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The asthmatic athlete: metabolic and ventilatory responses during exercise with and without pre-exercise.. Ienna, Tiziana Mona 1994-12-31

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THE ASTHMATICATHLETE: METABOLICAND VENTILATORYRESPONSESDURING EXERCISEWITH AND WITHOUTPRE-EXERCISEMEDICATIONByTIZIANA MONA IENNAA THESIS SUBMrTTEDIN PARTIAL FULFILLMENTOF THEREQUIREMENTSFOR THE DEGREEOF MASTER OFSCIENCEinTHE FACULTYOF GRADUATESTUDIESSchool of HumanKineticsWe accept thisthesis as conformingto the requiredstandardTIlE UNiVERSiTYOF BRITISH COLUMBIAMay 1994© Tizana M. lenna,1994In presenting this thesisin partial fulfilmentof the requirementsfor an advanceddegree at the University ofBritish Columbia,I agree thatthe Libraryshall make itfreely available for referenceand study. Ifurther agree thatpermission forextensivecopying of this thesisfor scholarly purposesmay be grantedby the head ofmydepartment or byhis or her representatives.It is understoodthat copying orpublication of this thesisfor financial gainshall not be allowedwithout my writtenpermission.(Signature)_______________________Department of_________________The University of British ColumbiaVancouver, CanadaDateL%DE-6 (2/88)ABSTRACTTo determine whether asthmatic athletes have normal physiological responses toexercise without pre-exercise medication, we studied 17 female and male asthmaticsubjects, 9 highly trained(Hi’) (age = 26.1 ± 5.7 yrs; ht = 173.6 ± 10.5 cm; wt = 66.4 ±10.8 kg;VO2max = 57.0 ± 4.9 ml.kg-’.min-’), and 8 moderately trained (MT) (age =24.1 ± 3.1 yrs; ht 183.1 ± 11.8 cm; wt = 78.6 ± 15.3 kg;VO2max = 51.3 ± 4.8 ml•kg1min-)with exercise-induced asthma (ETA) under 2 randomly assigned experimentalconditions: salbutamol(S)(2 puffs = 200 jig) or placebo (PL) was administered viametered-dose inhaler 15 minutes prior to exercise. The exercise task was 4 continuous5minute increments on an electronically braked cycle ergometer representing25, 50, 75,and 90% of the subject’sVO2max. V02,minute ventilation (VE), respiratory exchangeratio (RER), % saturation(Sa02), and HR were continuously measured during exercise.A venous catheter was inserted in the subject’s antecubital vein to allow measurement ofblood lactate (La) each minute throughout exercise and recovery. Post-medication,exercise, and recovery measurements of peak expiratory flow rates (PEFR) weremadeusing a Mini-Wright flow meter.The data failed to show significance (p > 0.05) between treatment conditions atany stage of exercise with respect to V02,VE,RER, HR, andSa02. However, amongthe HT group the mean HR for the 4 exercise conditions was significantly higher underplacebo (151.7 (PL) vs. 147.2 (S):p = 0.01). No difference was found in La duringexercise or in recovery. Pre-exercise PEFR was significantly higher (582(S)vs. 545L.sec-’(PL):p=0.003)when pretreatment was salbutamol, but prior to treatment therewas no difference between the two pre-exercise PEER’s. Mean PEER measures for theexercise and recovery conditions were significantly higher(600.1(S) vs. 569.6 (PL):p =0.002) with the salbutamol treatment. Scheffe’s post-hoc comparisons indicated aIIsignificant difference in mean PEER measures with respect to the two treatments betweenlow intensities (25 % and 50 %) and high intensities (75 % and 90 %) of exercise.Therewas no difference in the physiological response to exercise between groups based ontraining status. It was concluded that although salbutamol affects the PEER, theseasthmatic athletes do not have altered metabolic or ventilatory responses during exercise.mTABLE OF CONTENTSAbstract iiTable of ContentsivList of TablesvList of Figures xList of Abbreviations and Symbols xiiAcknowledgements xivIntroduction 1Methods 4Subjects 4Methacholine Challenge Test5Maximal Oxygen Uptake Test6Experimental Procedures 6Lactate Analysis8Statistical Analysis8Results 10Discussion 22References 28Appendix A- Review of Literature34Appendix B- Tables53Appendix C- Figures90ivLIST OF TABLESTable 1 Physical characteristics of the subjects (mean ± SD, range) 10Table 2V02, YE,HR, RER, andSa02of all subjects(n = 17), group data 11Table 3 V02,VE,HR, RER, andSa02of highly trained (n = 9), groupdata 12Table 4. V02,YE,HR, RER, andSa02of moderately trained (n=8) groupdata 12Table 5. Lactate (mmol.Fl) of all subjects, highly trained and moderately trained,group data 13Table 6 PEFR (l.sec-1) of all subjects, highly trained and moderately trained,group data 13Table 7 Age, height, weight,VO2max, and PC2O,individual data of subjectsin the Highly trained group 53Table 8 Age, height, weight,VO2max,andPC2O,individual data of subjectsin the Moderately trained group 54Table 9YE,V02,RER, PEFR, andSa02at 25 %VO2maxwith placebo,individual subject data(n = 17) 55Table 10VE,V02,RER, PEFR, and5a02 at25 %VO2max with salbutamol,individual subject data(n = 17) 56Table 11YE, V02,RER, PEFR, andSa02at 50%VO2maxwith placebo,individual subject data(n = 17) 57VTable 12VE,V02,RER, PEFR, andSa02at 50 %VO2maxwith salbutamol,individual subject data(n = 17)58Table 13VE,V02,RER, PEFR, andSa02 at 75 % VO2maxwith placebo,individual subject data(n = 17)59Table 14VE,V02,RER, PEFR, andSa02at 75 %VO2maxwith salbutamol,individual subject data(n = 17) 60Table 15VE,V02,RER, PEFR, andSa02 at 90% VO2maxwith placebo,individual subject data(n = 17)61Table 16VE,V02,RER, PEFR, andSa02 at 90 % VO2maxwith salbutamol,individual subject data(n = 17)62Table 17VE,V02,RER, PEFR, and Sa02at 25 %VO2maxwith placebo,individual subject data for the HT group63Table 18VE,V02,RER, PEFR, andSa02 at25 %VO2maxwith salbutamol,individual subject data for the HT group 63Table 19VE,V02,RER, PEFR, andSa02 at 50 % VO2max with placebo,individual subject data for the HT group 64Table 20VE,V02,RER, PEER, andSa02 at 50 % VO2max with salbutamol,individual subject data for the HT group 64Table 21VE, V02,RER, PEER, andSa02 at 75 % VO2max with placebo,individual subject data for the HT group65Table 22VE,V02,RER, PEER, andSa02 at 75 % VO2max with salbutamol,individual subject data for the HT group65Table 23VE, V02,RER, PEER, and Sa02 at 90 % VO2max with placebo,individual subject data for the HT group 66viTable 24 VE, V02,RER, PEFR, andSa02at 90 %VO2max with salbutamol,individual subject data for the HT group 66Table 25 VE, V02, RER, PEFR, andSa02 at 25 % VO2maxwith placebo,individual subject data for the MT group 67Table 26 VE,V02,RER, PEFR, andSa02at 25 %VO2maxwith salbutamol,individual subject data for the MT group 67Table 27 VE, V02, RER, PEFR, and Sa02 at 50%VO2maxwith placebo,individual subject data for the MT group 68Table 28 VE,V02,RER, PEFR, andSa02 at 50 % VO2maxwith salbutamol,individual subject data for the MT group 68Table 29 VE, V02,RER, PEFR, andSa02 at 75 % VO2maxwith placebo,individual subject data for the MT group 69Table 30 VE, V02,RER, PEFR, and Sa02 at 75 %VO2maxwith salbutamol,individual subject data for the MT group 69Table 31 VE, V02,RER, PEFR, and Sa02 at 90%VO2maxwith placebo,individual subject data for the MT group 70Table 32 VE,V02,RER, PEFR, andSa02 at 90 % VO2max with salbutamol,individual subject data for the MT group 70Table 33 Pre and post medication and recovery PEFR measures with placebo,individual subject data(n = 17)71Table 34 Pre and post medication and recovery PEFR measures with salbutamol,individual subject data(n = 17)72Table 35 Pre and post medication and recovery PEER measures with placebo,individual subject data for the HT group 73vIITable 36 Pre and post medication and recovery PEFR measures with salbutamol,individual subject data for the HT group73Table 37 Pre and post medication and recovery PEFR measures with placebo,individual subject data for the MT group74Table 38 Pre and post medication and recovery PEFR measures with salbutamol,individual subject data for the MT group74Table 39 Blood lactates (mmoltl) at 25, 50, 75, and 90 %VO2max with placebo,individual subject data(n = 17)75Table 40 Blood lactates (mmol.l1)measures at rest and recovery conditionswith placebo, individual subject data(n = 17)76Table 41 Blood lactates(mmol.1-1)at 25, 50,75, and 90 %VO2max withsalbutamol, individual subject data (n = 17)77Table 42 Blood lactates (mmol•l-1)measures at rest and recovery conditionswith salbutamol, individual subject data(n = 17)78Table 43 Blood lactates(mmol l) at 25, 50, 75, and 90 %VO2max withplacebo, individual subject data for the HT group79Table 44 Blood lactates (mmoitl) measures at rest and recovery conditionswith placebo, individual subject data for the lIT group 79Table 45 Blood lactates (mmol.[l) at 25, 50, 75, and 90 %VO2maxwithsalbutamol,individual subject data for the HT group 80Table 46 Blood lactates (mmolt1)measures at rest and recovery conditionswith salbutamol, individual subject data for the HT group80Table 47 Blood lactates (mmol.P1)at 25, 50, 75, and 90 %VO2maxwithplacebo,individual subject data for the MT group 81vi’Table 48 Blood lactates (mmol.l1)measures at rest and recovery conditionswith placebo, individual subject data for the MT group 81Table 49 Blood lactates (mmol.1l) at 25, 50,75, and 90 %VO2max withsalbutamol,individual subject data for the MT group 82Table 50 Blood lactates (mmol.1l) measures at rest and recovery conditionswith salbutamol, individual subject data for the MT group 82Table 51 The duration of exercise test with salbutamol and placebo, individualsubject data (n = 17)83Table 52 The duration of exercise test with salbutamol and placebo, individualsubject data for the HT and MT groups 84Table 53 RMANOVA summary (N =17) 85Table 54 RMANOVA summary for PEFR and Blood lacatate measurements 85Table 55 RMANOVA summary for the lIT group 86Table 56 RMANOVA summary for the MT group 87Table 57 RMANOVA summary for subjects with aPC2O< 4.0 mg.ml1 88Table 58 Baseline spirometry for the lIT group 89Table 59 Baseline spirometry for the MT group 89ixLIST OF FIGURESFigure 1 PEFR (l•sec-1)measures under salbutamol and placebo conditionsat various exercise intensities and 3 to 15 minutes into recovery, allsubject data(n = 17)16Figure 2 PEFR (l•sec-1)measures under salbutamol and placebo conditionsat various exercise intensities and 3 to 15 minutes into recovery, HTgroupdata(n=9) 17Figure 3 PEFR (l.sec1)measures under salbutamol and placebo conditionsat various exercise intensities and 3 to 15 minutes into recovery, MTgroupdata(n=8) 18Figure 4 PEFR (l.secl) measures under salbutamol and placebo conditionsat various exercise intensities and 3 to 15 minutes into recovery,PC2O<4.0mg. mF1 (n =6) group data 19Figure 5 Blood lactate(mmol.11)at various exercise intensities and 1 to 10minutes into recovery, all subject data(n = 17)20Figure 6 HR (bpm) responses at various exercise intensities, HT groupdata(n=9) 21Figure 7 V02 (l.nthrl) responses at various exercise intensities (%VO2max),all subject data(n = 17) 90Figure 8 V02(l•min4)responses at various exercise intensities(%VO2max),HT subject data 91Figure 9 V02(l.miir1)responses at various exercise intensities (%VO2max),MT subject data 92Figure 10VE(Fmin1)responses at various exercise intensities (%VO2max),all subject data(n = 17) 93Figure 11VE(lmiir1)responses at various exercise intensities (%VO2max),Hi’ subject data 94Figure 12VE(1.mlir4)responses at various exercise intensities (%VO2max),HT subject data 95xFigure 13 HR (bpm) responses at various exercise intensities (%VO2max),allsubjectdata(n=17)96Figure 14 HR (bpm) responses at various exercise intensities(% VO2max),MT subject data97Figure 15 RER responses at various exercise intensities (%VO2max),aflsubjectdata(n=17)98Figure 16 RER responses at various exercise intensities (%VO2max),HT subject data99Figure 17 RER responses at various exercise intensities(%VO2max),MT subject data100Figure 18Sa02responses at various exercise intensities (%VO2max),all subject data(n = 17)101Figure 19Sa02 responses at various exercise intensities (% VO2max),HT subject data102Figure 20Sa02responses at various exercise intensities (%VO2max),MT subject data103Figure 21 Blood lactate (mmol.li) at various exercise intensities(%VO2max),HT subject data104Figure 22 Blood lactate (mmol.11)at various exercise intensities(%VO2max),MT subject data105xiList of Abbreviations &Svmbols(X alpha(A-a)D02alveolar-arterial difference(A-a)P02alveolar-arterial partial pressure of oxygenANOVA analysis of variancebetaCa calcium ioncAMP cyclic adenosine monophosphateCNS central nervous systemEIA exercise-induced asthmaEIH exercise-induced hypoxemiaEIh exercise-induced hyperventilationFEF25..75mid-maximal expiratory flowFEV1forced expiratory volume in one secondFVC forced vital capacityHR heart rateHT highly trainedbC International Olympic CommissionLa blood lactateMMEF mid-maximal expiratory flowMT moderately trainedPEFR Peak expiratory flow ratexI1Pa02arterial partial pressure of oxygenPaCO2 arterial partial pressure of carbon dioxidePC20 concentration of agent that will provoke a 20 % fall inFEV1pHa arterial pHRER respiratory exchange ratioRMANOVA repeated-measures analysis of varianceSa02 oxygen saturation of arterial hemoglobinVA/Q alveolar ventilation-perfusion ratioVE volume of air expired per minuteV02 rate of oxygen uptakeVO2max maximal rate of oxygen uptakexliiAcknowledgementsI would like to express my thanks and appreciation to the subjects for theirparticipation and cooperation in this study, and to several individuals who contributedtothe evolution and successful completion of this thesis. First, my thanksto my thesiscommittee members Drs. Don McKenzie, Ken Coutts, and Pierce Wilcox for their helpand guidance. I would like to give special thanks to my advisor, Don McKenzie for hisendless encouragement and support, both emotional and fmancial. As well, hisenthusiasm, expertise, and quality of research in the area of exercise physiology has beenan invaluable contribution to the development of my own interests and research skills. Ihope to continue these standards in my future endeavors. To Diana Jespersen, whosepractical knowledge and skills in the lab were an invaluable contribution during my datacollection period. Also, for her help and patience in teaching me how to use theequipment and solving any problems that arose. To Dr. Coutts for his expertise andknowledge in the lab, and problem solving ability made the completion of my thesispossible. Thanks also goes to HanJ00 Eom for all his statistical advice.To AngeloBelcastro for allowing me access to his lab and offering his equipment and expertise inthe lactate analyses. To my lab-mates and fellow colleagues, Trevor andSue whoassisted me in subject recruitment and always provided a stimulating learningenvironment, and special thanks to Jim Potts for his kindness, support and encouragementthroughout my graduate studies. I would also like to acknowledge GlaxoCanada Inc. fortheir financial support. Finally, to my dearest friends Annita and Gavin who I havelearned a lot from and whose unconditional support and encouragement havehelped meto explore my unique interests, talents, and potential.xivINTRODUCTIONExercise-Induced Asthma (EIA) is a reversible airway diseasethat occurs inalmost all individuals with asthma when challenged under appropriate exerciseconditions. Among competitive athletes the prevalence of asthma is higher than onewould expect; sixty-seven of the 597 (11.2%) athletes competing in the1984 Olympicgames suffered from EIA (67).The type of exercise performed plays a major rolein the severity ofbronchoconstriction. Running outdoors is the most asthmogenic followedby treadmillrunning indoors, cycling, swimming, and walking (2). Intermittentactivities such assoccer or baseball are better tolerated than continuous activities suchas rowing or cross-country skiing. 