Treatment of reversible disease of the airways with bronchodilator drugs is generally advocated because of subjective and objective improvement in the obstruction of the airways. A more difficult question arises in the patient with chronic obstructive pulmonary disease (COPD) without evidence of reversible disease of the airways. Various methods of selection of such patients with COPD for treatment with bronchodilator drugs have been proposed. Reports of improvement in cardiac function and reduction of pulmonary vascular resistance with parenterally administered aminophylline and terbutaline, along with supporting evidence from radionuclide studies of cardiac ejection fraction, suggest that there may be a role for such agents beyond the simple involvement of spirometric measurements of disease. These studies also suggest a possible role for these drugs in the improvement of cardiopulmonary function during exercise, which might translate into a patients greater sense of well-being; however, the clinical applicability of the information from these studies to the ambulatory patient with irreversible obstruction of the airways is uncertain, since the information was obtained after parenteral administration of the drug, and in patients in whom reversible disease of the airways had not been rigidly excluded.
The purpose of our study was to evaluate cardiorespiratory physiology both at rest and with exercise in carefully selected patients with irreversible obstruction of the airways. The patients’ responses to ordinary oral doses of bronchodilator drugs were compared to placebo in a double-blind crossover study and constitute the basis for this report.
Materials and Methods
Selection of Patients
Fifteen male veterans (aged 50 to 69 years) were studied; all were ambulatory stable outpatients with a clinical diagnosis of COPD. Their disease was graded as severe, each having a forced expiratory volume in one second (FEVj) less than 50 percent of his predicted value. Means (± SD) for spirometric values and blood gas levels were as follows: FEV1? 1.03 ±0.34 L; forced vital capacity (FVC), 2.26 ±0.58 L; mean forced expiratory flow during the middle half of the FVC (FEF25-75%), 0.43 ±0.15 L/sec; arterial oxygen tension (PaOJ, 69.1 ±10.6 mm Hg; and arterial carbon dioxide tension (PaCOj, 44.3±6.5 mm Hg. All patients had a smoking history of greater than 20 pack-years. All had been dyspneic for many years without a significant symptom-free interval, despite various therapeutic regimens including bronchodilators. No patient had evidence of cor pulmonale; none was receiving oxygen at home.
Criteria for exclusion are listed in the following tabulation (the presence of any of these factors disqualified the patient):
Reversible Obstruction of Airflow:
History of bronchial asthma History of episodic, acute wheezing dyspnea Presence of greater than 5 percent eosinophils on peripheral blood smear Following inhaled isoproterenol: improvement of FEVj by more than 10 percent of the patients predicted value or rise in FEV, to 50 percent of predicted Primary Cardiovascular Disease:
Ventricular arrhythmia (ventricular extrasystoles paired, multifocal, or numbering more than 10/min)
Coronary arterial disease (history or angina or myocardial infarction; angiographically documented coronary occlusion)
Sustained systemic hypertension
Valvular heart disease (other than mild tricuspid regurgitation)
Evidence of left ventricular decompensation Other Complicating Systemic Illness
Care was taken to define patients with an “asthmatic” component to their obstruction of airflow and to avoid those with evidence of cardiovascular disease.
After informed consent was obtained, all medications with cardiopulmonary effect were discontinued for 72 hours. History and physical examination, complete blood count and chemistry profile, serum theophylline level, spirometric studies, chest roentgenogram, and 24-hour ambulatory electrocardiogram were performed on the first day. On the second day an incremental exercise test was performed to exhaustion on equipment and in surroundings identical to those to be used in subsequent tests. The patient was placed in the supine position on a cycle ergometer (Collins), with the back and head elevated 30° to the horizontal. Four-lead electrocardiographic monitoring was continued throughout exercise. Expired air was collected directly into the mouthpiece of a metabolic measurement cart (Beckman) (calibrated daily for both zero and upscale values for all measurements) for analysis of the expired gas. Work load, oxygen consumption (Voj) carbon dioxide production (VcoJ, heart rate (HR), respiratory rate, tidal volume (Vt), minute ventilation (Ve), actual respiratory quotient (RQ), and expired carbon dioxide fraction were recorded for each minute of exercise. The work load on the ergometer was increased each minute in increments of 50 kilopondmeters/min; this was continued, with careful supervision and encouragement of best effort, until the patient signaled exhaustion. The work load at which this occurred was recorded as maximal for that patient.
After an overnight rest the patient was exercised at a constant work load for six minutes. The work load used in each case was 60 percent of the maximal work load determined on the previous day and has been shown in such patients to represent a physiologic stress while allowing attainment of steady-state conditions. The measurements noted previously were recorded during each of the six minutes, thus confirming the presence of steady-state exercise; values from the last two minutes were averaged to serve as values during “exercise” for each measurement Samples of arterial blood were obtained by radial arterial puncture at rest and during the last minute of steady-state exercise, thus allowing calculation at the actual RQ of the alveolar-arterial oxygen pressure difference (P[A-a]0*) and the ratio of physiologic dead space to tidal volume (VDp/Vr), corrected for anatomic dead space (VDan) and mechanical dead space (VDm) by the following standard equations:
where Pb is barometric pressure and where FIo2is the fractional concentration of oxygen in the inspired gas and equals 0.21 for room air.
The equation for VDp corrected for VDan and VDm is as follows:
where PeC02 is the partial pressure of carbon dioxide in the expired air, VDan equals 4.5 x 10~ x height (cm), (from Wood et al), and Vd is Bohr dead space and equals (PaC02– PECOJ/PaCOg x Vt.
The equations for predicted maximal values during exercise are as follows:
HRmax (beats/min) = 210 – 0.65 x age (yr)
Vo2max (L/min) = 4.2 – 0.032 x age
VEmax (L/min) = 35 x FEV, (L)
Radial arterial puncture may not be ideal but has not been shown to introduce significant error. “Oxygen pulse” was obtained by dividing V02 (in ml/min) by the corresponding HR; the ventilatory equivalent for oxygen (VeOJ was obtained by dividing Ve (in L/min) by Vo2(in IVinm).
Protocols for Medication
With baseline studies having been completed, the patient was discharged on one of four regimens of oral medication: (1) theophylline (Elixophylline), 200 mg four times daily; (2) terbutaline (Brethine), 5 mg three times daily; (3) a combination of theophylline (100 mg) plus terbutaline (2.5 mg), both four times daily; and (4) matched placebo. The regimens were assigned and coded in the pharmacy, randomly sequenced (to avoid any “training” effect), and double-blinded.
A printed “patients log” was given and explained to the patient, wherein he was asked to record the date and time of each dose of medication, along with symptoms of shortness of breath or wheezing (severity graded subjectively from zero to three) recorded daily. A “symptom score” was later calculated for each of the two symptoms by averaging the daily scores over the period of medication.
Each regimen of medication was prescribed for ten days. The patient then returned to the hospital while receiving the medication and underwent repeat spirometric studies and measurement of the serum theophylline level. While still taking the medication, the patient performed another six-minute steady-state exercise test, at the same previously determined work load, and in the manner defined in the preceding section.
The patient was then sent to the pharmacy for the next regimen of medication in his sequence, to return ten days later to repeat the previously described testing, until he had completed testing on all four regimens of medication. There are different ways of drugs ordering and My Canadian Pharmacy are the best one.
Analysis of Data
Measurement at rest and during the last two minutes of steady-state exercise were compared with placebo for each regimen. Students f-test for paired data was used for comparison; a value for p less than 0.05 was considered significant.
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