only 7575 percent percent ofof the the predicted predicted heart (2) ItItisis possible possible that that aa significant significant increase increase heart rate. rate." (2)
40 40
in in maximum maximum exercise exercise capacity capacity would would have have occurred occurred
;; C
... a. L I.. aI
following fOllowing atropine atropine had had the the increases increases inin power power output output been 15 watts, watts, or or had had the the study study population population been smaller smaller than than 15 been larger. However, such small changes, if seen, seen, been larger. However, such small changes, if
30 30
• S
> >
would significant. (3) (3) Several Several would not not have have been been clinically clinically significant.
20 20
patients mouth, but but this this patients noted noted aa sensation sensation ofof dryness dryness ofofmouth, did did not not appear appear toto account account for for aa decrease decrease inin performperform-
10 10
O+----r---.----,---.----,
ance. ance. A fOr the the discrepancy discrepancy between between A possible possible explanation explanation for improvement improvement in in mechanics mechanics and and inin exercise exercise capacity capacity isis as as follows: follows: Although Although there there was was aa substantial substantial increase increase inin mean mean FEY, FEV! with with atropine, atropine, this this measurement measurement involves involves only In contrast, contrast, breathbreathonly aa single single expiratory expiratory maneuver. maneuver. In
30 30
j E
£•S
••
S n
ee
ing inspiratory and ing during during exercise exercise requires requires both both inspiratory and
20 20
expiratory ventilation. The The mean mean increase increase inin expiratory phases phases ofof ventilation. MYY-a MVV-a maneuver maneuver which which also also requires requires inspiratory inspiratory
10 to
and efforts-was only II percent, only 11 percent, far far short short and expiratory expiratory efforts-was of of the the improvement improvement noted noted inin FEY,. FEV!. One One would would not not
0
expect VEmax toto increase increase by by more more than than the the expect the the YEmax increase increllfe seen seen inin MYY. Mvv. Indeed, Indeed, the the mean mean increase increase inin
1.5 1.5
VEmax VEmax ofof
77 percent percent approximates approximates that that seen seen inin the the
MVY. Mvv. Thus, Thus, itit appears appears that that the the improvement improvement inin sussus:
...
I-
tainable VEmax) may may be be overovertainable ventilatory ventilatory capacity capacity (or (or VEmax)
1.0 1.0
one examines examines only only the the change change inin the the estimated ifif one estimated FEY,. FEV!. We sought to determine whether We sought to determine whether the the nine nine patients patients
aI
0.5 Plac.bo .-Placebo
...-.
-- .... ) Ateepini ~ AtrOltlne
O+----r---.----.---.----, Rest R••t
0O.atta watts
0.25 0.25
0.50 0.50
0.75 0.75
1.00 1.00
WL/WLmaa WL/WL max
FIGURE and pattern FIGURE 2. 2. Minute Minute ventilation ventilation and pattern ofofventilation ventilation atat rest rest and and atat comparable comparable levels levels ofofwork work following lOllowing placebo placebo (closed (closed circles circles and an~ solid solid lines) lines) and and following lOllowing atropine atropine (open (open circles circles and and broken broken lines). lines). VE VE did did not not differ differ significantly signiftcantly under under any any condition condition evaluated. evaluated.
who who appeared appeared toto have have aa greater greater maximum maximum exercise exercise capacity the remaining be distinguished distinguished from from the remaining capacity could could be nine We nine patients patients who who failed failed toto improve improve with with the the drug. drug. We hypothesized hypothesized that that individuals individuals with with the the largest largest inincreases be likely likely toto have have an an improveimprovecreases inin FEY, FEV! would would be ment ment inin exercise exercise capacity, capacity, and and conversely. conversely. However, However, the was the percentage percentage increase increase in in FEY, FEV! with with the the drug drug was CHEST CHEST /1 89 89
Ii11 1 I JANUARY, JANUARY. 1986 1988
99
virtually the two virtually identical identical inin the two groups. groups. Although Although there there was trend for the nonimprovers nonimprovers to have a a lower was aa trend fur the to have lower plapla-
cebo FEV" Mvv, and Vozmax, and and aa smaller increase cebo FEY1, MV\ and Yo,max, smaller increase in MVV with atropine, none of of these these differences differences was was in MVV with atropine, none significant. Similarly, no differences in in any other significant. Similarly, no differences any other patient characteristics (ie, other pulmonary pulmonary function patient characteristics (is, other function measurements, age, etc) could could be be detected detected in in the measurements, age, etc) the two two groups of Thus, groups of patients. patients. Thus, there there was was no no clear clear separation separation of and patients, and of "improving" “improving” and "nonimproving" “nonimproving” patients, and there does not to justification fur there does not appear appear to be be any any justification for furmally separating these groups. Although we we have formally separating these groups. Although have recently shown shown that that repeated repeated exercise exercise testing in recently testing in groups groups of with reproducible,lI5 and of patients patients with CAO CAO is is highly highly reproducible,’8 and the the trend toward improvement the present present study is trend toward improvement in in the study is on variagreater than greater than we we expect expect on the the basis basis of of random random variation, we rule variation as tion, we cannot cannot rule out out random random variation as a partial partial explanation fur improvement in some paexplanation for apparent apparent