5-8 minutes of exercise at an intensity of60-80 % of predicted maximaloxygen consumption increase the chances of an attack; exercising any longer than this,may diminish the response (59). Exercising in environmental conditions wherethe air iswarmed and humidified can provide a protective effect on theairways (19, 37).Similarly, warm-up exercises and regular aerobic conditioning can attenuateand decreasethe incidence of EIA (31, 48). Although many preventative measurescan be taken tomodify the severity of asthma, pharmacological intervention is oftenedrequired. Inhaledsalbutamol(Ventolin®),af2-agonist, is a commonly used medication in theprophylactic management of EIA (20, 28). Its powerful bronchodilating effectand132selectivity can virtually abolish bronchospasm when taken 10-15 minutes priortoexercise. The effects of salbutamol on physiological parameters suchas pH, arterial gastensions for oxygen(PaO2)and carbon dioxide(PaCO2), maximal oxygen consumption1(VO2max)and minute ventilation(VEmax) during exercise have been shown to beminimal in untrained asthmatics (33, 56).Few studies have looked at the physiological responses of asthmatics to exercisewithout the use of pre-exercise medication. Physiological parameters such as maximalheart rate (HR),VEmax, VO2max, PaCO , andPa02have all been shown to be withinnormal range in asthmatics when free of an attack; any abnormalities seen in thesevariables have been concluded to be due to the untrained state of the asthmatic subjectstested. For example, higher blood lactates have been reported in asthmatics by severalauthors (1, 5, 10, 53),but these individuals were untrained and their higher levels couldbe more representative of their lower fitness level. Conversely, Anderson et al., (1) foundasthmatics to have higher plasma lactate (LA) compared to non-asthmatics of similarfitness level exercising at the same oxygen consumption.Oxyhemoglobin saturation (Sa02)and arterial oxygen tension (Pa02)in healthyindividuals stay relatively consistant throughout exercise, but approximately 50 % ofhighly trained (HT) athletes who are free of asthma, exhibit arterial hypoxemia anddesaturation of hemoglobin at maximal exercise. This phenomenon known as exercise-induced hypoxemia (Effi), defined as a reduction in Sa02of 4% below resting values, isthought to be attributed to two causes: a lower alveolarP02(PAO2)due to an inadequateventilatory response to exercise, and secondly, excessive widening of the alveolar-arterialP02 difference((A-a)D02)) caused byveno-arterial shunt, ventilation/perfusion (VA/Q)non-uniformity, and diffusion limitations (15, 55). HT athletes are capable of achievingextreme metabolic capacities(VO2max valuesgreater than 5.0 lmin1and cardiacoutputs as high as 30-35 lmin-1)through physiological adaptations of the cardiovascular2system and oxidative capacities of skeletal muscle. However, the pulmonary system isthought to be the least trainable organ system which may, in turn, limit exerciseperformance (16). In asthmatics, Anderson et al., (1) found in one subject a significantdecrease in arterial oxygen tension during exercise. Therefore, the lIT asthmatic athlete,who may experience gas exchange limitations, and experience other abnormalities due totheir asthma, may be compromised at maximal exercise. All of the studies addressing themetabolic and ventilatory response of asthmatics to exercise have been conducted onuntrained asthmatic subjects. To date, no study has looked at these variables in HTasthmatics. Therefore, the purpose of this study is to examine the metabolic andventilatory responses to submaximal and maximal exercise in highly trained asthmaticathletes with and without pre-exercise medication.3METHODSSubjectsSeventeen subjects, 9 highly trained athletes(5 females, 4 males; age = 26.1 ± 5.7yrs; ht. = 173.6 ± 10.5 cm; wt. 66.5 ± 10.6 kg;V02 max = 57.2 ± 4.8 ml.kg-1min-1),and 8 moderately trained athletes (1 female, 7 males; age = 24.1 ± 3.1 yrs; ht.= 183.1 ±11.8 cm; wt. = 78.8 ± 15.5 kg;V02max = 51.2± 4.8 nil•kg -i.min1),with EIAparticipated in this study. Subjects in this study demonstrated mild to moderateairwayresponsiveness and all but three of the subjects had a history of asthma. Baselinespirometry indicated 6 of the 17 subjects had a FEV1% of <80 %. The criteria forinclusion in the study was a positive methacholine challenge test whichwas defmed as adecrease in Forced Expiratory Volume of 20% or greater in one second(FEVi)at amethacholine concentration of 16.0 mg.mll or less(PC2O16 mg•n*’). Subjects wereplaced into one of the two groups depending on their fitness level; thehighly trainedgroup consisted of subjects who had achieved aV02max 60 ml.kg-1min- for malesand 50 ml.kg-1•min-1for females; all other subjects were placed in the moderatelytrained group, but had to achieve a minimumVO2max 45 mlkg mi1for males and40 ml.kg-1•min-1for females. Prior to entering the study, informed consentwasobtained. This study was approved by the Clinical Screening CommitteeforExperimental Involvement of Human Subjects.4Methacholine Challenge TestThis procedure was used to assess the bronchial reactivity of each subject. Beforethe inhalation test, a baseline FEVi was measured using a Medical GraphicsMetabolic Cart with 1070 Pulmonary Function Software. Aerosols were administeredusing a Wright nebulizer attached to a face mask , calibrated to deliver the aerosols ata rate of 0.13 mlmin1.Aerosols were inhaled for periods of 2 minutes followed by 30and 90 secondFEVideterminations. After a baselineFEV1 was established with saline,methacholine was inhaled in doubling concentrations (.125, .25, .5, 1.0, 2.0,4.0, 8.0, and16.0 mg•m11)every 5 minutes (34).FEVi wasmeasured every 30 and 90 seconds aftereach concentration until a fall in FEV1 of 20 %(PC20),compared to the saline controlwas achieved. The percentage fall in FEV1was calculated from the lowest FEV1 aftereach methacholine inhalation and thePC20 wasdetermined by using the followingequation;PC20= antilog[log Ci+ (logC2 - log Cn(20-Ri)]R2-Riwhere: Ci = second last concentration (<20% FEV1fa11)C2 = last concentration (>20 % FEV1 fall)Ri = % fall FEV1 after CiR2 = % fall FEV1 after C2APC2O16 mgm11was chosen as indicative of asthma for this study (41).Prescribed inhaled bronchodilators were withheld for 12 hours prior to the test, however,subjects on inhaled steroids were allowed to continue taking their medication in regulardoses.5Maximal Oxygen Uptake testPrior to this test subjects were permitted to take their pre-exerciseasthmaticmedication. The maximal oxygen uptake test was performed on an electronicallybrakedMijnhardt KEM 3 cycle ergometer ramped continuously at 30 wattsmin-1until thesubject reached volitional fatigue. Oxygen uptake (V02),carbon dioxide(VCO2),andminute ventilation(VE) were continuously sampled with a Metabolic Measurement Cart(Beckman LB-2C02 Analyzer, and Ametek Oxygen Analyzer S-3A/1), which calculatedand reported 15 second averages. Heart rate (KR) was monitored continuouslywith aPolar VantageXL7Mheart rate monitor set to record HR’s in 15 second intervals. Aregression equation using workload and oxygen uptake was generated for eachsubject;from this data the workloads in watts were determinedto elicit 25, 50, 75, and 90 % ofthe subject’sV02 max. Attainment of VO2max was determined when at least three ofthe following four criteria were met: (1) a plateau of oxygenconsumption with increasingworkloads, (2) a respiratory exchange ratio> 1.10, (3) 90 % of predicted maximal HRwas achieved, or (4) volitional fatigue.Experimental ProceduresSubjects performed two randomized exercise tests one week apart, one using preexercise salbutamol and the other a pre-exercise placebo. All bronchodilator drugs werewithheld for 12 hours prior to each session, while subjects on corticosteroids wereallowed to continue taking their medication. Fifteen minutes priorto testing subjectsreceived two puffs from a coded metered-dose inhaler containing either salbutamol (2006jig) or the placebo given in a double blind fashion. Before the start of exercisea 20gauge venous catheter (kept patent with normal saline and heparin, 1000 units/500m1)was inserted in the subject’s antecubital vein and a pre-exercise blood sample(—0.5 ml)was withdrawn. Pre - and post-medication Peak Expiratory Flow Rates (PEFR)weremeasured using a Mini-Wright flow meter. The exercise protocol consisted ofa 20minute cycle on an electronically braked cycle ergometer divided into 4 continuousfiveminute increments. The workloads, predetermined from theVO2max test, were set toelicit 25, 50,75, and 90 % of the subject’sVO2max.Respiratory gas exchange variables,V02,VCO2, VE, and RER, were continuously measured with a Metabolic Cart (BeckmanLB-2 CO2 Analyzer, and Ametek Oxygen Analyzer S-3A/1). The means of the fourconsecutive 15 second averages in the third minute of each increment were reported.Sa02was measured with a Hewlett Packard (47201A) oximeter attachedto the subject’sear and secured by a head band. To improve perfusion of blood to the ear, the helix ofthe ear was rubbed with Finalgon (Boehringer Ingelheim), a vasodilator cream,The earoximeter, interfaced to an IBM compatible computer, reportedSaO2in 15 secondaverages. For the purpose of this study only 1 minute averages ofV02,VE,HR, RER,andSa02were calculated 3 minutes into each stage of exercise. In the fourth minute ofeach exercise task the subjects momentarily removed the mouth piece (measuringrespiratory gases) and forcibly expired into the peak flow meter , this was followedby ablood sample. PEFR measurements were made 3, 5, 10, and 15 minutes of recovery andblood samples were taken 1, 3, 5, and 10 minutes after the cessation of exercise.7Lactate AnalysisThe initial 0.5 ml of blood drawn from the subject was added to 2 ml of chilledperchloric acid (10%). After vortexing, the samples were placed in an ice bath for atleast 5 minutes. These samples were centrifuged at 2500 rpm for 10 minutes and thesupernatant was collected and split into duplicates before being stored at -700C. Thelactate concentrations were measured using a modification of an enzymatic assaycommercially available from SigmaDiagnostics®.The samples were allowed to thaw toroom temperature before proceeding. The pH of the samples was neutralized by adding500pL of the sample tol5OiiLof Tris-OH buffer (pH). After mixing, 20pL of thebuffered sample was added to lml of the lactate reagent. Samples were incubated for 15minutes which allowed for colour development. The absorbance of each sample wasmeasured at 540 nm with a UV-160 Spectrophotometer, and the blank, consisting of thelactate reagent alone, and the samples were compared to lOpL of a Lactate StandardSolution (4.44 m•mo11lactic acid (40 mg.dLl)).Statistical AnalysisThe independent variables were the treatment factor which had two levels;Salbutamol and Placebo, and the exercise condition which had 4 levels for the dependentvariables; V02,VE, fiR, RER, Sa02; 8 and 9 levels for PEFR and LA, respectively. The4 levels of the exercise condition consisted of 25 % , 50 %, 75 %, and 90 % of thesubject’s VO2max and the 9 levels included the resting condition, the 4 exerciseconditions, and 1, 3, 5, and 10 minutes into recovery for the dependent variable LA. The88 levels for the dependent variable PEFR included the four exercise conditions and 3, 5,10, and 15 minutes into recovery.All subject comparisons between the 2 treatments for the 7 dependent variableswere made by a repeated measures analysis of variance (ANOVA). V02,VE,FIR, RER,and Sa02 were statistically analysed with a 2 (Treatment factor) X 4 (Exercise condition)ANOVA with repeated measures on both factors. PEFR and blood lactates wereanalysed with a 2 X 8 and 2 X 9 repeated measures ANOVA, respectively.Between and within-group comparisons were also performed by a repeatedmeasures ANOVA to determine any differences between the male and female subjects,males in the FIT group from males in the MT group, and the highly trained from themoderately trained group. A post-medication rise in PEFR was expected after theadministration of salbutamol, so independent t-tests were conducted on pre- and post-medication measures with a level of significance (a) set at p < 0.01. Post hoccomparisons using Tukeys HSD and Scheffe’s method were performed on significantmain effects and significant interaction effects, respectively. The level of significance(a) was set at ap<0.05 for all of the analyses of variance comparisons. All statisticalanalyses were performed using Systat software(5.0 version, Systat, Inc.)9RESULTSMean values for the physical characteristics of the highly trained and moderatelytrained subjects are presented in Table 1.Table 1. Physical Characteristics (mean ± SD , range)Subjects Highly trained Moderately trainedSEX 5 females, 4 males 1 female, 7 malesAGE (years) 26.1 ± 5.7 (19-35) 24 .1 ± 3.1 (21-31)HEIGHT (cm) 174.0± 10.5 (162-190) 183.1± 11.8 (161-200)WEIGHT (Kg) 66.4 ± 10.8 (51-85) 78.6 ± 15.3 (49-94)VO2max (m1Kgmin) 57.0 ± 4.9 (50-63) 51.3 ± 4.8(4557)*PC2O (mg.ml) 7.2 ±5.8 (0.7-15.8) 7.6 ± 5.0 (0.8-15.9)P < 0.05AU subjects passed the baseline criteria of a positivemethacholine(PC2O16.0 mg.mll)with a mean PC20 of 7.2 ± 5.8 mg•mP1for the highly trained group and 7.6 ± 5.0 mgm11 for the moderately trained group. There was a statistically significant difference inmeanVO2maxvalues between the highly trained and moderately trained groups (57.0 ±4.9 vs. 51.3 ± 4.8;p= 0.002) and male and female subjects(55.5 ± 6.0 vs. 52.3 ± 4.4; p= 0.007). Although the duration of the experimental test varied for each subject, therewas no statistical difference in duration of the exercise protocol between the placebo andsalbutamol.10Analysis of variance performed on all subjects revealed no significant differencein the pretreatment with either salbutamol or placebo at any stage of exercise with respecttoV02, VE,HR, RER,Sa02,and LA. The group means and standard deviations areshown in Tables 2 and 5.Table 2.V02, VE,FIR, RER,andSaO2of all subjects(n = 17), group dataSalbutamol PlaceboVariables 25% 50% 75% 90% 25% 50% 75% 90%V021/min1.17±.23 1.98±.39 3.09±.63 3.70±.81 1.16±26 2.03±.49 3.14±.65 3.74±.76yE btps313 ± 5.6 51.8 ± 9.0 92.9 ± 19.6 131.8 ± 30. 31.6 ± 4.8 52.9 ± 10.8 93.8 ± 20.8 135.7 ± 32.2HRbpm 104.5± 10.0 134.4± 11.8 169.0±9.5 183.9±7.3 103.7± 10.9 135.6± 12.9 171.6± 10.1 186.7±6.5RER0.80 ± .06 0.88 ± .08 0.99 ± .08 1.05 ± .09 0.81 ± .06 0.87 ± .06 0.99 ± .06 1.05 ± .07Sa0296.9±1.4 96.7±1.0 95.8±0.8 94.6±1.5 96.9±0.6 96.5±0.7 95.5±0.9 94.7±1.5Pre-exercise PEFR was signfficantly higher (582 vs. 545 l•sec-1:p = 0.003) when thepretreatment condition was salbutamol, but prior to treatment there was no differencebetween the two PEFR’s. PEFR increased significantly over the course of exercise forall subjects, and averaged over the exercise and recovery conditions was significantlyhigher with the salbutamol treatment (600.1 vs. 569.6:p = 0.002) than the placebo. Thesignificant drug by exercise condition interaction (p = 0.00 1) indicates, with respect tothe 2 treatments, a different pattern of change in PEFR measures over exercise and therecovery conditions. Post hoc pairwise comparisons using Scheffe’s test revealed asignificant difference between PEFR measures at low intensities (25 % and 50 %) withhigh intensities (75% and 90 %) of exercise and differences in the first two recovery11conditions(3 and 5 mm.) with the last two (10 and 15 mm.). There was a largerdifference in the two treatments at lower intensities and not at the higher intensities ofexercise and a greater difference 10-15 minutes as opposed to 3-5 minutes of recovery(Figure 1).Comparisons made between the lIT and MT groups indicated no significantdifference at any stage of the experimental protocol between the two groups with respectto V02,VE, HR, RER, Sa02, and LA (Tables 3-6).Table 3. V02,VE,HR, RER, andSa02of highly trained (n= 9), group dataSalbutamol PlaceboVariables 25% 50% 75% 90% 25% 50% 75% 90%V02 L/mm 1.08 ± 0.21 1.91 ± 0.38 2.98 ± 0.61 3.48 ± 0.66 1.06 ± 0.26 2.00 ± 0.59 3.08 ± 0.71 3.57 ± 0.77VEbips30.2 ± 6.1 51.0 ± 8.7 95.3 ± 21. 132.5 ± 30. 29.8 ± 4.3 52.5 ± 11.9 98.5 ± 222 139.4 ± 35.HRbpm104.1 ± 8.9 133.8 ± 11. 168.4 ± 10. 182.4 ± 8.2 104.3 ± 7.9 139.8 ± 11. 175.8 ± 9.3 186.7 ± 7.6RER0.79 ± 0.05 0.87 ± 0.06 1.00 ± 0.06 1.05 ± 0.08 0.81 ± 0.06 0.86 ± 0.06 1.00 ± 0.06 1.05 ± 0.08Sa0297.1 ± 1.7 96.6 ± 1.3 95.7 ± 1.0 93.9 ± 1.2 97.0 ± 0.7 964 ± 0.8 95.2 ± 0.8 94.2 ± 0.9Table 4. VO2,VE, HR, RER, andSa02of moderately trained (n = 8), group dataSalbutamol PlaceboVariables 25% 50% 75% 90% 25% 50% 75% 90%V02 L/mm1.27 ± 0.21 2.06 ± 0.41 3.21 ± 0.67 3.96 ± 0.92 1.28 ± 0.21 2.08 ± 0.39 3.21 ± 0.61 3.91 ± 0.75VEbtps32.6 ± 5.0 52.6 ± 9.8 90.2 ± 18.5 130.9 ± 32.3 33.6 ± 4.8 53.3 ± 10.1 88.5 ± 19.2 131.5 ± 30.1HR bpm 104.9 ± 11.7 135.2 ± 13.2 169.7 ± 9.3 185.7 ± 6.2 103.0 ± 14. 130.9 ± 14.( 166.9 ± 92 186.7 ± 5.6RER 0.82 ± 0.07 0.89 ± 0.09 0.98 ± 0.10 1.04 ± 0.10 0.80 ± 0.06 0.88 ± 0.06 0.97 ± 0.06 1.05 ± 0.07Sa0296.5 ± 1.0 96.6 ± 0.5 95.8 ± 0.7 94.7 ± 1.0 97.1 ± 0.8 96.8 ± 0.5 95.9 ±0.9 95.1 ± 1.612However, among the Hi’ group the mean HR averaged overthe 4 exerciseconditions was significantly higher under the placebo condition (147.2 (S)vs. 151.7 (PL)bpm: p = 0.01). The significant drug by exercise condition interaction(p = 0.002)demonstrates a greater change in HR under the placebo treatment than the salbutamolforthe same level of exercise (Figure 6). A Tukey’s post hoc analysis indicated significancebetween the two treatments only at a workload of 75 %VO2max (168.4 (S) vs. 176.8(PL) bpm: p < 0.05).Table 5. Lactate(mmol•l-1)of all subjects, highly trained and moderatelytrained, group dataLACTATE (mmol•11)n=17 n=9 n=8CONDITION Salbutamol Placebo HT-Salb. HT-Placebo MT- Salb. MT- PLREST 0.8 ± 0.5 0.9 ± 0.3 0.9 ± 0.6 1.0 ± 0.3 0.8 ± 0.5 0.8 ± 0.425 %VO2max 1.1 ± 0.8 1.2 ± 0.6 1.0 ± 0.8 1.1 ± 0.4 1.3 ± 0.9 1.3 ± 0.750 % VO2max 1.5 ± 0.6 1.6 ± 0.7 1.6 ± 0.7 1.5 ± 0.4 1.4 ±0.5 1.7 ± 0.975 % VOmax 5.7 ± 2.4 5.4 ± 2.2 6.0 ± 2.6 6.4 ± 1.95.3 ± 2.3 4.3 ± 2.090 % VO2max 10.3 ± 3.9 11.1 ± 4.0 10.6 ± 4.4 12.5 ± 4.2 10.0 ± 3.49.6 ± 3.41 mill Post Ex. 11.1 ± 4.0 112 ± 3.7 11.6 ± 4.9 12.5 ±3.5 10.5 ± 2.9 9.7 ± 3.53 mm Post Ex. 10.7 ± 3.7 10.7 ± 3.6 11.7 ± 4.7 11.4 ± 3.2 9.6 ± 2.39.8 ± 4.15 mm Post Ex. 9.8 ± 4.1 10.4 ± 3.6 10.6 ± 5.8 10.8 ± 3.8 92 ± 2.8 9.9 ± 3.610 mm Post Ex. 8.2 ± 4.2 8.3 ± 3.6 8.8 ± 5.1 9.1 ±3.3 7.7 ± 3.2 7.4 ± 3.9Analysis of subjects within the HT group revealedsignificantly higher meanPEFR values (569.3 vs. 539.3:p= 0.009) with the pretreatment of salbutamol (Figure 2)However, among the MT group no difference was found in PEFRat any stage of exerciseor recovery between the two experimental conditions (Figure3). The means and standard13deviations for PEFR measures for all groups are presented in Table 6 and illustrated ingraphical format in Figures 1-4. Between-group analysis of variance revealed nosignificant difference in mean PEFR values between the two groups based on trainingstatusTable 6. PEFR(lsec-1)of all subjects, highly trained and moderatelytrained, group dataPEFRI•sec1n=17 n=9 n8CONDITION Salbutamol Placebo HT-Salb. HT-Placebo MT- SaIb. MT- PLPRE-MED 563.8 ± 102.1 555.9 ± 96.1 528.9 ± 103.8 527.0 ± 92.4 603.0 ± 90.6 588.5 ± 95.1POST-MED 581.8 ± 100.4 545 ± 94.8 551.6 ± 98.6 522.8 ± 88.9 615.8 ± 97.0 570.0 ± 100.825 % VO2max 595.0 ± 98.2 550.6 ± 101.7 565.0 ± 92.8 513.3 ± 88.9 628.8 ± 98.8 592.5 ± 103.950 % VO2max 605.9 ± 96.4 567.7 ± 103.5 575.6 ± 88.7 536.1 ± 97.9 640.0 ± 98.6 603.1 ± 103.975 % VO2max 618.5 ± 101.1 602.9 ± 103.0 589.4 ± 93.0 571.7 ± 105.8 651.3 ± 105.6 638.1 ± 93.790 % VO2max 622.9 ± 108.3 612.9 ± 101.9 591.1 ± 99.5 572.8 ± 87.5 658.8 ± 112.9 658.1 ± 102.93mm Post Ex. 605.6 ± 1032 572.9 ± 108.2 572.8 ± 100.4 550.6 ± 105.4 642.5 ± 99.4 598.1 ± 112.75mm Post Ex. 583.5 ± 92.0 562.1 ± 103.1 561.7 ± 89.7 540.0 ± 95.6 608.1 ± 94.0 586.9 ± 111.810mm Post Ex. 582.4 ± 91.0 546.5 ± 103.1 556.1 ± 86.3 521.1 ± 92.9 611.9 ± 92.3 575.0 ± 112.615mm Post Ex. 587.1 ± 103.3 540.9 ± 97.5 560.6 ± 97.5 526.1 ± 97.5 616.9 ± 107.8 557.5 ± 101.2Comparing male and female subjects, males had significantly higher meanV02(2.79 vs. 1.97 l• mm-1:p= 0.000),VE(84.2 vs 65.91: p = 0.008) values, but there wereno differences in HR, RER,Sa02,and blood lactate. Male subjects did have statisticallyhigher PEFR values than female subjects. Comparisons made between males in the HTgroup with males in the MT group revealed no differences with respect to any of thevariables measured.14Statistical analysis performed on data of those subjects with aPC2O<4.0 mg•ml-1(n =6) showed no significant main drug effect with respect to HR,V02, VE,RER,Sa02,or lactate. Although not significantly different (p = 0.058), V02 was higher whenpretreatment was the placebo. PEFR (559.3 vs. 506.5:p= 0.03)averaged over theexercise and recovery conditions for this group was significantly higher with salbutamol(Figure 4). Post hoc comparisons were performed on the significant drugby exercisecondition interaction (p = 0.047). Figure 1. illustrates the larger differences in PEFRmeasures under the two treatments at the lower intensities as comparedto little differenceat higher intensities. For all subject groups tested, the greatest mean difference in PEFRmeasures between the two treatments was seen in the more severe asthmaticsubjects 10-15 minutes post-exercise.15Figure 1. PEFR (1 •sec1)measures under salbutamol and placebo conditionsat various exercise intensities (%VO2max)and 3 to 15 minutesinto recovery, all subjects data(n = 17)6406206000a,580LIUi0540520POST-MED.25% 50% 75% 90% 3mm 5mm 10mm 15mmExercise RecoveryMean values plotted; open circles, salbutamol; closed circles, placebo.The overallmean PEFR measures were statistically higher with salbutamol:p = 0.002. Post-medication PEFR values were statistically higher with salbutamol(*p < 0.05).*0Salbutamol•Placebo16Figure 2. PEFR (1.sec-i) measures at various exercise intensities(% V02max) and 3 to 15 minutes into recovery, Hi’ group data(n =9)600580560[40.520500 i.i.i.i...i.i.i...POST-MED25 % 50 % 75 % 90 % 3 mm 5 mm 10 mm 15 mmExerciseRecoveryValues are means; open circles, salbutamol; closed circles, placebo. The overallmean PEFR measures were statistically higher with salbutamol:p = 0.009. Post-medication PEFR measures were statistically higher with salbutamol(*p < 0.05).*0Salbutamol•Placebo17Figure 3. PEER (1.sec-l) measures at various exercise intensities(%VO2max),and 3 to 15 minutes into recovery, MT group data(n =8)680660640620600•5805601•1• I• I• I•I•POST 25 % 50 % 75 % 90 % 3 mm 5 mm io miii 15 miii- MEDExerciseRecoveryValues are means; open circles, salbutamol; closed circles, placebo :p = 0.078.° Salbutamol•Placebo18Values are means; open circles, salbutamol; closed circles, placebo. The overallPEER measures were statistically higher with salbutamol:p0.03 Post -medication PEER measures were statistically higher withsalbutamol(*p < 0.05)Figure 4. PEER (l.secl) measures at various exercise intensities(% VO2max),and 3 to 15 minutes into recovery,PC2O< 4.0 mgm1-1(n =6) groupdata.—0--- SALBUTAMOL!52O5oo.4804.440 Ipost-med 25% 50% 75% 90% 3 mm 5 mm 10 mm 15 mmExerciseRecovery19Figure 5. Blood lactate (mmol•l1)at various exercise intensities(% VO2max) and 1 to 10 minutes into recovery, all subject data(n=17).1614E 12_______0EE10€0C.)0Values are means ± SD; open circles, salbutamol; closed circles, placebo : p =0.688.—0—Salbutamol•PlaceboREST 25% 50% 75% 90% 1mm 3mm 5mm 10mmExercise Recovery20Figure 6. HR (bpm) responses at various exercise intensities (%VO2max),HT group data (n = 9).I I50% 75%Exercise (% V02 max)0—Salbutamol• PlaceboValues are means ± SD; open circles, salbutamol; closed circles, placebo. Theoverall mean HR measures were statistically higher with placebo:p = 0.01. Posthoc analysis on significant main effect revealed higher HR under the placebocondition only at 75 %VO2max(*p < 0.05).*210190170150-130110-9025% 90%21DISCUSSIONThe findings of the present study have demonstrated that highly trained andmoderately trained asthmatics have normal physiological responses during submaximaland maximal exercise. There was no difference between the pretreatment of salbutamolor placebo during all stages of exercise with respect toV02, VE,HR, andSa02, thussuggesting no impairment in oxygen delivery to the exercising muscles in the asthmaticsubjects that were tested. Packe et al., (53) found similar results in these variables whenthey compared untrained asthmatics and non-asthmatics exercising on a treadmill at 85 %VO2max.Ingeman-Hansen et a!., (33) also found no difference between inhaledsalbutamol and saline control for the variablesVE, V02,HR, PaCO2 measured in 5asthmatics during a 6 minute graded bicycle exercise test. Recently,Pa02, PaCO2,andpH were compared between asthmatics and non-asthmatics during steady state exerciseand were found to have similar responses; however,VEwas significantly lower in theasthmatic than in the non-asthmatic. In this latter study the subjects were not highlytrained and did not exercise to maximum (21).Recent studies have shown that approximately 50 % of HT endurance athletesdevelop a significant reduction (<91 %) in arterial hemoglobin saturation(Sa02)duringintense exercise(VO max 90 %)(15,54). This has been shown to have an adverseeffect on maximal oxygen consumption(—1% drop in VO2max for every % fall in Sa02)(15, 55) and total work output when mild (90%) and more severe (87 %) saturation levelswere induced (39). Therefore, the maximal performance capacity of the HT athlete’s canbe limited. Although, no study to date has looked at EIH in asthmatics, it is possible theHT asthmatic athlete, who may experience gas exchange limitations and experience otherabnormalities due to asthma, may be even more limited at maximal exercise.22Deal and coworkers (14) demonstrated the impact that changes inVEhave on the rate ofrespiratory heat loss (RHL). They suggested that the degree of RHL was directly relatedto the severity of the post-exercise bronchoconstriction. McFadden found that the rateand magnitude of bronchial rewarming affected the severity of bronchospasm (25, 45).In other words, the greater theVE,the greater the RHL, which in turn increases theseverity of exercise-induced bronchoconstriction. Hi’ athletes have high minuteventilations at maximal exercise, this may cause a large RHL which, may in turn,increase airway resistance and the work of breathing. In HT asthmatics, the combinationof a higher incidence of EIH and high minute ventilations may be limiting performanceatexercise intensities 75 % VOmax. In this study there was no difference inSa02 atintensities of 75 or 90 %VO2max between the placebo or salbutamol conditions andnone of the subjects had any evidence of respiratory obstruction at the higher workloadsas demonstrated by a significant rise in PEFR. Furthermore, none of the FiT subjectsdesaturated (< 91%) at maximal exercise. Interestingly, however,the lowest drop inSa02 (91.5 %)in the HT group occurred in the most severe asthmatic tested(PC2O= 0.7mg•mt1). Difference in protocols and fitness level may explain