improvement in some patients. tients. Relatively few studies have the Relatively few previous previous studies have evaluated evaluated the effects of classes of on effects of the the various various classes of bronchodilators bronchodilators on maximum exercise perfurmance in and maximum exercise performance in CAO, CAO, and these these results have results have been been conflicting. conflicting.56’6’8 5.6,16•• The cardiopulmonary cardiopulmonary responses to submaximol sssbmaximal exexThe responses to ercise study At ercise in in the the present present study are are of of interest. interest. At rest rest and and at at the minute ventilation was the "0" “0” watt watt work work load, load, when when minute ventilation was low, were insignificant decreases in low, there there were insignificant decreases in the the VOl Yo, fullowing atropine. However, at workfollowing atropine. However, at all all comparable comparable workloads above unloaded cycling, the decrease decrease in VOl !O, loads above unloaded cycling, the in fullowing atropine was (Fig the following atropine was significant significant (Fig 1). Although Although the work of of breathing breathing was not not measured measured in this this study, study, it it is is work was in reasonable to assume assume that the the improvement improvement in airway airway reasonable to that in mechanics fullowing atropine decreased the mechanics following atropine decreased the oxygen oxygen cost which was as cost of of breathing, breathing, which was then then expressed expressed as a a lower lower overall oxygen cost at at equivalent equivalent levels of external external overall oxygen cost levels of work. These These data are are consistent consistent with a recent recent report work. data with report that that demonstrated demonstrated a decrease decrease in in the the work work of of breathing breathing during in with 'J:1 It during exercise exercise in CAO GAO patients patients with theophylline. theophylline.’7 It is to that endurance is tempting tempting to speculate speculate that beneficial beneficial endurance effects Indeed, a previous effects might might be be seen seen with with atropine. atropine. Indeed, previous investigation has improvement in investigation has shown shown improvement in endurance endurance without an increase increase in maximum maximum exercise capacity folwithout an in exercise capacity following administration of to patient lowing administration of oxygen oxygen to another another patient group. group.’8 IS From this study, study, we concluded concluded that atropine-inatropine-inFrom this we that duced improvement in did duced improvement in airway airway mechanics mechanics did not not sigsignificantly improve the exercise nfficantly improve the group group mean mean maximum maximum exercise capacity of study population. Atropine capacity of the the current current study population. Atropine resulted in significant significant decreases in the the oxygen oxygen requireresulted in decreases in requirement equivalent levels work, ment to to perfurm perform equivalent levels of of submaximal submaximal work, presumably presumably because because of of aa lower lower oxygen oxygen cost cost of of breathbreathing. The The utility utility ofbronchodilating of bronchodilating agents in enhancing enhancing ing. agents in exercise performance in this patient group remains to exercise perfurmance in this patient group remains to be be defined. defined. ACKNOWLEDGMENTS: The authors authors thank Kay Kay Lines Lines and and Karen Karen ACKNOWLEDGMENTS: The thank LoPresti fOr the function tests and LoPresti for perfOrming performing the pulmonary pulmonary function tests and Marian Marian Berman Berman fOr for preparing preparing the the illustrations. illustrations.
10 10
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Bull iopathol Respir 1984; iopathol Respir 1984; 20:361-67 20:361-67 Leitch AG, Morgan Morgan A, Ellis Ellis DA, DA, Bell Bell G, C, Haslett Haslett C, McHardy McHardy AG, A, C, 77 Leitch GJR. Effect Effect of of oral oral salbutamol salbutamol and slow-release slow-release ammnophyllmne on and aminophylline on GJR. exercise tolerance in chronic chronic bronchitis. Thorax 1981; 36:787-89 36:787-89 exercise tolerance in bronchitis. Thorax 1981; 88 Leitch AG, JM, S, GJR. Leitch AG, Hopkin Hopkin JM, Ellis Ellis DA, DA, Merchant Merchant S. McHardy McHardy GJR. The effect effect of aerosol aerosol ipratropium bromide and salbutamol salbutamol on The of ipratropium bromide and on exercise tolerance in bronchitis. Thorax 1978; exercise tolerance in chronic chronic bronchitis. Thorax 1978; 33:711-13 33:711-13 Connellan SJ, Gough Gough SE. SE. The The effects effects of of nebulized nebulized salbutamol on 99 Connellan SJ, salbutamolon lung and tolerance in with aiJ'o lung function function and exercise exercise tolerance in patients patients with severe severe airflow obstruction. obstruction. Br J Dis Dis Chest Chest 1982; 76:135-42 76:135-42 flow Br 1982; 10 Knudson Knudson RJ, Slatin Slatin RC, RC, Lebowitz Lebowitz MD, Burrows Burrows B. The The maximal maximal 10 RJ, MD, B. expiratory flow-volume curve: normal standards, variability, and expiratory flow-wlume curve: normal standards, variability, and effects of age. age. Am Rev Rev Respir Respir Dis 1976; 1976; 113:587-600 effects of Am Dis 113:587-600 11 Cotes Cotes JE, Hall Hall AM. AM. The The transfer transfer factor fOr for the the lung; lung; normal 11 JE, fuctor normal values in adults. adults. In: Normal Normal values for respiratory respiratory function in values in In: values fOr function in man, Arcangeli Arcangeli ed. Torino, Torino, Italy: Panminerva Panminerva Med, 1970:3271970:327P, ed. Italy: Med, man, 43 43 12 12 Brown Brown SE, SE, Wiener WienerS, S, Brown Brown RA, BA, Marcarelli Marcarelli PA, PA, Ught Light RW, RW. Exe Exer- ... cise perfOrmance performance following carbohydrate load in in chronic chronic airflow cise fOllowing a carbohydrate load airflow obstruction. AppI Physioll985; Physiol 1985; 58:1340-46 58:1340-46 obstruction. J Appl 13 Otis Otis AB. AB. Quantitative Quantitative relationships in steady-state steady-state gas exchange. exchange. relationships in gas 13 In: Handbook Handbook of physiology. physiology. Respiration. Washington, DC: In: of Respiration. Washington, DC: American Physiological Society, vol 1, 1, chap chap 27, 27, 1964:681-98 1964:681-98 American Physiological Society, wI 14 Klock Klock LE, LE, Miller Miller TD, TD, Morris Morris AH, Watanabe Watanabe S. Dickman Dickman M. A A 14 AH, S, M. comparative study of atropine atropine sulfate and isoproterenol isoproterenol hydrocomparative study of suHBte and hydrochloride in chronic chronic bronchitis. Am Rev Rev Respir Respir Dis 1975; 1975; chloride in bronchitis. Am Dis 112:371-76 112:371-76 15 Marini Marini JJ, Lakshminarayan Lakshmmnarayan S. The The effect effect of of atropine atropine inhalation in 15 JJ, S. inhalation in ‘irreversible” chronic "irreversible" chronic bronchitis. bronchitis. Chest Chest 1980; 1980; 77:591-96 77:591-96 16 Tobin Tobin MJ, MJ, Hughes Hughes JA, Hutchison Hutchison DCS. Effects of ipratropium ipratropium JA, DCS. Effects of 16 bromide and fenoterol fenoterol aerosols on exercise exercise tolerance. Eur J Eur bromide and aerosols on tolerance. Respir Dis 1984; 1984; 65:441-46 65:441-46 Respir Dis 17 Gross Cross NJ, Skorodin Skorodin MS. Role Role of of the the parasympathetic parasympathetic system in 17 NJ, MS. system in airway obstruction due to to emphysema. emphysema. N Eng} Engl JJ Med Med 1984; 1984; 311: 311: airway obstruction due N 421-25 421-25 18 Gross Gross NJ, NJ, Skorodin Skorodin MS. Anticholinergic, Anticholinergic, antimuscarmnic bron18 MS. antimuscarinic bronchodilators. Am Rev Rev Respir Respir Dis 1984; 1984; 129:856-70 129:856-70 chodilators. Am Dis 19 Pak Pak CCF, CCF, Kradjan Kradjan WA, Lakshminarayan Lakshminarayan 5, Marini Marmni JJ. JJ. Inhaled Inhaled 19 WA, S, atropine sulfate: dose-response characteristics in adult adult patients patients atropine suHBte: dose-response characteristics in with chronic chronic airflow obstruction. Am Rev Rev Respir Respir Dis Dis 1982; 1982; 331331with airflow obstruction. Am 34 34 20 Kradjan Kradjan WA, Lakshminarayan Lakshminarayan S, Hayden Hayden PW, Larson Larson SW, M Mar20 WA, S, pw, Sw, .... mi JJ. Serum Serum atropine concentrations after inhalation inhalation of atropine atropine ini atropine concentrations after of sulfate. Am Rev Rev Respir Respir Dis Dis 1981; 1981; 123:471-72 123:471-72 sulfate. Am 21 Cavanaugh Cavanaugh MJ, Cooper Cooper DM. Inhaled atropine sulfate: dose MJ, OM. Inhaled atropine suHBte: dose 21 response characteristics. Am Rev Rev Respir Respir Dis 1976; 1976; 114:517-24 114:517-24 response characteristics. Am Dis 22 Larsen Larsen CL, Barron Barron RJ, CoHon Cotton EK, Brooks Brooks JG. JC. A A comparative comparative RJ, EK, 22 GL,
Exercise In In ChIOnIc Chronic AIrflow Airflow 0bIIructIan Obstruction (Brown et eta!) ExercIse (Blown eI)
23 23
24 24 25 25
26 26
study ofinhaled of inhaled atropine sulfate and hydrochloride study abopine suH8te and isoproterenol isoproterenol hydrochloride in cystic cystic fibrosis. Am Rev Rev Respir Dis 1979; 1979; 119:399-407 fibrosis. Am Bespir Dis 119:399-407 in Spiro SC, Hahn Hahn HL, HL, Edwards Edwards RH1 Pride NB. analysis of the the Spiro SG, lUI'I: Pride NB. An An analysis of physiological strain of submaDmal submaximal exercise in patients with physiological strain of exercise in patients with chronic obstructive bronchitis. Thorax 1975; 30:415-24 1975; 30:415-24· chronic obstructive bronchitis. 'Ihoru Jones NL, Campbell EJM. Clinical exercise testing, 2nd ed. ed. Jones NL, Campbell EJM. Clinical exercise testing, 2nd Philadelphia: WB Saunders, 1982 Philadelphia: WB Saunders, 1982 Brown SE, Fischer Fischer CE, Stansbury Stansbury DW, Light RW. ReproduciReproduciBrown SE, CE, Ow, Light Rw. bility of Vo,max in patients with chronic chronic air-flow obstruction. obstruction. Am aiP-flow Am bility ofVo.max in patients with Rev Bespir Respir Dis 1985; 1985; 131:435-38 131:435-38 Rev Dis Mahler DA, Matthay BA, Snyder Snyder PE, Wells Wells CK, CK, Loke Loke J. J. SusSusMahler OA, Matthay RA, PE,
tamed-release theophylline reduces dyspnea dyspnea in in nonreversible nonreversible tained-release theophylline reduces obstructive airway disease. Am Rev Rev Respir 1985; 131:22-25 131:22-25 obstructive airway disease. Am Bespir Dis Dis 1985; 27 Jenne JW, Siever Siever JR, Druz WS, Solano JV, Cohen Cohen SM, SM, Sharp Sharp JT. JT. 27 Jenne]\v, J8, Oruz WS, Solano]v, The effect effect of theophylhne therapy The of maintenance maintenance theophylline therapy on on lung lung wnrk work inin severe chronic obstructive pulmonary disease while standing standing and and disease while severe chronic obstructive pulmonary walldng. Am Rev Rev Bespir Respir Dis Dis 1984; 1984; 130:600-05 130:600-05 walking. Am 28 Bye Bye FfP, FTP, Anderson Anderson SD, Woolcock Woolcock AJ, Young IH, Alison JA. BiBi28 SO, AJ, Young IB, Alison]A. cycle endurance performance of patients with interstitial interstitial lung cycle endurance perfurmance of patients with lung disease air and oxygen. Am Rev Respir Dis 1982; 1982; 126: 126: disease breathing breathing air and oxygen. Am Rev Respir Dis 1005-12 1005-12
Critical Care Care Medicine Medicine Update Update 1986 1986 Critical The Johns Johns Hopkins Institutions will present present this course course at at The Johns Hopkins Hopkins Medical The Hopkins Medical Medical Institutions will this The Johns Medical Institutions, Baltimore, March 24-27. information, contact Catherine Sentrnan, 24-27. For For information, contact Ms. Ms. Catherine Sentman, Institutions, Baltimore, March Program Coordinator, Turner 720 Rutland Rutland Avenue, Baltimore 21205 (301:955-6046). Program CoordinatOJ; Thrner 22, 22, 700 Avenue, Baltimore 2l205 (301:955-6046).