the discrepancy seen inour results with respect to the incidence of Effi. Our subjects in the HTgroup were welltrained, but their meanVO2max is lower than other studies reporting higher incidences ofEIH (15, 55). Also, the exercise protocols used in the studies reporting higherincidences were shorter in duration and ramped as compared with the stepwiseprogressive incremental exercise used in our study.Previous studies have demonstrated a greater rise in blood lactate in asthmaticscompared to non-asthmatics exercising at the same oxygen consumption (1,5, 10).Although we did not compare our asthmatic subjects with normal subjectswe found nosignificant difference between the two experimental conditions. The rise in blood lactate23over the course of exercise was similar to that reported in non-asthmatic trainedindividuals (62, 65). A moderate increase in lactate concentration from rest to intensitiesof 50 % V02max was followed by an exponential increase as the exercise continued tomaximal levels (Figure 5). In this study, there was no statistical difference in LAconcentrations at submaxunal exercise (25 %, and 50 %) between the HT and MTgroups. However, within the HT group higher LA values were measured under theplacebo compared to the salbutamol condition at 90 %VO2max (12.5 (PL) vs. 10.6(S)).Furthermore, at the higher exercise intensities, comparisons between the HT and MTgroups demonstrated higher LA values for the HT group for both treatment conditions(HT=12.5 (PL) vs. MT=9.6(PL); HT=10.6(S) vs. MT= 9.9(S) mmol•[1),but this was notstatistically significant.. The capacity of the lactic acid system can be greatly developeddepending on the type of training;for example, one competitive rower in the HT group,had LA levels as high as 19.0 mmol•l1at 90 %VO2max,but this would be expected forthe type of training this sport demands. LA concentration of muscle and blood inindividuals without asthma return to near resting levels within 30-60 minutes intorecovery(30). In the present study subjects were not allowed to warm down, thereforereducing the rate of LA clearance; however, blood lactate samples taken up to 10 minutespost-exercise demonstrated a similar rate of clearance in the moderately and highlytrained asthmatic subjects as reported in normal individuals (30).The asthmatics in this study demonstrated the typical pattern of response toexercise indicated by changes in pulmonary function. During exercise, bronchodilationoccurred as indicated by a rise in PEFR measures followed by a fall in PEFR afterexercise, reaching the lowest levels at 10-15 minutes after the cessation of exercise.Bronchodilation is a normal physiological response to exercise due to a decrease in vagal24tone, catecholamine release, and the slow release of an inhibitory prostaglandin(60).Under both the salbutamol and placebo conditions, PEFR increased significantly over thecourse of exercise, but these were only different from each other in the first two stages ofexercise. Salbutamol proved to be an effective bronchodilator as the pre-exercise PEFRmeasure after inhalation of salbutamol was significantly higher(3.1% for all 17 subjectsand a 6.6 % rise in the more severe asthmatic group(PC20< 4.0 mg•m14))than the preexercise salbutamol or placebo condition, and provided protection throughout theexercise and recovery period (see Figure 4). Meeuwisse et aL, (49) also showedasimilar rise (4.5 %) after the administration of salbutamol, but in highly trained non-asthmatic subjects. A rise in circulating catecholamine levels during exercise has beendemonstrated in normal and asthmatic subjects(9). In this study, at higher intensities ofexercise (>75 %VO2max),the rise in PEFR under the placebo condition was nodifferent from measures under the salbutamol condition, thus suggestingthat theasthmatic subjects had a sufficient concentration of circulating adrenaline, enoughtoprevent any bronchoconstriction from occurring during exercise. Some studies havesuggested that asthmatics have a blunted sympathoadrenal system, which is responsiblefor the post-exercise bronchoconstriction (6, 64). Although catecholamine concentrationswere not measured in this study, this does not appear to be the case in theasthmaticstested. Fifteen minutes after stopping exercise, the mean PEFR for all subjects fell 12 %under the placebo and 6 % with salbutamol. The duration, intensity,and type of exerciseare determinants of the severity of the exercise-induced bronchospasm; this may explainwhy a greater fall in PEFR was not seen under the placebo condition as comparedtoother studies reporting larger falls in PEFR (1, 35, 56). The exercise protocolof 20minutes in duration on a cycle ergometer would account for this, as running hasbeenshown to be more asthmogenic than cycling and a duration of 6-8 minutesat 60-85 %25VO2maxhas been found to cause the greatest post exercise bronchoconstriction.(4, 59).Beyond this time the severity of the response is reduced and asthmatics have beenobserved to “run through” their asthma (19). Also, the first 10 minutes of theexperimental test consisted of a slow increase in workloads of intensities of 25 and 50 %VO2max;this submaximal warm-up could provide protection against EIA by facilitatingthe release of catecholamines. A recent study demonstrated a continuous warm-up of 15minutes at 60 %VO2maxcan significantly minimize EIA in moderately trainedasthmatics (48). Thus, a more progressive, short duration exercise protocol may haveproduced a greater physiological response in the asthmatics tested.A logical concern is whether the severity of one’s asthma is a determinant ofdisturbances in performance-related variables such asVE,V02,Sa02,RER, and LA. Inthe present study we chose aPC2Oof< 16 mg.mi1of methacholine as indicative ofcurrent asthma. Cockroft et al., (13) used a cut off point of 8 mg/mi and below to be asensitive indicator of asthma and concluded concentrations between 8 and 16 mg.m11tobe a” gray area” or borderline hyper-responsiveness. Malo et a!., (41) suggestedPC2O<16 mg•mP1as an acceptable concentration based on his findings that 8 % of a populationwould show a reaction in the asthmatic or abnormal range. The mean values for both theHT and MT groups were below 8 mg.ml1in the present study. Also, data analysisperformed on the more severe asthmatic subjects(PC20<4.0 mgm1-1)revealed nosignificant difference inVE, V02,RER,Sa02, andLA between the two experimentalconditions. However, mean PEFR measures averaged over the exercise and recoveryconditions were significantly higher with the pretreatment of salbutamol. Therefore, theseverity of asthma does not appear to have a greater disturbance on physiologicalparameters during exercise.26Of the 17 asthmatic subjects tested, 12 of the subjects felt the experimental testwith the placebo to be more difficult than with the salbutamol, while 5 subjects found nodifficulty in breathing in either of the exercise tests. 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Ingemann-Hansen, T., A. Bundguaard, J. Hallcjaer-Kristensen, J. SiggaardAndersen and B. Weeke. Maximal oxygen consumption rate in patients withbronchial asthma-the effect off2-adrenoreceptorstimulation. Scand. J. Clin. Lab.Invest. 40: 99-104, 1980.34. Juniper E. F., D. W. Cockcroft, and F. E. Hargreave. Histamine and methacholineinhalation tests: tidal breathing method. Canadian Thoracic Society, Ab Draco,Lund, Sweden, 1991.35. Katz, R. M., B. J. Whipp, E. M. Heimlich, and K. Wasserman. Exercise-inducedbronchospasm, ventilation, and blood gases in asthmatic children. J. of Allergy47(3): 148-158, 1971.36. Katz, R. M. Asthma and sports. Ann. Allergy. 51: 153-160, 1983.37. Katz, R. M. Prevention with and without the use of medications for exerciseinduced asthma. Med. Sci. Sports andEx. 18(3):331-333, 1986.38. Kivity, S., Y. B. Aharon, A. Man, and M. Topilsky. The effect of caffeine onexercise-induced bronchoconstriction. Chest 97 (5): 1083-1085, 1990.39. Koskolou, M. D. andD. C. 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Rhodes, D. R. Stirling, 3. P. Wiley, D. W. Dunwoody, I. B.Filsinger and A. Stevens. Salbutamol and treadmill performance in non-atopicathletes. Med. Sci. Sports Exerc. 15(6): 520-522, 1983.47. McKenzie, D. C. The asthmatic athlete: a brief review. Clin. J. Sport Med. 1:110-114, 1991.48. McKenzie, D. C., S. L. McLuckie,. The protective effects of continuous andinterval exercise in athletes with EIA. Med. Sci. Sport Ex.erc., In press, 1994.49. Meeuwisse, W. H., S. R. Hopkins, J. Roads, and D. C. McKenzie. The effects ofSalbutamol on performance in elite non-asthmatic athletes. Med. Sci. Sports &Exercise. 24(10): 1161-1 166, 1992.50. Meltzer, D. L. and J. P. Kemp. Beta2-Agonist: phannacology and recentdevelopments. J. Asthma. 28(3): 179-186, 1991.51. Morton, A. R. , C. A. Scott, and K. D. Fitch. The effects of Theophylline on thephysical performance and work capacity of well-trained athletes. J. ofAllergy &Clinical Immunology 83: 55-60, 1989.52. Morton, A. R., and K. D. Fitch. Asthmatic Drugs and Competitive Sport: AnUpdate. Sports Medicine 14(4): 228-242, 1992.3153. Packe, G. E., 3. Wiggins, B. M. Singh, M. Nattrass, A. D. Wright and R. M.Cayton. Blood fuel metabolites in asthma during and after progressivesubmaximal exercise. Clin. Sd. 73: 81-86, 1987.54. Page, C. P. Beta Agonists and the Asthma Paradox: Review article. J. ofAsthma.30 (3), 155-164, 1993.55. Powers, S. K., S. Dodd, 3. Lawler, G. Landry, M. Kirtley, T. McKnight, andS.Grinton. Incidence of exercise induced hypoxemia in elite endurance athletesatsea level. Eur. J. Appi. Physiol. 58: 298-302, 1988.56. Schmidt, A., B. Diamant, A. Bundgaard and P. L. Madsen. Ergogenic effect ofinhaled B2-Agonist in asthmatics. mt. J. Sports Med. 9: 338-340, 1988.57. Schoeffel, R. B., Anderson, S. D. and R. E. C. Altounyan. Bronchialhyperreactivity in response to inhalation of ultrasonically nebulizedsolutions ofdistilled water and saline. Br. Med. J. 283: 1285-1287, 1982.58. Shapiro, G. G., J. P. Kemp, R. DeJong and M. Chapko. Effects of albuterol andprocaterol on exercise-induced asthma. Ann. Allergy. 65:273-276, 1990.59. Silverman, M. and S. D. Anderson. Standardization of exercise tests inasthmaticchildren. Arc. Dis. Child. 47: 882-889, 1972.60. Spector, Sheldon L. Update on exercise-induced asthma. Annals ofAllergy. 71Dec.): 571-577, 1993.61. Sport Medicine Council of Canada and Sport Canada. Banned and restricteddoping classes and methods. Government of Canada, Fitness and Ameteur Sport,1989.62. Stanley, W. C., R. A. Neese, J. A. Wisneski, and E. W. Gertz. Lactate kineticsduring submaximal exercise in humans: Studies with isotopic tracers. JCardiopulmonary Rehabil 9: 331-340, 1988.63. Strauss, R. H., E. R. Mcfadden, R. H. Ingram, E. C. Deal and J. J. Jaeger.Influence of heat and humidity on the airway obstruction inducedby exercise inasthma. J. Clin. mv. 61:433-440, 1978.64. Warren, 3. B., R. 3. Keynes, M. 3. Brown, D. A. Jenner and M. W. McNicol.Blunted sympathoadrenal responses to exercise in asthmatic subjects. Br.J. Dis.Chest. 76: 147-150, 1982.65. Wasserman, K., W. L. Beaver, and B. J. Whipp. Mechanism and patterns of bloodlactate increase during exercise in man. Med. Sci. Sport Exerc. 18(3): 344-352,1986.3266. Weinberger, S. E.. Principles of pulmonary medicine. 1986 W. B. SaundersCompany, Toronto.67. Voy, R. 0. The U.S. Olympic Committee experience with exercise-inducedbronchospasm, 1984. Med. Sci. Sports Exerc. 18(3): 328-330, 1986.33APPENDIX A - Review of LiteratureEXERCISE INDUCED ASTHMAi) Introductionii) Clinical Presentationiii) Diagnosisiv) Pulmonary function testsv) Pathogenesisa) Hypernea, Hypocapnea, and Lactic acidosisb) Heat and Water Loss theoryvi) Preventionvii) Treatmenta) 3-Adrenergic receptor physiologyb) Salbutamol (f2 Adenergic agonsist)c) Other Pharmacological Agentsviii) Circulatory, Ventilatory, and Metabolic Responses to Exercise34REVIEW OF LITERATUREEXERCISE-INDUCED ASTHMAi) IntroductionExercise-Induced Asthma (EIA) is defined as a reversible airway narrowingprecipitated by physical activity. Exercise can be a potent stimulus for producingbronchoconstriction within minutes after exercise in most individuals with asthma.However, with the proper medication and management, asthmatics are encouraged toparticipate in sports. In fact, the prevalence of asthma among competitive athletes ishigher than one would expect; 11.2% of athletes competing in the 1984 Olympic gamessuffered from EIA (67). The attack of bronchoconstriction, classically displayed by signsof chest tightness, shortness of breath, wheezing, and coughing, is most apparent 5-15minutes after exercise (2). Clinically, this airflow obstruction is represented by adecrease in flow rate which can be measured by simple spirometry, Forced ExpiratoryVolume in 1 second (FEVi) or Peak Expiratory Flow Rate (PEFR).While the precise mechanism of EIA is still unclear, it is generally accepted thatcooling and drying of the airways associated with high ventilation represent the initiatingstimuli for the post-exercise bronchoconstriction (3, 14, 63). This popular theory hasbeen criticised and a new hypothesis suggesting EIA to be a vascular phenomenon has35been proposed (45). It has also been suggested that because exercise can cause airwaynarrowing in the absence of irritants or antigens, perhaps metabolic changes associatedwith exercise could trigger bronchoconstriction (5).ii) Clinical Presentation:The classical signs of an acute asthmatic attack are chest tightness, shortness ofbreath, coughing, and/or wheezing. However, some individuals with EIA may onlycomplain of one of these symptoms, eg., breathlessness or coughing may be apparentduring or shortly after moderate to strenuous exercise. Approximately 90 % individualswith asthma and 35-40% of those with allergic rhinitis/hay fever experience EIA(42).Exercising at a intensity of 65-85 % for 6-8 minutes produces maximalbronchoconstriction; above this intensity or duration diminishes the EIA response (59).The common physiological response of an individual with EIA to exercise is mildbronchodilation, usually persisting throughout exercise, followed by bronchoconstrictionin recovery. This increase in airway resistance peaks 8-15 minutes after exercise hasceased and normal pulmonary function