Annual Meeting, Meeting, Neurovascular Neurovascular Society of North Annual Society of North America and Society for Neurovascular Neurovascular Surgery AmerIca and SOciety for Surgery The third third annual annual meeting of the NSNA/SNVS held in in Chicago, April 17-19. 17-19. Deadline Deadline The meeting of the NSNAlSNVS will will be be held Chicago, April lbr abstracts is January 31. For For further inIbrmation, contact The Program Program Chairman, Chairman, NVSNAJ fOr abstracts is January 31. further information, contact The NVSNAI SNVS, Box Box 679, Oak Park, IL 60302 SNVS, 679, Oak Park, IL 60302 (312:482-3950). (312:482-3950).
CHEST I/ 88 89 IIl 1 I/ JANUARY, JANUARY, 1986 CHEST 1888
11
Chronic Airflow Airflow Obstruction* Obstruction* Chronic Effects Effects of of Inhaled Inhaled Atropine Atropine Sulfate Sulfate Stephen Stephen E. E. Brown, Brown, M.D., M.D., FC.C.P.; F.C.C.p.; Richard Richard S. Prager, M.D.; M.D.; Richard Richard A. A Shinto, Shinto, M.D.; M.D.; Claudia Claudia E. E. Fischer, M.D.; M.D.; David W. Stansbury, Stansbury, M.D.; M.D.; and and Richard Richard WW. Light, M.D., M.D., F.C.C.? F.C.C.P. David W.
The The purpose purpose of of this this study study was was to to evaluate evaluate the the effects effects of of inhaled inhaled atropine atropine sulfate sulfate on on the the exercise exercise capacity capacity and and cardiocardiopulmonary pulmonary responses responses to to exercise exercise inin patients patients with with chronic chronic airflow airftow obstruction obstruction (CAO). (CAO~ Eighteen Eighteen patients patients underwent underwent duplicate (15 watts/mm) watts/min) maximal mavmal cycle cycle ergomeergomeduplicate incremental incremental (15 ter 60 minutes ter exercise exercise tests tests 60 minutes after after either either inhaled inhaled atropine atropine (0.075 (0.075 mg/kg) mglkg) or or placebo, placebo, in in double double blind blind randomized randomized fashion fashion on on consecutive consecutive days. days. Bronchodilator Bronchodilator medications medications were Spirograms were were withheld withheld before before each each study. study. Spirograms were obtained obtained before before and and 60 60 minutes minutes after after each each aerosol aerosol treatment. treatment. AtroAtropine 1.37 ±± 0.49 pine increased increased the the FEy, FEV. by by 25 25 percent, percent, from from 1.37 0.49 to to 1.71±0.52 1.71±0.52 LL (p
Nlost ost patients with chronic airflow obstruction M (CAO) have limited exercise tolerance and compatients
(CAO)
have
with
limited
chronic
exercise
airflow
tolerance
obstruction
and com-
plain generally accepted accepted plain of of exertional exertional dyspnea. dyspnea. ItIt isis generally that these patients limited that the the exercise exercise tolerance tolerance ofof these patients isis limited predominantly of ventilatory ventilatory mechanmechanpredominantly by by impairment impairment of
the the ventilation ventilation at at exhaustion exhaustion (VEmax) (VEma) increased increased signifisigni&candy cantly (from (from 52.3±11.5 52.3 ± 1l.5 to to 55.9±10.0 55.9 ± 10.0 Lfmin, Umin, P<0.05) P
These These individuals individuals had had no no known known left left ventricular ventricular disease, disease, glaucoma, glaucoma, prostatic prostatic
hypertrophy, hypertrophy, or or other other disorders disorders which which would would preclude preclude
maximal maximal exercise exercise testing. testing. Characteristics Characteristics ofofthese these patients patients (receiving (receiving
bronchodilator therapy) therapy) were were defined de6ned on on aa preliminary preliminary screening screening day day bronchodilator as as follows: tollows: age, age, 62±6 62±6 yrs; yrs; wt, wt, 76.1±15.2 76.l±15.2 kg; kg; FEy,, FEV.. 1.56±0.41 l.56±O.41 L; L; FVC, FVC, 3.24±0.87 3.24±0.S7 L; L; FEV,/FVC, FEV/FYC, 0.48±0.08; 0.4B±0.08; TLC, TLC, 124±20% 124±2O% prepre-
ics.’4 Although bronchodilators bronchodilators have have become become aa mainmainics. l -4 Although
dicted; BY, 218±72% 2l8±72'11 predicted; predicted; and and dicted; FRC, FRC, 191±41% 191±41'll predicted; predicted; RV,
stay CAO, few studies have few studies have assessed assessed stay inin the the treatment treatment ofofCAO,
Dco, Dco, 58 58 ±± 22% 22'11 predicted. predicted.