returns in 30- 60 minutes.iii) Diagnosis:In diagnosing individuals with EIA, bronchial provocation tests with methacholineor histamine, or an exercise challenge can be used to measure the degree of bronchialhyperactivity in subjects. Bronchial provocation challenges with36pharmacological agents such as methacholine or histamine are performed by measuringchanges in lung function followed by inhalation of the agent, increasing in doublingconcentrations (60). The most popular method of administering phannacologicalprovocation tests is the continuous tidal volume breathing method from a nebulizer. Themost commonly used index of bronchial reactivity is thePC2O,the concentration ofmethacholine/histamine which provokes a fall in FEV1 to 20% below the control level.Histamine is thought to trigger airway constriction through stimulation of sensoryreceptors and direct action on bronchial smooth muscle (29). On the other hand,methacholine acts on cholinergic muscarinic receptors on airway smooth muscle, and inasthmatic airways, smaller doses of methacholine are needed to cause a bronchialresponse (40).A standardized exercise challenge test described by Silverman & Anderson (59)consists of a 6-8 minutes of steady state exercise on the treadmill or cycle ergometer at90% of the subjects predicted maximal HR. A 15 -20 % decrease in FEVi is consideredto be a positive exercise challenge test (34, 40). Several authors have compared thesetests and found the pharmacological challenge with methacholine to be better than thehistamine or the exercise challenge in distinguishing the asthmatics from the controls (11,40).37iv) Pulmonary Function Tests:In asthmatics, the typical pattern of change in pulmonary function during exerciseis a slight decrease in airway resistance which is measured by an increase in PEFR andFEVi, compared to normal subjects (26,47). This appears to be due to the release ofcatecholamines (24). However, within minutes after exercise, airway resistance increasesmarkedly with peak bronchospasm between 5-15 minutes (10) and recovers to baselinelevels within 30 to 40 minutes (2, 36). The response to exercise can be determinedbyseveral indexes of pulmonary function: FEV1,PEFR, and FEF 25-75% (MMEF). Achange in large and small airway resistance is quantified by the ratioFEVi/FVC. A fallin FEV1 of 20-30% is considered to be mild to moderate obstruction while a fall greaterthan 30% is considered severe (36).Forced expiratory flow between 25 and 75% (FEF 25-75% or maximal midexpiratory flow rate (MMEF))of volume expired during Forced Vital Capacity (FVC) isa sensitive measure of airflow obstruction in the smaller airways (36,47). Peak expiratoryflow rate (PEFR) measured by a Wright Flow Meter is the most commonly used methodof determining airway resistance in the small and large airways because of its portabilityand convenience, but more variable results have been shown using this methodcompared to FEV1 (66). Both FEV1 and PEFR are effort dependent measures and aretherefore not the most sensitive measure compared to the effort independent measureMMEF.Flow-volume curves illustrate in greater detail the specific airway conductance orflow at different lung volumes. Obstruction in the upper expiratory phase is apparentwhen the curve appears “scooped” or “curved” rather than a smooth continuous line as38seen in normal loops. However, the flow-volume ioop can be abnormal even when theFEVi/FVCratio is normal, thus implying the greater sensitivity of this test (66).v) Pathogenesis:For some time, asthma and EIA were thought to be two separate conditions. It isnow known that exercise is just another stimulus in provoking an asthmatic attack.Although the exact etiology of EIA is still unclear, several theories have been proposed.Earlier studies have speculated hyperventilation, hypocapnia, and acidosis to be causallyrelated to ETA (6, 10, 32, 43). The more widely accepted theory today is that water andheat loss from the respiratory mucosa represents the initiating stimulus for the post-exercise bronchoconstriction (3, 14, 63). This is based on earlier investigations whichhave consistently demonstrated that asthmatics exercising in warm, humid environmentsare less likely to experience an attack than while exercising in cool, dry environments (2).Recently, a new hypothesis by Mcfadden (45) suggests that ETA is a vascularphenomenon. This theory is built on the fact that asthmatics have a hyperplastic capillarybed in their airways that is highly sensitive to thennal stimuli.a) HYPERPNEA, HYPOCAPNEA, AND LACTIC ACIDOSISHyperventilation associated with exercise and consequent hypocapnia have beensuggested as possible causes of ETA based on earlier studies demonstrating that voluntaryhyperventilation at rest can increase airway resistance in asthmatics (10, 32). Fisher et39a!., (18) demonstrated by breathing an 8% CO2 gas mixture during vigorous physicalactivity, significantly reduced post-exercise bronchoconstriction. On the other hand,Chan-Yeung et al., (10) noted that the combination of hyper-ventilation and breathingCO2 actually increased airway resistance, measured by a greater decline in FEV1compared to breathing room air. This author concluded that “EIA” is probably exercise-induced hyperventilation “(EIh)”. Although the mechanism of EIh is probably differentfrom EIA, people who suffer from EIA generally develop a bronchial response tovoluntary hyperventilation. Some differences have been found between EIA and EIh;voluntary hyperventilation does not release catecholamines, so the bronchodilationnormally seen in asthmatics during exercise does not occur during the period of hyperneaand therefore a faster onset of bronchoconstriction occurs (29, 60). Also, with exercise adiminished responsiveness to exercise performed within 2 hours after the initial exertionhas been seen in some asthmatics; this refractory period may not occur with voluntaryhypernea (29, 60).Higher blood lactate levels have been reported in asthmatics working at the sameoxygen consumption as non-asthmatics with similar fitness levels (1). This lacticacidosis has been suggested to play a role in EIA based on the theory that high hydrogenion concentrations may cause the release of mediators from mast cells (43). However,the administration of bicarbonate, which buffers the excess H ions, did not appear toreduce post-exercise bronchospasm (43). Therefore, no substantial evidence in theliterature confirms these earlier hypotheses that hypocapnea, hyperventilation, or acidosisare causally related to EIA.40b) HEAT AND WATER LOSS THEORYChen and Horton (12) demonstrated the importance of water lossand/or heat lossby demonstrating that asthmatics who breathe fully saturated air at 37 degrees Celsiusduring exercise prevent EIA. More recent studies by McFadden and co-workers (43,63), who have looked at the effects of environmental conditions on exercise-inducedbronchoconstriction, have helped to clarify some of the earlier controversies regardingetiology. Strauss and McFadden (63) demonstrated a greater bronchospastic responsewhile breathing cold air during exercise, and a blunted response when breathing inspiredair at 37 degrees celsius and fully saturated (BTPS). These findings suggest that thisrapid rewanning of the airways significantly reduces EIA (63). Deal and co-workers (14)developed the heat-flux hypothesis using the following equation to determine heat loss:RHL=VE(HC[Ti-TeJ+Hv[Wi-We])where HC = heat capacity of air (3.04 x 10 Kcal•L10C1), Ti and Te are temperatureof inspired and expired air, respectively in0C, Hv = latent heat of evaporization forwater(5.8 Kcal.g1),and Wi and We = water content of the inspired and expired air atthe mouth, respectively (mg H20•L in air-1).This equation demonstrates that highminute ventilations will have a greater heat loss and a consequently greater airwayobstruction (14). These authors also showed that voluntary hyperventilation whilebreathing cold air produced an increase in airway resistance, suggesting that the stimulusof EIA was heat loss from the respiratory mucosa and not exercise. A weak link in therespiratory heat loss (RHL) theory comes from the fact that inspiring air as warm as 8041degrees causes no less of a bronchoconstriction than while breathing air at bodytemperature.Anderson and coworkers have emphasized the effects of drying of the airways tobe a more important stimulus of EIA than cooling (3, 63). They suggested that theincrease in osmolarity of the respiratory mucosa due to water loss was a possible stimulusof EIA (4). This is based on Schoeffel’s findings which demonstrated that the inhalationof hyper- and hypo-tonic solutions could elicit bronchoconstriction in resting asthmatics(57). This increase in osmolarity was speculated to stimulate the release of mediatorsfrom lung mast cells, thus causing airway narrowing. This is thought to either act onsmooth muscle or on cells in the respiratory mucosa by stimulating epithelial irritantreceptors and/or disrupting epithelial junctions (4). Despite the evidence for thecooling/drying hypothesis, some subjects can still develop EIA while breathing warmhumid air; thus implying thatH20and RFIL cannot be the sole trigger factors bythemselves (8).Gilbert and McFadden (24) have challenged the osmolarity theory, and havepresented a new hypothesis suggesting that exercise-induced asthma is a vascularphenomenon. These investigators demonstrated little change in surface osmolarity whenthe intrathoracic thermal fluxes were measured during hypemea. This indicates that therespiratory tract has a protective mechanism that prevents drying of the airways (24).McFadden (45) proposed a new hypothesis that suggests cooling of the airways afterexercise is followed by rapid warming and the development of mucosal hyperemia andedema, thus causing the airway narrowing. Recently Gilbert and McFadden tested thistheory and found both airway cooling and rapid rewarming after isocapnic42hyperventilation played a key role in the production of bronchial narrowing (25)Although they were not able to determine how rapid bronchial rewarming causes theobstruction, they suggested the development of mucosal hyperemia and edema to be apossible explanation. If this theory is correct, the degree of hyperemia would depend onthe rate of bronchial rewarming. Slow rewarming (ie. the subject warms down) has beenfound to abolish the effects of hyperventilation or hyperpnea during exercise, whereasrapid rewarming increases obstruction (45). It has also been shown that airways ofasthmatics rewarm twice as fast in the first minute of recovery than normal individuals(24). Because hyperemia increases local heat in the bronchial circulation, the main heatsource in the central airways, supports the hypothesis that EIA could be due to the heat-sensitive airway microcirculation responding to the fall that accompanies hyperpnea.However, rewarming may not be the trigger because asthmatics who are able to “runthrough” their asthma fail to develop bronchoconstriction after prolonged exercise, butstill rewarm their airways (29).vi) Prevention:EIA can be prevented in many asthmatic athletes who choose not to usemedication. Different types of activities are less asthmogenic; for example, exerciseperformed in warm humid environments, such as swimming, are less likely to provoke anattack than outdoor cold weather activities such as running, cycling, rowing, crosscountry skiing, and hockey. The duration of exercise is another determinant of theseverity of EIA; for example, sports involving intermittent running such as basketball,football, rugby, and baseball are better tolerated by the asthmatic athlete than continuous43running activities (2, 36). The intensity of exercise can also affect the severity ofexercise-induced bronchospasm; the greatest degree of exercise-induced airwayobstruction tends to occur most frequently in asthmatics exercising between 60 and 85 %of maximal oxygen consumption for 6-8 minutes (59). However, at greater exerciseintensities the degree of post-exercise bronchoconstriction appears unaltered andexercising longer than this generally diminishes the response (1, 19, 47). Performing acontinuous warm-up 15 minutes in duration at an intensity of 60 % of maximal oxygenconsumption prior to exercise significantly protects the airways of asthmatics frombronchoconstriction (48). The improvement in fitness level through aerobic training hasbeen shown to reduce the severity, frequency, and duration of attacks (22, 31). Othertechniques useful in minimizing EIA occurance are making a conscious effort to preventexaggerated hyperventilation by breathing slower and deeper and using nasal breathing,which warms and cleans the air (37).vii) TreatmentAlthough preventative measures can be taken for EIA, some asthmatic athletesrequire pharmacological intervention to overcome their asthma while exercising. Themost effective drugs for preventing EIA are thei2adrenergic agonists: salbutamol,terbutaline, fenoterol, or salmetorol. Salbutamol is the drug of choice by asthmaticathletes because of its powerful bronchodilator effects,2selectivity, and its use ispermitted by the International Olympic Committee (IOC) (67). Other classes ofmedication used are sodium cromoglycate, methyl xanthines, corticosteroids, and belladonna alkaloids.44a)f- Adrenergic receptor physiologyThe n-receptors, stimulated by the sympathetic limb of the autonomic nervoussystem, can be divided into two groups,f3iandP2. 