the these drugs drugs on on exercise exercise performance performance inin the effects effects ofof these
this studies have this patient patient group. group. Results Results of of previous previous studies have
Pulnwnary Pulmon4ry Function Function Tests Tests
a
seal
Spirometric 12 LL dry Spirometric measurements measurements were were made made with with a 12 dry rolling rolling seal
been con8icting.5-8 We We are are unaware unaware of of any any previous previous been conflicting.9 studies inhaled studies which which have have reported reported the the effects effects ofof inhaled
spirometer spirometer (CPI (CPI 221). 221). Lung Lung volumes volumes were were measured measured by by body body
atropine atropine on on cycle cycle ergometer ergometer exercise exercise performance performance inin
was was measured measured by by the the single-breath single-breath method. method. The The normal normal values values ofof
these was toto these patients. patients. The The purpose purpose ofofthe the present present study study was determine with aeroaerodetermine whether whether increasing increasing the the FEY, FEV1 with
voluntary voluntary ventilation ventilation was was performed perfOrmed for tor ten ten seconds seconds and and extrapoextrapo-
solized solized atropine atropine sulfate sulfate would would alter alter the the cardiopulmocardiopulmonary nary responses responses toto exercise exercise and/or and/or improve improve maximum maximum exercise CAO patients. patients. exercise performance performance inin CAO
plethysmography. plethysmography. The The diffusing diffusing capacity capacity ofof the the lung lung for tor CO CO (Dco) (Dco)
Knudson Knudson etet al’#{176} allO and and Cotes Cotes and and Hall” Hallu were were utilized. utilized. Maximum Maximum lated lated toto L/min, Umin, BTPS. BTPS.
Study Study Design Design Testing Testing was was performed perfOrmed inin aa randomized randomized double double blind blind crossover crossover fashion. each study, study, theophylline theophylline was was withheld withheld for tor 12 12 hours hours tashion. Prior Prior toto each
MATERIALS MATERIALS AND AND METHODS METHODS Patient lbtient Population PopultJtion Eighteen Eighteen subjects subjects with with moderate moderate toto severe severe CAO CAO were were evaluated. evaluated.
and and inhaled inhaled beta-adrenergic beta-adrenergic agents agents were were held held for tor six six hours. hours. Patients Patients gave gave their their written written informed infOrmed consent. consent. AA baseline baseline spirogram spirogram was was
performed was administered. perfOrmed and and the the aerosol aerosol treatment beatment was administered. On On one one study study day, day, the the aerosol aerosol treatment beatment consisted consisted ofof atropine atropine sulfate sulfide (0.075 (0.075 mg/kg) mWkg) administered administered inin aa concentration concentration ofofl1 mg/mI mglml via via an an aerosol aerosol T” 'T'
*From *From the the Department Department ofofMedicine, Medicine, Veterans Veterans Administration Administration MediMedi-
cal cal Center, Center, Long Long Beach, Beach, and and the the University University ofof California, California, Irvine. Irvine. This This study study was was supported supported by by the the VA VA Research Research Service. Service. Manuscript Manuscript received received May May 27; 27; revision revision accepted accepted July July 23. 23. Reprint lIeprint requests: requests: Dr Dr. Brown, Brown, VA VA Medical Medical Center, Center; liP, 111p, 5901 5901 East East 7th 7th Street, Street, Long Long Beach Beach 90822 908J2
medication medication nebulizer. nebulizer. Nebulization Nebulization was was continuous continuous and and was was not not timed occur only only during during inspiration. inspiration. On On the the other other day, day, an an equal equal timed toto occur volume volume ofof saline saline (placebo) (Placebo) was was used. used. One One hour hour following tollowing treatment, treatment, spirograms spirograms were were repeated. repeated. Thereafter, Thereafter, exercise exercise testing testing was was carried carried out. out.
CHEST II 89 89 IIl 1 II JANUARY, JANUARY, 1888 CHEST 1986
77
After
Table Table 1-Spirograms l-Spirograma Before Before and and After Atropine Atropine and and Placebo Placebo (n18, (n=18, mean±SD)* mean±SD)*
Table =18, Table 3-Maximum 3-Mtaimum Exercise E:rerciae Data Data (n(n=18,
Placebo Placebo
Atropine Atropine
1.35± 0.48 1.35±0.48
1.39± 0.44 1.39±0.44
60 60 mm min Postaerosol Postaerosol
Placebo Placebo
Atropine Atropine
1.37±0.49 0.49 1.71±0.52* 1.37± 1. 71± 0.52· FVC,L 2.89±0.74 2.89±0.74 2.98±0.69 2.98±0.69 3.07±0.81 3.07±0.81 3.65±0.89* 3.65±0.89· FYC, L 58.4±18.4# 51.2± 10.9 Mvv, L/min Umin 51.2± 10.9 58.4± 18.4# MV\ FEY1, FEV" LL
p
placebo and and atropine. atropine. placebo
YE, VE,
Llmin BTPS Umin BTPS VT, L BTPS VT, L BTPS Fb, breaths/min Fb, breaths/mm Io,, L/min STPD Vo., Umin STPD Veo., Vco,, Umin L/min STPD STPD rr VE/VO, VElVo. VE/VCO, VElVco.