13ireceptors are more potentlystimulated by norepinephrine and are responsible for the chronotropic and inotropiceffects of the heart, decrease in intestinal motility, and lipolysis, whileP2receptorsmediate bronchodilation of airway smooth muscle, cause uterus, bladder, intestinalrelaxation, and dilation of arteries supplying smooth muscle.P2-receptorscan be foundin many different cell types within the lung; including smooth muscle of all airways fromthe trachea down to the terminal bronchioles. Activation of these receptors by 3 agonistscauses relaxation of central and peripheral airways. In addition to relaxation of smoothmuscle, agonists also reduce the release of mediators from mast cells, and may reducemucosal edema. Those drugs activatingPtreceptors cause a number of outcomes thatare unacceptable for use in international sport competitions. Therefore, drugs whichhave a greater selectivity forP2-receptorswith minimal effects oni-receptorsarepreferred because of fewer cardiovascular side effects and their use has been sanctionedby the International Olympic Commission (IOC) (52).The cascade of events is initiated by the stimulation ofP2receptors by aP2adrenoreceptor agonist (ie. catecholamines); this activates the enzyme adenylate cyclase,causing the formation of a second messenger, cyclic AMP (cAMP). Intracellular cAMPactivates protein kinase A, which in the case of bronchial smooth muscle, causes areduction of Ca dependent coupling of actin and myosin, resulting in smooth musclerelaxation. It has been suggested that the increase in bronchial reactivity seen inasthmatics is most likely caused by a decrease in the -adrenergic response (50).45b)132Adrenergic agonist (Salbutamol)Salbutamol is one of the first generations of132- adrenergic agonists developed fortreating asthma. Inhaled Salbutamol given 15 minutes prior to exercise is very effectivein preventing the post-exercise fall in PEFR (27, 58). Subjects given a placebo will showa 40% drop in peak flow and only a 10% drop with salbutamol, which is within normallimits. This drug has full bronchodilator effects for up to 3 hours with partial activity upuntil 6 hours (58). Inhalation of12agonists is the more preferred method of deliveryover oral, sublingual, or parental (intravenous or intramuscular) routes because of itsrapid onset of action, direct route to the respiratory tract, and fewer side effects.However, some subjects have experienced tremors, which are caused by directstimulation of132adrenoreceptors in skeletal muscle (50). There is a growing concern ofthe overuse of sympathomimetic drugs based on a number of studies demonstrating theregular use of132agonists can lead to an increase in bronchial hyperresponsiveness (54).The use of salbutamol has been permitted by I.O.C. based on the assumption thatthis 13-agonist has no ergogenic effect in the asthmatic athlete. Studies that have looked atthis drug in asthmatics and non-asthmatics as a possible performance enhancer, havereported conflicting results (7, 46, 49, 56). Bedi et al., (7) found salbutamol to increasesprint time in normal subjects, while others have reported no ergogenic benefit in non-asthmatics (46,49). Schmidt et al., (56) also found this drug to have no effect on exerciseperformance in asthmatics, thus encouraging its use by the asthmatic athlete to minimizeEIA in competitive events. More recently Meeuwisse et al., (49) conducted a similarstudy to Bedi et al., (7) on elite non-asthmatic cyclists and found salbutamol to have noperformance enhancing effect when given in therapeutic doses.46c) Other Pharmacological AgentsSodium Cromoglycate is a safe and effective drug for the prophylacticmanagement of asthma. In the treatment of EIA sodium cromoglycate can be used incombination with other drug classes and has been shown to be effective in preventingEIA when given before the start of exercise, but has little effect once EIA has beeninduced. Its mode of action was once thought to be a mast cell stabiliser but appears tohave effects on other systems. There are no cardiovascular effects or performanceenhancing qualities, therefore, sodium cromoglycate is allowed in international sportingcompetition (20, 52).Methyl Xanthenes; one of the most extensively ingested drug of this group iscaffeine. It has been shown to cause relaxation of bronchial smooth muscle and cansignificantly prevent EIA in high doses (7 mg/Kg) (38). Caffeine is banned incompetition if serum concentrations exceeds 12 mg.L1(61). Theophylline, a methylatedxanthene, is not as effective of a bronchodilation in the management of asthma as132agonists, but are used effectively by individuals who do not tolerate132stimulants.Theophylline is comparable to sodium cromoglycate in inhibiting EIA. However, thereare a number of side effects including tacchycardia, mild CNS stimulation, diarrhea,headache, and nausea which are not compatible for use by an athlete during competition(51).Oral and intravenous glucocorticosteroids play a valuable role in the managementof severe chronic and acute asthma. The use of systemic corticosteroids have beenbanned from international sport competitions due to their potential to enhanceperformance. Inhaled glucocorticosteroids , on the other hand, have been found to have47no ergogenic effects, but like oral glucocorticosteroids , stabilize asthma, and have littleeffect on EIA if administered just prior to exercise. Taken on a regularbasis, inhaledglucocorticosteroids reduce inflammatory cell filtrate, bronchial hyperreactivity,andimprove the effectiveness of pre-exercisef32agonist in reducing the severity of EIA (52).Belladonna Alkaloids are anticholinergic agents that play a role in themanagement of asthma. Ipratropium bromide is an example of this class andisadministered via aerosol or by a nebulised solution. As a bronchodilator ipratropiumbromide is used by individuals who do not respond well to 3 agonists or givenincombination with agonists and/ or sodium cromoglycate to give better protectionthanusing either drug alone. Side effects are rare with this drug, however some asthmaticscomplain of dryness of the throat. It is doubtful whether anticholinergic agents playarole in preventing EIA or whether these drugs will enhance performance(20).48vii) Circulatory, Ventilatory, and Metabolic Responses to ExerciseFew studies have examined the physiological responses of asthmaticsduringexercise. In the data available, asthmatics have generally responded similarlyto normalsubjects when free from an attack (44). Any differences in these variables havebeenconcluded to be due to the sedentary state of the asthmatics tested; for example,higherblood lactate levels in asthmatics have been reported by several authors (1,5,10,53).These individuals were inactive, so these higher levels could be morerepresentative oftheir lower fitness level. On the other hand, Andersonet al., (1) found unusually highlevels of lactate in asthmatics working at the same oxygen consumption as similarlytrained non-asthmatics. It is not clear whether this response is due to the presenceofasthma. If so, this greater degree of metabolic acidosis mayaffect the optimalperformance of these athletes with EIA.During the initial phase of exercise, many asthmatics develop mildbronchodilation, which is thought to be due to the release of catecholamines (26, 29).This bronchodilation usually persists throughout the duration of exercise,but maygradually decrease as indicated by a fall in PEFR. However, within minutes ofcompleting exercise, there is a profound drop in PEFR (orFEVi) due tobronchoconstriction. The failure of normal catecholamine release during exercise may beresponsible for this post-exercise airway narrowing seen in individuals with EIA. Muchdebate exists in the literature as to whether asthmatics actually have an alteredcatecholamine response to exercise. Some investigators have found significantly lowerplasma adrenaline and noradrenaline levels in asthmatics when compared to matched49control subjects (6, 64), while other studies have not (9). This inconsistency may lie inthe different protocols used. The former studies measured catecholamine levels at theend of exercise, whereas in the latter study blood samples were obtained throughout theexercise period.The alveolar to arterial P02 [A-aD02]is a good indicator of the adequacy ofpulmonary gas exchange. In normal subjects(A-a)D02decreases during moderateexercise, due to an improvement of perfusion(Q)at the lung apices, but increases duringhigher intensities of exercise. Katz et al., (35) found the distribution of ventilation-perfusion (VA/Q) over the lung became more uneven during a progressive exerciseperformance in asthmatic children. Changes that develop in gas tension in asthmaticsduring exercise have been shown to be variable. Some authors have found no change inarterial oxygen tension (21), while others have reported a significant rise inPa02fromresting levels in asthmatics performing progressive exercise (1, 35). After exercise, a fallin Pa02 has been observed to develop concomitantly with bronchoconstriction. Thishypoxemia may be a result of inequalities in the VA/Q relationship due to airwaynarrowing(1). ArterialPCO2was found to be variable in asthmatics during exercise(1, 21), while unchanged in others (35). Following exercise, hypercapnia may developin asthmatics due to marked bronchoconstriction, but this does not occur in normalindividuals.Arterial oxygen (Pa02) and arterial PCO2 of normal subjects stay relativelyconsistant throughout exercise, although some HT athletes(VO2max> 68 ml.kg.miw1who are free of asthma, exhibit arterial hypoxemia at maximal exercise. Thisphenomenon in HT athletes is called exercise-induced hypoxemia (EIH), and maysuggest that the lungs are the “limiting” factor for exercise performance in these athletes50(16). Although the exact etiology is still unknown, one of the causes is due to theexcessive widening of(A-a) D02 . It would be interesting to determine whether HTasthmatic athletes, who show arterial desaturation, are limited at maximal exercise.Several investigators have found physiological parameters such as HR,V02, VE,FEVi,and work capacity in asthmatics during submaximal and/or maximal exercise tobe within normal range (1, 33, 53, 56). Anderson et al., (1) compared metabolic andventilatory responses in 5 asthmatic subjects during a 6-8 minute test on both a cycleergometer and a treadmill. The treadmill running did produce the greatestbronchoconstriction, indicated by a fall in PEFR measures, and the higher lactates wereobserved during the cycle. The levels of lactate observed in these asthmatics during thecycle were found to be higher when compared to non-asthmatics exercising at similaroxygen consumptions. Packe et al., (53) tested 10 untrained asthmatics with 10 matchednon-asthmatics during progressive exercise test on a treadmill to 85 % maximal V02. Nodifference was found between the two groups with respect to V02,VE, Sa02,and RERduring exercise, but RER values were higher in the asthmatics thus, indicatinga normalfat metabolism in these subjects. Also, the similar levels ofV02, VE,and Sa02 incomparison to the non-asthmatics, indicated no impairment of oxygen delivery toexercising muscle in asthmatics (53). Ingemann-Hansen et al., (33) measured metabolicand ventilatory variables (maximal V02,VE,and HR) in asthmatics during a gradedbicycle exercise and found no difference between inhaled salbutamol and saline control.All of the studies to date, investigating the metabolic and ventilatory responses ofasthmatics to exercise, have tested unfit subjects; therefore,the lower maximal oxygenconsumption (VO2max), work capacity, and higher levels lactate reported in asthmaticshave been due to the lower fitness level of these individuals.51In the literature, no study has looked at metabolic and ventilatory variablesin highlytrained athletes(VO2max > 60 mi/kg/mm). if higher lactate levels and alterations in gasexchange develop in asthmatics due to the presence of their disease, it is possibletheseabnormalities could limit these individuals in athletic performance.52APPENDIX BTablesTABLE 7. Age, height, weight,VOmax, andPC2O,individual data of subjectsin the Highly trained groupSUBJECT SEX AGE HEIGHT WEIGHT VO2maxPC2Oyears cm kgmlkgmin1mg•mI1HT groupCL F 22 175 63.357.8 3.9JH M 23 180 72.9 63.46.3PMS F 24 158 50.853.9 6.1PH M 24 180 72.863.3 15.8PM F 33 162 55.3 54.40.7PR M 32 19085.0 58.8 11.5RH M 19 182 74.160.3 3.1SH F 35 170 64.050.3 15.6SS F 23 165 59.1 50.9 1.6MEAN±SD 26±6 174 ± 11 66.4± 10.8 57.0 ± 4.9 7.2 ± 5.853Table 8. Age, height, weight,VOmax, andPC2O,individual data of subjectsin the Moderately trained groupSUBJECT SEX AGE HEIGHT WEIGHT VO2max PC2Oyears cm kgmFkgmhr1MT groupAB M 23 192 87.0 57.0 11.2GK M 21 180 72.0 46.4 0.8PK M 23 187 85.1 57.3 8.9RC M 23 189 93.5 48.7 1.6RF M 23 175 71.4 53.1 9.4SB M 26 182 75.5 54.6 5.0SM M 23 200 96.0 48.6 15.9CM F 31 161 48.6 45.1 8.0MEAN ±SD 24±3 183 ± 12 78.6 ± 15.3 51.3 ± 4.9 7.6 ± 5.054Table 9.YE,V02,RER, HR, PEFR, andSa02at 25 % VO2max withplacebo, individual subject data(n = 17)SUBJECT YE V02 RER HR PEFR Sa02btps1•min-1bpm1•sec-125%CL 33.2 1.16 0.89 96.0 500 96.0JH 31.9 1.14 0.78 101.3 640 96.5PMS 26.7 0.73 0.89 113.0 410 97.3PH 32.5 1.20 0.80 105.8 600 97.3PM 23.8 0.76 0.84 91.3 355 96.5PR 34.8 1.49 0.78 114.5 520 96.5RH 27.1 0.98 0.74 99.8 560 97.3SH 24.6 0.83 0.71 110.5 545 97.8SS 34.1 1.26 0.87 106.5 490 97.8AB 39.4 1.67 0.77 117.8 730 97.3GK 34.2 1.23 0.85 113.8 470 96.0PK 29.2 1.29 0.78 85.5 600 96.8RC 39.8 1.26 0.78 81.5 530 96.3RF 28.4 1.17 0.72 101.8 670SB 32.2 1.23 0.89 97.8 620 97.3SM 37.2 1.47 0.87 118.0 680CM 28.1 0.95 0.77 108.3 440MEAN±SD 31.6±4.8 1.16±.26 0.81±.06 103.7±10.9 550±102 96.9±0.655Table 101E.V02,RER, HR, PEFR, andSa02at 25 % VO2max withsalbutamol, individual subject data (n = 17)SUBJECTVE V02RER HR PEFR Sa02btps1•min1bpm1•sec-125%CL 32.4 1.13 0.81 90.0 490 97.3iii 36.5 1.31 0.85 106.0 630 97.3PMS 36.0 1.09 0.86 117.3 420 98.3PH 36.7 1.28 0.81 108.3 710PM 20.0 0.67 0.77 97.3 485 94.0PR 30.8 1.32 0.72 102.8 590 96.5RH 24.2 0.88 0.82 98.8 660 95.8SH 30.6 1.01 0.73 116.3 565 99.3SS 24.4 1.00 0.76 100.3 535 98.3AB 31.0 1.47 0.74 106.8 710 95.5GK 32.0 1.24 0.87 111.5 510 96.5PK 35.3 1.37 0.91 89.0 640 96.0RC 39.5 1.32 0.72 89.8 640 97.5RE 26.3 1.03 0.78 104.8 650 97.8SB 32.1 1.30 0.85 106.0 720 97.8SM 38.6 1.55 0.87 125.5 710 95.8CM 26.1 0.92 0.82 106.0 450MEAN ±SD 31.3 ± 5.6 1.17± .23 0.80± .06 104.5 ± 10.0 595 ±98 96.9 ± 1.456Table 11 VE, V02,RER, HR. PEFR, and Sa02 at 50 % VO2max withplacebo, individual subject data(n = 17)SUBJECT YE V02 RER HR PEFR Sa02btps1•min1bpmI•sec-150%CL 53.2 2.07 0.87 133.3 520 95.8JH 59.2 2.20 0.88 136.5 640 95.5• PMS 48.7 1.49 0.95 149.3 440 96.3PH 52.8 2.33 0.81 144.0 675 95.5PM 39.2 1.51 0.85 126.8 370 96.8PR 80.5 3.32 0.86 147.8 525 95.8RH 45.5 1.81 0.75 136.0 610 96.5SH 45.7 1.41 0.82 158.8 565 98.0SS 47.6 1.84 0.92 125.5 480 96.5AB 61.0 2.65 0.84 144.5 700 97.0GK 59.7 2.03 0.96 145.8 480 96.3PK 44.3 1.91 0.82 109.3 615 96.0RC 70.1 2.43 0.91 114.3 585 96.8RF 