O.-Pulse, mllbeat 0,-Pulse, mI/beat
Fc, Fc, beats/mm beats/min
VE
VE max, max, L/min Umin BTPS BTPS VT VT max, max, LL BTPS BTPS
Fb, Fb, breaths/mm breaths/min
Va. max, max, Limin Umin STPD STPD STPD Vco. max, max, L/min Umin STPD
VO, rr
VElVo. VE/VCO, VElVco. VE/VO,
Table 2-Resting 2-Re3ting Data Data (n (n =18, mean ± SD) Table 18, mean ± SD)
Fc, Fc, beats/mm beats/min
Workload, watts Workload, watts
0,-Pulse, O.-Pulse, mI/beat mllbeat
Placebo Placebo
Atropine Atropine
79±18 79±18
88±19 p<0.025 88±19 p
14.7±3.0 14.7±3.0 0.63±0.12 0.63±0.12 20±3 20±3 0.327±0.065 0.327±0.065 0.265±0.049 0.265±0.049 0.81±0.06 0.81±0.06 45.2±4.9 45.2±4.9 55.8±6.1 55.8±6.1 4.27±0.96 4.27±0.96
Maximal Exerci8e Tests Maximal Exercise Tests
Exercise testing was on cycle Exercise testing was perfurmed performed on an an electrically-braked electrically-braked cycle previously described by this ergometer in similar to ergometer in a a manner manner similar to that that previously described by this laboratory. resting measurements, patients pedaled at laboratory.”2 UI Following Following resting measurements, patients pedaled at fOr one one minute; minute; the the workload was "0" watts watts (unloaded (unloaded cycling) cycling) for workload was subsequently increased by until subsequently increased by 15 15 watts watts each each minute minute until the the patient patient became exhausted. Expired volume (YE) was measured with (VE) was measured with aa became exhausted. Expired volume turbine. Analysis of the mixed expired fractions of oxygen oxygen (FEO,) turbine. Analysis of the mixed expired fractions of (FEO.) was with gas gas analyzers. and dioxide (FECO.) and carbon carbon dioxide (FECO,) was perfurmed performed with analyzers. fOr measurements were Standard calculations Standard calculations for metabolic metabolic measurements were utilized.13 utilized.0
Statistical Analysis Statistical Analysis Data were were analyzed analyzed at rest rest and and at at maximum maximum exercise following Data at exercise fOllowing placebo and In comparisons fOr meaplacebo and atropine. atropine. In addition, addition, comparisons for selected selected measurements were also also made made at at equivalent equivalent work loads, loads, corresponding surements were work corresponding
95±28 95±2B 126± 12 126±12 52.3± 11.5 52.3±1l.5 1.45± 0.36 1.45±0.36 34±6 34±6 1.36±0.30 l.36±O.30 1.22±0.36 l.22±O.36 0.97±0.12 0.97±0.12 40.5± 8.3 40.5±8.3 42.4±8.6 42.4±8.6 10.98±2.62 10.98±2.62
SD) SD)
Atropine Atropine
Placebo Placebo
Preaerosol Preaerosol
mean mean ±±
101± 19 101±19 131±23 131±23 55.9±10.0 55.9±10.0
p<0.05 p
1.52± 0.27 1.52±0.27 35±6 35±6 1.33±0.21 1.33±O.21 1.36±0.27 1.36±O.27 1.02±0.09 1.02±0.09 43.9±6.4 43.9±6.4 p
to approximately 25 100 to approximately 25 percent, percent, 50 50 percent, percent, 75 75 percent, percent, and and 100 percent of the work load. were analyzed percent of the placebo placebo maximum maximum work load. Data Data were analyzed using Student’s paired t-test. A value of p
Resting Data Resting Data
The The preaerosol preaerosol FEV! FEY, values values on on the the placebo placebo and and atropine days did did not not differ differ significantly significantly (Table 1). 1). The (Thble The atropine days FEY, increased 25 percent percent (to 1. 1.71± 71± 0.52 0.52 FEV! increased by by aa mean mean of of25 (to L) following following atropine (p<0. 001), but but was was not not altered altered by L) atropine (p<0.001), by placebo (Table 1). 1). Additional Additional resting data are are summasumma(Thble resting data placebo rized in in Table increased the cardiac cardiac fre'Thble 2.2. Atropine Atropine increased the frerized quency (Fc) from from 79 79 ± ± 18 18 to to 88 88 ± ± 19 19 beats beats per per minute minute quency (Fc) (p
Group mean mean data data at at exhaustion exhaustion are summarized summarized in Group are in Table 3. 3. The The "Emax ‘Emax increased by 7 7 percent percent following 'Thble increased by following V02 AT AT REST REST AND AND DURING DURING EXERCISE EXERCISE VOt
1.4
1.2
1.0
.,..
0...0a. C
0.8
f E
.
~
0.'
.~>9
__.. Placebo _Placebo
0.4 FIGURE ‘o, atat rest and at at comparable comparable levels of of work work FIGURE 1.1. VOl rest and levels fOllowing following placebo placebo (closed (closed circles circles and and solid solid line) line) and and (open circles and line). bars atropine atropine (open circles and broken broken line). Vertical Vertical bars represent 11 SE. is as of represent SE. Workload Workload is expressed expressed as aa fraction fraction of the placebo placebo maximum work load. load. VOl Vo, was was lower lower fOllowfollowthe maximum work ing at 0.50 0.75 ing atropine atropine at the the 0.25 0.25 (p<0.025), (p
8
fl_fl *t,opi,e ( : , - 0 Atropine
0.2
Rssl Re"
wallS o0 •• tt.
0.25 0.21
0.50 0.80
0.75 0.78
1.00 1.00
WL.IWLmaam•• WL/WL
Exercise in in Chronic Chronic Airflow Airflow Obstruction Obstruction (Brown et et a/) al) Exen:18e (BIOINI'I
atropine atropine (from (from 52.3±11.5 52.3±1l.5 toto 55.9±10.0 55.9±10.0 L/min, Umin, p
haustion were were not not significantly significantly altered altered with with atropine. atropine. haustion
DISCUSSION DISCUSSION
Atropine Atropine was was an an effective effective bronchodilator bronchodilator inin this this patient patient group, group, resulting resulting inin aa mean mean increase increase inin FEY, FEV! ofof 25 25 percent. percent. Similar Similar degrees degrees ofof improvement improvement have have previously previously been been reported reported inin other other patient patient groups groups with with
of the the drug. drug. !4-11 CAO using using varying varying doses doses of CAO The The major major finding finding ofof the the present present study study isis that that the the
Submaximal Submaximal Exercise Exercise
substantial airway substantial atropine-induced atropine-induced improvement improvement inin airway
The “0” watts The ‘‘2Vo. atat rest rest and and atat "0" watts decreased decreased insignifiinsignificantly "0" watts, watts, cantly with with atropine. atropine. At At all all workloads workloads above above “0”
in capacity. AlAlin the the group group mean mean maximum maximum exercise exercise capacity. though 18 study though nine nine ofof the the 18 study patients patients had had aa higher higher
the VOl was was significantly significantly lower lower following fOllowing atropine atropine (Fig (Fig the Yo, 1). Minute 1). Minute ventilation ventilation was was not not significantly significantly altered altered following (Fig 2). 2). There There was was aa trend trend for fOr aa larger larger following the the drug drug (Fig tidal (VT) and and aa lower lower respiratory respiratory frequency frequency tidal volume volume (YT) (Fr), significant. (Fr), but but these these differences differences were were not not significant. VENTILATION VENTILATION AT AT REST REST AND AND DURING DURING EXERCISE EXERCISE
80 80
50 50
mechanics significant improvement mechanics did did not not result result inin aa significant improvement
maximum fOllOwing atropine, atropine, maximum maximum maximum workload workload following workload was unchanged unchanged inin six six patients patients and and decreased decreased workload was in in three. three. Several for this this discrepancy discrepancy bebeSeveral possible possible reasons reasons for tween be tween mechanics mechanics and and exercise exercise performance performance must must be
considered. (1) (1) ItIt isis possible possible that that the the exercise exercise tolerance tolerance considered. of was limited limited predominantly predominantly by by factors factors of our our patients patients was other other than than ventilatory ventilatory mechanics. mechanics. This This appears appears unlikely 115 unlikely since since the the patients patients achieved achieved aa mean mean ofof 115 percent percent ofof the the FEV,-adjusted FEV!-adjusted predicted predicted ventilation ventilation atat exhaustion,> exhaustion,1I3 and and only only 7575 percent percent ofof the the predicted predicted heart (2) ItItisis possible possible that that aa significant significant increase increase heart rate. rate." (2)
40 40
in in maximum maximum exercise exercise capacity capacity would would have have occurred occurred
;; C
... a. L I.. aI
following fOllowing atropine atropine had had the the increases increases inin power power output output been 15 watts, watts, or or had had the the study study population population been smaller smaller than than 15 been larger. However, such small changes, if seen, seen, been larger. However, such small changes, if
30 30
• S
> >
would significant. (3) (3) Several Several would not not have have been been clinically clinically significant.
20 20
patients mouth, but but this this patients noted noted aa sensation sensation ofof dryness dryness ofofmouth, did did not not appear appear toto account account for for aa decrease decrease inin performperform-
10 10
O+----r---.----,---.----,
ance. ance. A fOr the the discrepancy discrepancy between between A possible possible explanation explanation for improvement improvement in in mechanics mechanics and and inin exercise exercise capacity capacity isis as as follows: follows: Although Although there there was was aa substantial substantial increase increase inin mean mean FEY, FEV! with with atropine, atropine, this this measurement measurement involves involves only In contrast, contrast, breathbreathonly aa single single expiratory expiratory maneuver. maneuver. In
30 30
j E
£•S
••
S n
ee
ing inspiratory and ing during during exercise exercise requires requires both both inspiratory and
20 20
expiratory ventilation. The The mean mean increase increase inin expiratory phases phases ofof ventilation. MYY-a MVV-a maneuver maneuver which which also also requires requires inspiratory inspiratory
10 to
and efforts-was only II percent, only 11 percent, far far short short and expiratory expiratory efforts-was of of the the improvement improvement noted noted inin FEY,. FEV!. One One would would not not
0
expect VEmax toto increase increase by by more more than than the the expect the the YEmax increase increllfe seen seen inin MYY. Mvv. Indeed, Indeed, the the mean mean increase increase inin
1.5 1.5
VEmax VEmax ofof
77 percent percent approximates approximates that that seen seen inin the the
MVY. Mvv. Thus, Thus, itit appears appears that that the the improvement improvement inin sussus:
...
I-
tainable VEmax) may may be be overovertainable ventilatory ventilatory capacity capacity (or (or VEmax)
1.0 1.0
one examines examines only only the the change change inin the the estimated ifif one estimated FEY,. FEV!. We sought to determine whether We sought to determine whether the the nine nine patients patients
aI
0.5 Plac.bo .-Placebo
...-.
-- .... ) Ateepini ~ AtrOltlne
O+----r---.----.---.----, Rest R••t
0O.atta watts
0.25 0.25
0.50 0.50
0.75 0.75
1.00 1.00
WL/WLmaa WL/WL max
FIGURE and pattern FIGURE 2. 2. Minute Minute ventilation ventilation and pattern ofofventilation ventilation atat rest rest and and atat comparable comparable levels levels ofofwork work following lOllowing placebo placebo (closed (closed circles circles and an~ solid solid lines) lines) and and following lOllowing atropine atropine (open (open circles circles and and broken broken lines). lines). VE VE did did not not differ differ significantly signiftcantly under under any any condition condition evaluated. evaluated.