49.5 1.97 0.83 134.5 650SB 53.3 2.11 0.95 134.5 670 97.5SM 50.7 2.19 0.90 142.3 705 97.0CM 37.9 1.34 0.82 122.5 420MEAN ±SD 52.9 ± 10.8 2.03 ± .49 0.87 ± .06 135.6 ± 12.9 567 ± 104 96.5 ± 0.757Table 12 VE, V02,RER, HR. PEFR, and Sa02 at 50 % VO2max withsalbutamol, individual subject data (n = 17)SUBJECTYE V02 RER HR PEFR Sa02btps1.min-1bpm1•sec150%CL 54.2 1.92 0.92 119.3 535 97.0JH 64.2 2.32 0.98 138.0 660 97.0PMS 46.5 1.56 0.90 138.3 490 97.3PH 57.2 2.30 0.82 142.5 680 98.3PM 39.8 1.45 0.88 123.5 420 94.5PR 59.2 2.53 0.83 132.3 600 96.5RH 45.0 1.75 0.86 134.0 675 96.0SH 53.7 1.72 0.78 154.3 580 98.8SS 39.6 1.64 0.85 122.3 540 95.5AB 56.9 2.64 0.82 138.5 690 96.3GK 52.7 1.83 1.03 145.3 510 96.8PK 41.9 1.84 0.90 112.0 670 96.5RC 69.4 2.42 0.77 120.0 700 97.3RF 48.1 1.94 0.80 140.8 660 97.0SB 54.6 2.12 0.92 141.0 710 97.3SM 59.0 2.34 1.01 151.5 720 95.8CM 38.5 1.33 0.90 132.3 460MEAN±SD 51.8±9.0 1.98±.39 0.88±.08 134.4±11.8 606±96 96.7±1.058Table 13 VE, V02, RER, HR, PEFR, and Sa02 at 75 % VO2max withplacebo, individual subject data (n = 17)SUBJECT YE V02 RER HRPEFRSa02btps1mm1bpm 1.sec-175%CL 107.3 3.31 0.99 170.5 550 95.0JH 110.4 3.31 1.04 173.3 660 94.3PMS 79.0 2.23 1.05 185.5 460 95.3PH 115.3 3.86 1.02 180.3 690 96.5PM 66.0 2.38 0.96 173.3 385 94.5PR 128.0 4.30 1.00 175.0 580 94.5RH 96.8 3.25 0.87 173.5 700 96.8SH 114.6 2.61 1.09 191.8 600 95.8SS 69.4 2.51 0.98 159.3 520 95.3AB 110.6 3.99 0.98 172.3 715 96.8GK 91.6 2.95 1.03 172.0 495 96.3PK 71.8 3.44 0.90 150.0 620 94.3RC 120.3 3.62 1.01 161.3 640RE 79.0 3.00 0.92 168.0 660 95.5SB 90.5 3.25 1.04 171.3 730 96.3SM 81.5 3.47 1.01 179.5 735 96.3CM 63.0 1.95 0.90 160.8 510MEAN ±SD 93.8 ± 20.8 3.14 ± .65 0.99 ± .06 171.6 ± 10.1 602 ± 103 95.5 ± 0.959Table 14 VE, V02,RER, HR, PEFR, and Sa02 at 75 % VO2max withsalbutainol, individual subject data (n = 17)SUBJECTVE V02 RER HR PEFR Sa02btpsI. min1bpm1 . sec-175 %CL 106.9 3.02 1.08 163.8 520 95.8IH 115.4 3.55 1.07 170.8 690 96.3PMS 71.7 2.21 0.99 170.0 485 95.3PH 120.0 3.72 1.03 176.3 710PM 65.4 2.24 0.98 169.0 460 94.0PR 95.7 3.72 0.92 160.5 610 96.5RH 100.5 3.02 1.04 170.0 690 95.0SH 113.3 2.98 0.94 186.3 590 97.0SS 68.7 2.34 0.96 149.5 550 96.0AB 102.0 4.16 0.95 171.5 720 96.0GK 94.3 2.81 1.11 176.0 500 95.3PK 70.7 3.28 0.97 154.3 680 95.5RC 125.7 3.74 0.81 159.5 700RE 84.1 3.13 0.89 175.3 670 95.8SB 88.9 3.23 1.01 173.8 730 97.0SM 89.3 3.45 1.07 182.3 740 95.3CM 66.5 1.89 1.03 165.3 470MEAN ±SD 92.9 ± 19.6 3.09 ± .63 0.99 ± .08 169.0 ± 9.5 618 ± 101 95.8 ± 0.860Table 15 VE, V02,RER, HR, PEFR, and Sa02 at 90 % VO2maxwithplacebo, individual subject data (n = 17)SUBJECT VE V02RER HR PEFR Sa02btps1mm4bpm 1 . sec-i90%CL 133.4 3.70 0.95 175.3 540 95.0JH 167.6 3.98 1.16 189.0 680 93.5PMS 107.7 2.60 1.12 195.0480 94.8PH 179.2 4.30 1.08 188.0 700 97.8PM 95.4 2.91 1.05 195.8 450 92.5PR 164.9 4.58 1.04 181.5 550 94.0RH 184.4 4.33 0.92 188.5 650 95.0SH 122.5 2.72 1.09 191.8 58094.5SS 99.2 3.01 1.04 175.8525 94.3AB 178.1 4.88 1.06 189.8 750 95.8GK 135.9 3.51 1.03 187.3490 95.5PK 108.9 4.36 1.04 177.0 700 91.5RC 163.6 4.41 1.05 184.5 675 96.3RF 118.4 3.61 1.04 190.8 660 94.8SB 147.2 3.97 1.17 190.8 740 96.0SM 110.5 4.13 1.11 192.8 740CM 89.5 2.40 0.91 180.5 510MEAN ±SD 135.7 ± 32.2 3.73 ± .76 1.05 ± .07 186.7 ± 6.5 612 ± 102 94.7 ± 1.561Table 16 VE, V02,RER, HR, PEFR, and Sa02 at 90 % VO2max withsalbutamol, individual subject data (n = 17)SUBJECTYE V02RER HR PEFR Sa02btpsI•min-1bpmI.sec-190%CL 116.0 3.24 1.03 171.8 515 93.3JH 173.3 4.25 1.11 185.0 700 93.3PMS 104.9 2.68 1.07 187.3 490 94.0PH 162.0 4.08 1.05 182.5 725 98.0PM 101.3 2.78 1.13 194.3 460 91.5PR 130.0 4.43 1.00 175.0 600 94.5RH 173.8 3.71 1.18 183.8 710 94.3SH 130.4 3.25 0.91 190.8 560 95.5SS 101.0 2.86 1.01 171.3 560 94.8AB 147.4 5.06 1.04 185.0 690 95.8GK 133.0 3.27 1.15 189.3 520 95.5PK 105.1 4.22 1.08 178.3 700 93.3RC 192.9 4.72 0.84 182.0 730 95.8RF 133.7 4.17 1.01 192.5 670 93.8SB 137.8 4.11 0.99 189.8 750 95.3SM 112.0 4.06 1.12 192.0 760 94.8CM 85.0 2.09 1.10 176.5 450MEAN ±SD 131.8 ± 30.2 3.70 ± .81 1.05 ± .09 183.9 ± 7.3 623 ± 108 94.6 ± 1.562Table 17VE,V02,RER, PEFR, andSa02at 25 %VO2maxwithplacebo, individual subject data for NT groupSUBJECT VE V02 RER HR PEFR Sa02btps1• mm1bpmI. sec-125%CL 33.2 1.16 0.89 96.0 500 96.0IH 31.8 1.14 0.78 101.3 640 96.5PMS 26.7 0.73 0.89 113 410 97.3PH 32.5 1.20 0.80 105.8 600PM 23.8 0.75 0.84 91.3 355 96.5PR 34.8 1.49 0.78 114.5 520 96.5RH 27.1 0.98 0.74 99.8 560 97.3SH 24.6 0.82 0.71 110.5 545 97.8SS 34.1 1.26 0.86 106.5 490 97.8MEAN±SD 29.8±4.3 1.06±.26 0.81±.06 104.3±7.9 513±89 96.9±0.7Table 18VE,V02,RER, HR, PEFR, andSa02at 25 %VO2maxwithsalbutamol, individual subject data for the NT groupSUBJECT VEV02 RER HR PEFRSa02BTPS1 mm1bpm1 sec-125%CL 32.4 1.13 0.81 90.0 490 97.3JH 36.5 1.31 0.85 106.0 630 97.3PMS 36.0 1.09 0.86 117.3 420 98.3PH 36.7 1.28 0.81 108.3 710PM 20.0 0.67 0.77 97.3 485 94.0PR 30.8 1.32 0.72 102.8 590 96.5RH 24.2 0.88 0.82 98.8 660 95.8SH 30.6 1.01 0.73 116.3 565 99.3SS 24.4 1.00 0.76 100.3 535 98.3MEAN±SD 30.2±6.1 1.08±.21 0.79±.05 104.1±8.9 565±93 97.1±1.763Table 19VE,V02,RER, PEFR, andSa02at 50%VO2maxwithplacebo, individual subject data for HT groupSUBJECT VE V02 RER HR PEFRSa02btpsI - mm1bpmi . sec-i50%CL 53.2 2.07 0.87 133.3 520 95.75JH 59.2 2.19 0.88 136.5 640 95.5PMS 48.7 1.49 0.95 149.3 440 96.25PH 52.8 2.33 0.81 144.0 675PM 39.2 1.51 0.85 126.8 370 96.75PR 80.5 3.32 0.86 147.8 525 95.75Rh 45.5 1.81 0.75 136.0 610 96.5SH 45.7 1.41 0.82 158.8 565 98SS 47.6 1.84 0.92 125.5 480 96.5MEAN±SD 52.5± 11.9 2.00± .59 0.86±.06 139.8± 11.0 536±98 96.4±.8Table 20VE, V02,RER, FIR, PEFR, and Sa02at 50%VO2max withsalbutamol, individual subject data for the HT groupSUBJECT YEV02 RER HR PEFRSa02btps I. mm4 bpmI - sec150%CL 54.2 1.92 0.92 119.3 535 97.0JH 64.2 2.32 0.98 138.0 660 97.0PMS 46.5 1.56 0.90 138.3 490 97.3PH 57.2 2.30 0.82 142.5 680PM 39.8 1.45 0.88 123.5 420 94.5PR 59.2 2.53 0.83 132.3 600 96.5RH 45.0 1.75 0.86 134.0 675 96.0SH 53.7 1.72 0.78 154.3 580 98.8SS 39.6 1.64 0.85 122.3 540 95.5MEAN±SD 51.0±8.7 1.91±.38 0.87±.06 133.8±11.1 575±89 96.6±1.364Table 21VE, V02,RER, PEFR, andSa02 at 75 %VO2max withplacebo, individualsubject data for UTgroupSUBJECT YE V02RER HRPEFRSa02btps1• mini bpm1• sec-175%CL 107.33.31 0.99170.5550 95.0JH 110.43.31 1.04173.3 66094.3PMS78.9 2.231.0475 185.5460 95.3PH 115.33.86 1.02180.3690PM 65.92.38 0.96173.3 38594.5PR 128.04.30 0.99175.0 58094.5RH96.8 3.250.87 173.5700 96.8SH 114.62.611.09 191.8600 95.8SS 69.42.51 0.98159.3 52095.3MEAN ±SD 98.5± 22.2 3.08 ± .71 1.00± .06 175.8 ±9.3 571 ± 10695.2 ± 0.8Table 22VE, V02, RER, fIR, PEFR, andSa02 at 75 % VO2max withsalbutamol, individualsubject data for theHT groupSUBJECT YE V02RERHR PEFRSa02btpsI. mini bpmI sec175%CL 106.93.02 1.08163.8 52095.8JH 115.43.55 1.07170.8 69096.3PMS 71.72.21 0.99170.0 48595.3PH 120.03.72 1.03176.3 710PM 65.42.24 0.98169.0 46094.0PR 95.73.72 0.92160.5 61096.5RH 100.53.02 1.04170.0 69095.0SH 113.32.98 0.94186.3 59097.0SS 68.72.34 0.96149.5 55096.0MEAN ±SD 95.3 ± 21.42.98 ± .61 1.00 ± .06168.4 ± 10.2 589 ±93 95.7 ± 0.965Table 23VE,V02,RER, PEFR, andSa02at 90 %VO2maxwithplacebo, individual subject data for HT groupSUBJECT VEV02 RER HR PEFR Sa02btps1 mm4bpmI.• sec-190%CL 133.4 3.70 0.95 175.3 540 95.0JH 167.6 3.98 1.16 189.0 680 93.5PMS 107.7 2.59 1.12 195.0 480 94.8PH 179.2 4.29 1.08 188.0 700PM 95.4 2.91 1.05 195.8 450 92.5PR 164.9 4.58 1.04 181.5 550 94.0RH 184.4 4.33 0.92 188.5 650 95.0SH 122.5 2.72 1.09 191.8 580 94.5SS 99.2 3.01 1.04 175.8 525 94.3MEAN ±SD 139.4 ± 35.2 3.57 ± .77 1.05 ± .08 186.7 ± 7.6 572±87 94.2 ± 0.9Table 24 VE, V02, RER, HR, PEFR, and Sa02 at 90% VO2max withsalbutamol, individual subject data for the FIT groupSUBJECT VEV02 RER HR PEFRSa02btps 1•min4 bpm1• sec-190%CL 116.0 3.24 1.03 171.8 515 93.3JH 173.3 4.25 1.11 185.0 700 93.3PMS 104.9 2.68 1.07 187.3 490 94.0PH 162.0 4.08 1.05 182.5 725PM 101.3 2.78 1.13 194.3 460 91.5PR 130.0 4.43 1.00 175.0 600 94.5RH 173.8 3.71 1.18 183.8 710 94.3SH 130.4 3.25 0.91 190.8 560 95.5SS 101.0 2.86 1.01 171.3 560 94.8MEAN ±SD 132.5 ± 30.1 3.48 ± .66 1.05 ± .08 182.4 ± 8.2 591 ± 99 93.9 ± 1.266Table 25VE, V02,RER,HR, PEFR, andSa02, at 25 % VO2max, individualsubject data for the MT groupSUBJECT YE ‘102 RER HR PEFRSa02btps1mm4bpm1sec-125 %AB 39.4 1.67 0.77117.8 730 97.25GK 34.2 1.23 0.85113.8 470 96PK 29.2 1.29 0.78 85.5600 96.75RC 39.8 1.26 0.7881.5 530 96.25RF 28.4 1.17 0.72101.8 670SB 32.2 1.23 0.8997.8 620 97.25SM 37.2 1.47 0.87118.0 680CM 28.1 0.95 0.77108.3 440MEAN±SD 33.6 ± 4.8 1.28 ± .21 0.80 ±.06 103.0±14.1 593 ± 103 96.9 ±0.6Table 26VE, V02, RER, HR, PEFR, and Sa02 at 25 % VO2max withsalbutamol, individual subject data for the MTgroupSUBJECT YEV02RER HR PEFRSa02btps1mm4 bpmi sec425%AB 31.0 1.47 0.74106.8 710 95.5GK 32.0 1.24 0.87111.5 510 96.5PK 35.3 1.37 0.9189.0 640 96RC 39.5 1.32 0.7289.8 640 97.5RE 26.3 1.03 0.78 104.8650 97.8SB 32.1 1.30 0.85 106.0 72097.8SM 38.6 1.55 0.87 125.5 71095.8CM 26.1 0.92 0.82 106.0450MEAN±SD 32.6±5.0 1.27±.21 0.82±.07 104.9±11.7 628±9996.7±.967Table 27VE,V02 RER, HR, PEFR, andSa02 at 50 % VO2maxwith placebo, individual subject data for MT group.SUBJECT VE V02 RER HR PEFRSa02btpslmin4bpm1 sec-150%AB 61.0 2.65 0.84 144.5700 97.0GK 59.7 2.03 0.96 145.8 48096.3PK 44.3 1.91 0.82109.3 615 96.0RC 70.1 2.43 0.91 114.3585 96.8RF 49.5 1.97 0.83 134.5 65097.3SB 53.3 2.11 0.95 134.5670 97.5SM 50.7 2.19 0.90 142.3705 97.0CM 37.9 1.34 0.82 122.5 420MEAN ±SD 53.3 ± 10.1 2.08 ± .39 0.88 ± .06 130.9 ± 14.0603 ± 104 96.8 ± 0.5Table 28VE,V02,RER, HR, PEFR, andSa02 at 50 % VO2max withsalbutamol, individual subject data for the MTgroupSUBJECT VE V02 RER HR PEFRSa02btps1 mm-1bpm1 sec450%AB 56.9 2.64 0.82 138.5690 96.25GK 52.7 1.83 1.03145.3 510 96.75PK 41.9 1.84 0.90112.0 670 96.5RC 69.4 2.42 0.77 120.0700 97.3RE 48.1 1.94 0.80 140.8 66097SB 54.6 2.12 0.92 141.0 71097.3SM 59.0 2.34 1.01 151.5 72095.8CM 38.5 1.33 0.90 132.3 460MEAN±SD 52.6±9.8 2.06±.41 0.89±.09 135.2±13.2640±98 96.7±.668Table 29YE, V02 RER, HR. PEFR, and Sa02 at 75 % VO2max withPlacebo, individual subject data for MTgroup.SUBJECT VEV02RER HR PEFRSa02btps1mm4 bpm1 sec-175%AB 110.6 3.99 0.98172.3 715 96.8GK 91.6 2.95 1.03 172.0495 96.3PK 71.8 3.44 0.90150.0 620 94.3RC 120.3 3.62 1.01 161.3640RF 79.0 3.00 0.92 168.0660 95.5SB 90.5 3.25 1.04171.3 730 96.3SM 81.5 3.47 1.01179.5 735 96.3CM 63.0 1.95 0.90 160.8510MEAN ±SD 88.5 ± 19.2 3.21 ± .61 0.97 ± .06 166.9± 9.2 638±94 95.9 ± 0.9Table 30VE, V02,RER, HR. PEFR, and Sa02 at 75 %VO2max withsalbutamol, individual subject data for the MT groupSUBJECTYEV02 RER HRPEFR Sa02btpsImin1bpm1sec175%AB 102.0 4.16 0.95 171.5720 96GK 94.3 2.81 1.11 176.0500 95.25PK 70.7 3.28 0.97154.3 680 95.5RC 125.7 3.74 0.81 159.5700RF 84.1 3.13 0.89175.3 670 95.8SB 88.9 3.23 1.01173.8 730 97.0SM 89.3 3.45 1.07182.3 740 95.3CM 66.5 1.89 1.03 165.3470MEAN±SD 90.2± 18.5 3.21 ± .67 0.98± .10169.7 ± 9.3 651 ± 106 95.8 ± .769Table 31VE, V02 RER, HR, PEFR, and SaO2at 90 % VO2max withplacebo, individual subject data for MT group.SUBJECT VEV02RER HR PEFRSa02btps 1mm4 bpm1 sec-190%AB 178.1 4.88 1.06 189.8750 95.8GK 135.9 3.51 1.03187.3 490 95.5PK 108.9 4.36 1.04177.0 700 91.5RC 163.6 4.41 1.05 184.5675 96.3RF 118.4 3.61 1.04190.8 660 94.8SB 147.2 3.97 1.17190.8 740 96.0SM 110.5 4.13 1.11 192.8 74095.8CM 89.5 2.40 0.91 180.5 510MEAN±SD 131.5±30.1 3.91±.75 1.05±.07186.7±5.6 658± 103 95.1± 1.6Table 32VE,V02,RER, HR, PEFR, andSa02 at 90 % VO2max withsalbutamol, individual subject data forthe MT groupSUBJECT VE BTPS V02 RER HR PEFRSa021 min1bpm1 . sec90%AB 147.4 5.06 1.04185.0 690 95.8GK 133.0 3.27 1.15189.3 520 95.5PK 105.1 4.221.08 178.3 700 93.3RC 192.9 4.72 0.84 182.0730 95.8RF 133.7 4.17 1.01192.5 670 93.8SB 137.8 4.11 0.99 189.8750 95.3SM 112.0 4.06 1.12 192.0760 94.8CM 85.0 2.09 1.10176.5 450MEAN±SD 130.9±32.3 3.96±.92 1.04±.10185.7±6.2 658± 113 94.8± 1.070Table 33 Pre and post medication and recovery PEFR measures withplacebo, individual subject data (N = 17)SUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm 15 mmPEFR PEFR PEFR PEFR PEFR PEFRCL 525 503 530 520 510 500JH 623 621 660 650 610 620PMS 447 443 430 440 430 430PH 630 633 700 665 635 660PM 338 362 390 390 370 375PR 520 500 540 520 470 480RH 603 610 650 640 635 640SH 545 533 565 540 540 540SS 512 500 490 495 490 490AB 673 673 710 710 700 660GK 437 427 450 440 400 400PK 602 613 650 620 610 620RC 562 503 560 510 500 500RF 640 632 660 660 640 640SB 647 612 675 670 670 650SM 687 667 670 660 640 550CM 460 433 410 425 440 440MEAN±SD 556±96 545±95 573± 108 562± 103 546103 541±9771Table 34 Pre and post medication and recovery PEFR measures withsalbutamol, individual subject data (N = 17)SUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm 15 mmPEFR PEFR PEFR PEFR PEFR PEFRCL 480 483 520 540 500500JH 615 630 640 610570 630PMS 427 443 450 465 475475PH 662 690 725 700 690725PM 342 403 440 425 420415PR 550 567 580 570 570560RH 637 667 700 675 670665SH 547 548 560 540 560 540SS 500 533 540 530 550 535AB 693 667 700 680680 690GK 473 500 510 510505 470PK 600 643 680 640 640670RC 622 670 690 660 680680RF 628 633 670 660 640590SB 653 663 720 700 700700SM 695 717 710 585 610700CM 460 433 460 430 440 435MEAN±SD 564± 102 582± 100 605± 103 584±92 582±91587± 10372Table 35 Pre and post medication and recovery PEFR measures withplacebo, individual subject data for the FIT groupSUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm 15 mmPEFR PEFR PEFR PEFR PEFR PEFRlIT groupCL 525 503 530 520 510500JH 623 621 660 650 610 620PMS 447 443 430 440 430 430PH 630 633 700 665 635 660PM 338 362 390 390 370 375PR 520 500 540 520 470 480RH 603 610 650 640 635 640SH 545 533 565 540 540 540SS 512 500 490 495 490 490MEAN±SD 527±92 523±89 551± 105 540±96 521±93 526±98Table 36 Pre and post medication and recovery PEFR measures withsalbutamol, individual subject data for the HT groupSUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm is mmPEFR PEFR PEFR PEFR PEFR PEFRHT groupCL 480 483 520 540 500500JH 615 630 640 610 570 630PMS 427 443 450 465 475 475PH 662 690 725 700 690 725PM 342 403 440 425 420 415PR 550 567 580 570570 560RH 637 667 700 675 670665SH 547 548 560 540560 540SS 500 533 540 530 550 535MEAN±SD 529± 104 552±99 573± 100 562±89 556±86 560±9773Table 37 Pre and post medication and recovery PEFR measures withplacebo, individual subject data for the MT groupSUBJECT Pre- med. Post-med. 3 mm 5 mill 10 mm 15 millPEFR PEFR PEFR PEFR PEFR PEFRMT groupAB 673 673 710 710 700660GK 437 427 450 440 400 400PK 602 613 650 620 610 620RC 562 503 560 510 500500RF 640 632 660 660 640 640SB 647 612 675 670 670650SM 687 667 670 660 640 550CM 460 433 410 425 440 440MEAN±SD 589±95 570±101 598± 113 587± 112 575113 558± 101Table 38 Pre and post medication and recovery PEFR measureswithsalbutamol, individual subject data for the MT groupSUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm is millPEFR PEFR PEFR PEFR PEFR PEFRMT groupAB 693 667 700 680 680690GK 473 500 510 510 505 470PK 600 643 680 640 640670RC 622 670 690 660 680680RE 628 633 670 660 640590SB 653 663 720 700 700700SM 695 717 710 585 610700CM 460 433 460 430 440 435MEAN ±SD 603±91 616 ± 97 643 ± 99 608 ± 94 612 ± 92617 ± 10874Table 39 Blood lactates (mmol.l-l) at 25, 50,75, and 90 %VO2max with placebo,individual subject data(n = 17)Lactate Placebo(mmoll4) 25 % 50 % 75 %90 %SubjectsCL 1.30 1.53 6.34 7.27il-I 1.23 1.91 6.46 19.04PMS 1.42 1.87 6.13 9.07PH 0.97 1.55 8.86 14.83PM 1.83 1.47 3.66 13.48PR 1.26 2.05 8.12 8.79RH 0.82 0.82 4.84 18.15SH 0.63 1.02 8.90 11.76SS 0.56 1.46 4.45 9.72AB 1.69 2.08 5.85 15.16GK 2.77 3.40 7.73 11.93PK 1.06 1.34 2.17 6.86RC 0.93 0.88 3.33 7.24RF 0.87 1.08 4.24 11.95SB 1.83 2.42 5.90 11.61SM 0.56 1.07 3.43 6.72CM 0.75 0.93 1.79 5.61MEAN±SD 1.20±.58 1.58±.67 5.42±2.20 11.13±4.0275Table 40 Blood lactate (mmol.11)measures at rest and recovery conditions withplacebo, individual subject data (n = 17)Lactate Rest 1 mm 3 mm 5 mm 10 mm(mmol•l1) PlaceboSubjectsJH 0.94 17.22 16.03 18.15 15.69PH 0.84 13.61 13.19 12.22 10.08PR 1.34 9.18 7.84 6.07 6.46RH 1.11 15.68 15.34 13.36 12.05AB 1.00 13.47 15.41 13.94 10.26GK 1.13 10.96 8.78 10.33 8.69PK 1.18 7.37 7.80 7.49 6.07RC 0.44 7.53 7.43 7.43 3.33RF 0.56 13.38 11.26 12.21 7.53SB 1.36 12.58 16.16 14.95 14.91SM 0.37 8.71 7.18 7.83 4.68CL 0.93 7.36 6.90 10.33 7.41PMS 1.47 12.36 10.13 7.15 6.64PM 1.22 13.22 12.00 10.58 10.48SH 0.87 15.05 12.10 12.34 8.08SS 0.64 8.34 9.35 6.92 5.24CM 0.64 3.52 4.6 4.64 3.89MEAN ± SD 0.94 ± .33 11.15 ± 3.66 10.68 ± 3.62 10.35 ± 3.63 8.32 ± 3.5776Table 41 Blood lactates (mmol.l-1)at 25, 50,75, and 90 %VO2max withsalbutamol, individual subject data (n = 17)Lactate Salbutamol(mmol11)25 % 50 % 75 % 90 %SubjectsCL 0.39 1.17 7.97 8.26JH 0.76 2.42 8.73 17.62PMS 1.18 1.39 4.288.86PH 0.57 1.50 6.03 7.74PM 0.91 1.77 3.29 12.67PR 0.27 0.22 2.49 4.28RH 2.85 2.59 8.85 16.63SH 1.08 1.43 8.57 11.52SS 0.95 1.73 3.74 7.64AB 1.02 1.74 5.99 7.95GK 0.97 1.63 5.59 9.98PK 0.49 0.80 2.458.95RC 1.57 2.13 6.589.73RF 3.18 1.21 4.14 13.48SB 1.93 2.08 9.93 16.42SM 0.59 0.83 3.81 6.55CM 0.60 0.95 3.78 6.72MEAN ± SD 1.14 ± 0.82 1.51 ± 0.62 5.66 ± 2.42 10.29 ± 3.8777Table 42 Blood lactate(mmol.l-1)measures at rest and recovery conditionswithsalbutamol, individual subject data(n = 17)Lactate Rest 1 mill 3 mm 5 mill 10 mm(mmol11) SalbutamolSubjectsCL 9.10 10.47 9.05 6.60 0.20JH 16.66 19.31 18.88 19.040.66PMS 8.99 6.09 7.065.50 0.80PH 10.51 8.49 6.425.50 1.06PM 12.16 12.87 9.487.09 0.91PR 4.94 8.28 3.883.07 0.36RH 21.46 17.39 18.31 15.10 2.14SH 12.17 13.51 11.699.53 0.87SS 8.75 8.00 7.80 7.33 0.75AB 9.14 7.06 6.84 4.211.23GK 9.15 10.51 7.30 9.190.22PK 9.93 9.098.70 7.53 0.36RC 9.26 8.43 9.086.21 1.34RF 12.57 12.07 11.71 8.940.91SB 16.72 13.68 14.95 14.341.17SM 9.63 8.66 8.02 6.310.29CM 7.71 7.66 7.22 4.680.65MEAN±SD 11.11 ±3.97 10.68±3.67 9.79±4.148.24±4.24 0.82±0.4978Table 43 Blood lactates (mmolt1)at 25, 50,75, and 90 %VO2maxwith placebo,individual subject data for the HT groupLactate Salbutamol(mmol•l1)25 % 50 % 75 %90 %SubjectsCL 1.30 1.53 6.34 7.27JH 1.23 1.91 6.46 19.04PMS 1.42 1.87 6.139.07PH 0.97 1.55 8.86 14.83PM 1.83 1.47 3.66 13.48PR 1.26 2.05 8.128.79RH 0.82 0.82 4.8418.15SH 0.63 1.028.90 11.76SS 0.56 1.46 4.45 9.72MEAN±SD 1.11±0.41 1.52±0.40 6.42±1.91 12.46±4.22Table 44 Blood lactate(mmol.11)measures at rest and recovery conditions withplacebo, individual subject data for the HT groupLactate Rest 1 mm 3 mm5 mm 10 mm(mmol14)PlaceboSubjectsCL 0.93 7.36 6.90 10.33 7.41JH 0.94 17.22 16.03 18.1515.69PMS 1.47 12.36 10.13 7.156.64PH 0.84 13.61 13.19 12.2210.08PM 1.22 13.22 12.00 10.5810.48PR 1.34 9.18 7.846.07 6.46RH 1.11 15.68 15.34 13.3612.05SH 0.87 15.05 12.10 12.348.08SS 0.64 8.34 9.35 6.92 5.24MEAN ± SD 1.04 ± 0.27 12.45 ± 3.45 11.43 ± 3.16 10.79 ± 3.81 9.12 ± 3.2979Table 45 Blood lactates (mmoltl) at 25, 50,75, and 90 %VO2maxwithsalbutamol, individual subject data for the Hi’ groupLactate Salbutamol(mmol11)25 % 50 % 75 % 90 %SubjectsCL 0.39 1.17 7.97 8.26JH 0.76 2.42 8.73 17.62PMS 1.18 1.39 4.28 8.86PH 0.57 1.50 6.03 7.74PM 0.91 1.77 3.29 12.67PR 0.27 0.22 2.49 4.28RH 2.85 2.59 8.85 16.63SH 1.08 1.43 8.57 11.52SS 0.95 1.73 3.74 7.64MEAN ± SD 1.00 ± 0.76 1.58 ± 0.70 5.99 ± 2.59 10.58 ± 4.42Table 46 Blood lactate(mmol.11)measures at rest and recovery conditions withsalbutamol, individual subject data for the HT groupLactate Rest 1 mill 3 mm 5 mm 10 mill(mmol•11) SalbutamolSubjectsCL 0.20 9.10 10.47 9.05 6.60JH 0.66 16.66 19.31 18.88 19.04PMS 0.80 8.99 6.09 7.06 5.50PH 1.06 10.51 8.49 6.42 5.50PM 0.91 12.16 12.87 9.48 7.09PR 0.36 4.94 8.28 3.88 3.07RH 2.14 21.46 17.39 18.31 15.10SH 0.87 12.17 13.51 11.69 9.53SS 0.75 8.75 8.00 7.80 7.33MEAN ± SD 0.86 ± 0.55 11.64 ± 4.88 11.69 ± 4.69 10.57 ± 5.75 8.75 ± 5.1280Table 47 Blood lactates ( mmol•F1)at 25,50, 75, and 90 %VO2max with placebo,individual subject data for the MT groupLactate Placebo(mmoll1) 25 % 50 % 75% 90 %SubjectsGK 2.77 3.40 7.7311.93PK 1.06 1.34 2.176.86RC 0.93 0.88 3.33 7.24RE 0.87 1.08 4.24 11.95SB 1.83 2.42 5.90 11.61SM 0.56 1.07 3.436.72CM 0.75 0.93 1.79 5.61MEAN ± SD 131 ± .74 1.65 ± 0.90 4.30 ± 2.049.63 ± 3.45Table 48 Blood lactate(mmol•l-l) measures at rest and recovery conditions withplacebo, individual subject data for the MT groupLactate Rest 1 mm 3 mm5 mm 10 mill(mmolP1) PlacebosubjectsAB 1.00 13.47 15.41 13.9410.26GK 1.13 10.96 8.78 10.338.69PK 1.18 7.37 7.80 7.496.07RC 0.44 7.53 7.43 7.433.33RE 0.56 13.38 11.26 12.217.53SB 1.36 12.58 16.16 14.9514.91SM 0.37 8.71 7.18 7.83 4.68CM 0.64 3.52 4.60 4.643.89MEAN ± SD 0.84 ± 0.38 9.69 ± 3.53 9.83 ± 4.129.85 ± 3.61 7.42 ± 3.8681Table 49 Blood lactates(mmol.14)at 25,50,75, and 90 %VO2maxwithsalbutamol, individual subject data for the MT groupLactate Salbutamol(mmol11) 25 % 50 % 75 % 90 %SubjectsAB 1.02 1.74 5.99 7.95GK 0.97 1.63 5.59 9.98PK 0.49 0.80 2.45 8.95RC 1.57 2.13 6.58 9.73RF 3.18 1.21 4.14 13.48SB 1.93 2.08 9.93 16.42SM 0.59 0.83 3.81 6.55CM 0.60 0.95 3.78 6.72MEAN±SD 1.29±.91 1.42±.55 5.28±2.32 9.97±3.40Table 50 Blood lactate(mmol•l-1)measures at rest and recovery conditions withsalbutamol, individual subject data for the MT groupLactate Rest 1 mm 3 mm 5 mm 10 mm(mmol•11) SalbutamolSubjectsAB 1.23 9.14 7.06 6.84 4.21GK 0.22 9.15 10.51 7.30 9.19PK 0.36 9.93 9.09 8.70 7.53RC 1.34 9.26 8.43 9.08 6.21RF 0.91 12.57 12.07 11.71 8.94SB 1.17 16.72 13.68 14.95 14.34SM 0.29 9.63 8.66 8.02 6.31CM 0.65 7.71 7.66 7.22 4.68MEAN ± SD .77 ± .45 10.52 ± 2.85 9.64 ± 2.28 9.23 ± 2.78 7.68 ± 3.2482Table 51 The duration of exercise test with salbutamol and placebo,individualsubjectdata(n= 17)Subjects Salbutamol PlaceboCL 16.2 15.5JH 19.220.0PMS 19.116.5PH 15.3 17.2PM 20.0 20.0PR 20.0 16.5RH 20.0 20.0SH 16.1 16.3SS 20.0 20.0AB 20.0 20.0GK 17.1 17.1PK 20.020.0RC 17.317.3RF 20.0 20.0SB 20.0 20.0SM 17.1 17.1CM 16.4 20.0MEAN±SD 18.5±1.8 18.4±1.883Table 52 The duration of exercise test withsalbutamol and placebo, individualsubject data for the HT and MT groupsSubjects Placebo Salbutamol SubjectsPlacebo SalbutamolTime (mm) Time(mm)lIT group MTgroupCL 15.5 16.2 AB20.0 20.0JH 20.0 19.2 GK17.1 17.1PMS 16.5 19.1 PK20.0 20.0PH 17.2 15.3RC 17.3 17.3PM 20.0 20.0 RF20.0 20.0PR 16.5 20.0SB 20.0 20.0RH 20.0 20.0 SM17.1 17.1SH 16.3 16.1 CM20.0 16.4SS 20.0 20.0MEAN ±SD 18.0 ± 1.9 18.4 ± 2.018.9 ± 1.46 18.5 ± 1.784Table 53 RMANOVA Summary (N= 17)Effect DEPENDENT VARIABLESV02 VE HR RER Sa02lmin1 l•min4 bpmSex (5)p= .000*p=008*p = .843p= .903p= .950Drug (D)p = .531 p = .492 p= .138p= .936p= .747Trained (T)p = .902p= .786p= .137p= .971p= .574condition (C) p = .000p= .000p= .000p= .000p= .000DXS p=.927 p=.738 p=.209 p=.764D X T p = .439p= .482p=.003*p= 851p= .777DXCXTp=.454p=.283p=007*p553D X C X S p = .578p= .786 p= .289p= .274p= .332cc*p<005Table 54 RMANOVA Summary for PEFR and Blood lactate measurementsEffect DEPENDENT VARIALBLESPEFR l•sec1 LACTATE (mmol.l)Drug(D) p= .002*p= .688Sex(S) p= .000*p= .259Trained(T) p=.215 p=.342Condition(C) p= .000*p= .000*DXS p=.334 p=.816DXT p=.8’75 p=.5l7DXCp=.00l*p—838DXCXT p=.24.’7 p=.369DXCXS p=.392 p=.947a=p <0.0585Table 55 RMANOVA summary for the HT groupEffect DEPENDENT VARIABLESV02 VEHR RERSa021•min1 l•min1 bpmDrug(D) p=.429 p.345p.010*p1.00 p=.699Condition (C)p=0(JrJ* p=000* p=0(J0* p_0(J(J* p_000*D X C p=.’13ó p=.243p=002*p’740 p=322DEPENDENT VARIABLESEffect PEFR Lactate1•sec1 mmol•11Drug (D)p=.009*Condition (C)p=OIJO*p=.000*DXCp=.031**p <0.0586Table 56 RMANOVA summary for the MT groupEffect DEPENDENT VARIABLESV02 VE HR RER Sa02lmin1 lmin1 bpmDrug (D) p=.869 p=.945 p=.l46 p=.8l9p.955Condition (C)p=0(J0* p=0(J(J* p=0(JO* p=(J(JO* p=015*D X C p=.825 p=.9l5 p=.O’75 p=.’749 p=.762DEPENDENT VARIABLESEffect PEFR Lactate1•sec1 mmol•1’Drug (D) p=.O78 p=.836Condition (C)p=.000*p=0(J0*D X C p=.8O6p=.027**p<0.0587Table 57 RMANOVA summary for subjects with aPC20< 4.0 mg/miEFFECT DEPENDENT VARIABLESV02 yE HR RERSa02lmiir1 Fmin1 bpmDrug (D) p =.058 p =.717p =.206 p =.806 p =.336Condition(C) p=.0OOp=YJJpJ(J*pyjij*pYJJDXC p =.395 p =.663 p =.477p =.ll0 p=.9&3DEPENDENT VARIABLESEffect PEFR Lactate1sec1 mmol•11Drug (D) p=.031*p .477DxCp=04’7*p =470<00588Table 58 Baseline Spirometry for the HT groupHT GROUP FVC FEV1 FEV1/FVC%CL 5.09 4.34 85IH 6.32 5.22 83PMS 4.19 3.49 83PH 4.53 3.84 85PM 3.77 2.54 67PR 5.00 3.53 71RH 5.31 4.91 92SH 4.15 3.62 87SS 4.34 3.71 85MEAN ± SD 4.74 ± 0.78 3.91 ± 0.81 82 ± 7.9Table 59 Baseline Spirometry for the MT groupMT GROUP FVC FEVi FEV1/FVC%AB 8.37 6.24 75GK 5.61 4.05 72PK 6.56 5.17 78RC 6.30 4.06 64RF 5.91 4.96 83SB 6.00 4.96 83SM 6.94 6.20 89CM 3.91 3.30 82MEAN ± SD 6.20 ± 1.26 4.87 ± 1.04 78 ± 7.7892.50APPENDIX CFiguresFigure 7.V02 (1mlir1)responses at various exercise intensifies(% VO2max),aflsubjectsdata(n= 17)4.53.5,1.50.50SalbutamolS Placebo25%I —50% 75%Exercise (%VO2max)90%Values are means ± SD; open circles, salbutamol; closed circles,placebo : p=O.531904.5.4.0•3.5.3.OFigure 8.V02(l.min-1)responsesat various exercise intensities(%VO2max),HT subjectsdata0Salbutamol•Placebo25% 50%75%Exercise(% V02 max)90%Values are means ± SD;open circles, salbutamol;closed circles, placebop = .42991Figure 9. V02(lmin-1)responsesat various exerciseintensities(%VO2max),MT subjects data5.04.5.4.O3.5.3.O2.50>2.OSalbutamol1.5Placebo1.0•O.5 •• •25% 50%75% 90%Exeitise(% V02 max)Values are means± SD; open circles, salbutamol;closed circles, placebo: p = .869-0-92Figure 10.VE (l.minl )responses at various exerciseintensities(%VO2max),aflsubjectdata(n=17)180160140120’.E 100060____4020Values are means ± SD;open circles, salbutamol;closed circles,placebo :p = .49225%—0-——Salbutamol•Placebo• I50% 75%Exercise(% VO2max)90%93Figure 11.VE (l.min-l )responses at various exerciseintensities(%VO2max),HT subject data1801601401201oo80__604020Values are means ± SD; opencircles, salbutamol; closed circles,placebo : p = .3450Salbutamol•Placebo25% 50%75% 90%Exeicise(% V02 max)94VE(l•min-1)responses at variousexercise intensities (%VO2max),MT subject data1801601401201100.80604020Exercise(% V02 max)Values are means ± SD; open circles,salbutamol; closed circles, placebo: p = .945Figure 12.-0-SalbutamolPlaceboI • I • I25% 50% 75%90%95Figure 13. HR (bpm)responses at variousexercise intensities(%VO2max),all subject data(n = 17)Values are means± SD; open circles,salbutamol; closed circles,placebo :p = .138210-190 -170 -a150-130-110-900Salbutamol.Placebo25%I • I •50% 75%90%Exercise(% VO2max)96200180160140120100Figure 14. HR (bpm)responses at variousexercise intensities(%VO2max),MT subject data800Salbutamol•Placebo25%I • I -50% 75%Exercise(% V02 max)90%Values are means ± SD;open circles, salbutamol;closed circles, placebo: p =. 14697I • I50% 75%Exeicise(% V02 max)SalbutamolPlaceboFigure 15. RERresponses at variousexercise intensities(%VO2max),all subject data(n = 17)1.1 -1.0-0.9 -0.8 -0.7-90%Values are means ±SD; open circles,salbutamol; closedcircles, placebo: p =.936—0-25%98HT subjectdataI •I--—50%75%Exercise(% V02 max)Values are means ±SD; open circles,salbutamol; closedcircles, placebop=1.00Figure 16. RERresponses at variousexercise intensities(%“O2max),1.21.11.0•0.90.80.7-0-SalbutamolPlacebo25%190%99Figure 17. RERresponsesat various exerciseintensities(%VO2max),MT subjectdata1.1 -1.0-0.9-0.8 -______0.7 -Values are means ±SD; open circles,salbutamol; closedcircles, placebo: p = .8191.2-25%0Salbutamol•PlaceboI I50% 75%Exercise(% V02 max)90%10099.9897.Values are means ±SD; open circles, salbutamol;closed circles, placebo: p= .747101Figure 18.Sa02 measures at various exerciseintensities(%VO2max),all subject data(n = 17)0Salbutamol•Placebo9225%I I50% 75%Exercise(% VO2max)90%Figure 19.Sa02 measures at various exerciseintensities(%VO2max),HT subjectdata99.9897.96Ti)9594.93Values are means± SD; open circles,salbutamol; closedcircles, placebo: p= .6991020Salbutamol•Placebo9225%I • I50% 75%Exercise(% V02 max)90%Figure 20.Sa02 measures at various exerciseintensities(%VO2max),HT subject data99 -98_______= 97,96’1)95.94.Values are means ± SD;open circles, salbutamol;closed circles, placebo: p= .9550Salbutamol•Placebo93 —i -.• I25% 50%75%Exeicise(% VO2max)90%103Figure 21. Bloodlactate(mmol•11)at various exercise intensities(% VO2max)and 1 to 10 minutesinto recovery, HTsubject data1816140E‘ 60420ist 25% 50% 75%90% 1 mm 3 mm 5mm io mmExeitiseRecoveryValues are means ±SD; open circles, salbutamol;closed circles, placebo: p = .4630Salbutamol•Placebo104Figure 22. Bloodlactate(mmoll1)at various exerciseintensities (%VO2max)and 1 to 10 minutesinto recovery, MTsubject data1412_______E864.20•Values are means ± SD;open circles, salbutamol;closed circles, placebo: p = .836OSalbutainol•PlaceboI—I—I.I.I.I.I.I.REST 25%50% 75% 90% 1mm3mm 5mm 10mmExerciseRecovery105

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