who who appeared appeared toto have have aa greater greater maximum maximum exercise exercise capacity the remaining be distinguished distinguished from from the remaining capacity could could be nine We nine patients patients who who failed failed toto improve improve with with the the drug. drug. We hypothesized hypothesized that that individuals individuals with with the the largest largest inincreases be likely likely toto have have an an improveimprovecreases inin FEY, FEV! would would be ment ment inin exercise exercise capacity, capacity, and and conversely. conversely. However, However, the was the percentage percentage increase increase in in FEY, FEV! with with the the drug drug was CHEST CHEST /1 89 89
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virtually the two virtually identical identical inin the two groups. groups. Although Although there there was trend for the nonimprovers nonimprovers to have a a lower was aa trend fur the to have lower plapla-
cebo FEV" Mvv, and Vozmax, and and aa smaller increase cebo FEY1, MV\ and Yo,max, smaller increase in MVV with atropine, none of of these these differences differences was was in MVV with atropine, none significant. Similarly, no differences in in any other significant. Similarly, no differences any other patient characteristics (ie, other pulmonary pulmonary function patient characteristics (is, other function measurements, age, etc) could could be be detected detected in in the measurements, age, etc) the two two groups of Thus, groups of patients. patients. Thus, there there was was no no clear clear separation separation of and patients, and of "improving" “improving” and "nonimproving" “nonimproving” patients, and there does not to justification fur there does not appear appear to be be any any justification for furmally separating these groups. Although we we have formally separating these groups. Although have recently shown shown that that repeated repeated exercise exercise testing in recently testing in groups groups of with reproducible,lI5 and of patients patients with CAO CAO is is highly highly reproducible,’8 and the the trend toward improvement the present present study is trend toward improvement in in the study is on variagreater than greater than we we expect expect on the the basis basis of of random random variation, we rule variation as tion, we cannot cannot rule out out random random variation as a partial partial explanation fur improvement in some paexplanation for apparent apparent improvement in some patients. tients. Relatively few studies have the Relatively few previous previous studies have evaluated evaluated the effects of classes of on effects of the the various various classes of bronchodilators bronchodilators on maximum exercise perfurmance in and maximum exercise performance in CAO, CAO, and these these results have results have been been conflicting. conflicting.56’6’8 5.6,16•• The cardiopulmonary cardiopulmonary responses to submaximol sssbmaximal exexThe responses to ercise study At ercise in in the the present present study are are of of interest. interest. At rest rest and and at at the minute ventilation was the "0" “0” watt watt work work load, load, when when minute ventilation was low, were insignificant decreases in low, there there were insignificant decreases in the the VOl Yo, fullowing atropine. However, at workfollowing atropine. However, at all all comparable comparable workloads above unloaded cycling, the decrease decrease in VOl !O, loads above unloaded cycling, the in fullowing atropine was (Fig the following atropine was significant significant (Fig 1). Although Although the work of of breathing breathing was not not measured measured in this this study, study, it it is is work was in reasonable to assume assume that the the improvement improvement in airway airway reasonable to that in mechanics fullowing atropine decreased the mechanics following atropine decreased the oxygen oxygen cost which was as cost of of breathing, breathing, which was then then expressed expressed as a a lower lower overall oxygen cost at at equivalent equivalent levels of external external overall oxygen cost levels of work. These These data are are consistent consistent with a recent recent report work. data with report that that demonstrated demonstrated a decrease decrease in in the the work work of of breathing breathing during in with 'J:1 It during exercise exercise in CAO GAO patients patients with theophylline. theophylline.’7 It is to that endurance is tempting tempting to speculate speculate that beneficial beneficial endurance effects Indeed, a previous effects might might be be seen seen with with atropine. atropine. Indeed, previous investigation has improvement in investigation has shown shown improvement in endurance endurance without an increase increase in maximum maximum exercise capacity folwithout an in exercise capacity following administration of to patient lowing administration of oxygen oxygen to another another patient group. group.’8 IS From this study, study, we concluded concluded that atropine-inatropine-inFrom this we that duced improvement in did duced improvement in airway airway mechanics mechanics did not not sigsignificantly improve the exercise nfficantly improve the group group mean mean maximum maximum exercise capacity of study population. Atropine capacity of the the current current study population. Atropine resulted in significant significant decreases in the the oxygen oxygen requireresulted in decreases in requirement equivalent levels work, ment to to perfurm perform equivalent levels of of submaximal submaximal work, presumably presumably because because of of aa lower lower oxygen oxygen cost cost of of breathbreathing. The The utility utility ofbronchodilating of bronchodilating agents in enhancing enhancing ing. agents in exercise performance in this patient group remains to exercise perfurmance in this patient group remains to be be defined. defined. ACKNOWLEDGMENTS: The authors authors thank Kay Kay Lines Lines and and Karen Karen ACKNOWLEDGMENTS: The thank LoPresti fOr the function tests and LoPresti for perfOrming performing the pulmonary pulmonary function tests and Marian Marian Berman Berman fOr for preparing preparing the the illustrations. illustrations.
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Critical Care Care Medicine Medicine Update Update 1986 1986 Critical The Johns Johns Hopkins Institutions will present present this course course at at The Johns Hopkins Hopkins Medical The Hopkins Medical Medical Institutions will this The Johns Medical Institutions, Baltimore, March 24-27. information, contact Catherine Sentrnan, 24-27. For For information, contact Ms. Ms. Catherine Sentman, Institutions, Baltimore, March Program Coordinator, Turner 720 Rutland Rutland Avenue, Baltimore 21205 (301:955-6046). Program CoordinatOJ; Thrner 22, 22, 700 Avenue, Baltimore 2l205 (301:955-6046).
Annual Meeting, Meeting, Neurovascular Neurovascular Society of North Annual Society of North America and Society for Neurovascular Neurovascular Surgery AmerIca and SOciety for Surgery The third third annual annual meeting of the NSNA/SNVS held in in Chicago, April 17-19. 17-19. Deadline Deadline The meeting of the NSNAlSNVS will will be be held Chicago, April lbr abstracts is January 31. For For further inIbrmation, contact The Program Program Chairman, Chairman, NVSNAJ fOr abstracts is January 31. further information, contact The NVSNAI SNVS, Box Box 679, Oak Park, IL 60302 SNVS, 679, Oak Park, IL 60302 (312:482-3950). (312:482-3950).
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