Typoxemia is a common occurrence in patients with asthma, a fact attributed to ventilation-perfusion (Va/Q) inequality secondary to uneven airway narrowing. Recent studies measuring continuous distributions of Va/Q ratios have detected considerable blood flow perfusing areas in the lung which have low Va/Q ratios. Uneven distribution of ventilation is undoubtedly a major factor causing Va/Q inequality in asthma;2 however, changes in the distribution of pulmonary blood flow are important. In some asthmatic subjects, hypoxemia may be aggravated by the administration of aminophylline2 or isoprenaline,2 perhaps because these drugs act by counteracting compensatory pulmonary vasoconstriction. Compensatory pulmonary vasoconstriction in response to alveolar hypoxia redistributes blood flow to match ventilation, thereby minimizing hypoxemia.
Wagner et al, in a study of five asymptomatic asthmatic patients and one acutely ill asthmatic patient, measured continuous Va/Q distributions using the multiple inert gas elimination technique. They found that five subjects had perfusion to abnormally low Va/Q units, which increased five minutes after isoproterenol was administered by aerosol. After 15 minutes more, all the Va/Q distributions had returned to their control states. These results suggest that the isoproterenol counteracted compensatory pulmonary vasoconstriction, resulting in increased perfusion of low Va/Q units. Va/Q distributions were measured after four subjects with broad control Va/Q distributions breathed 100 percent oxygen for 30 minutes. No change in the Va/Q distributions was observed. The feet that 100 percent oxygen did not have the same effect suggests that compensatory pulmonary vasoconstriction may not be hypoxia induced in asthma, but possibly chemically induced by mediator release.
In response to hypoxia, histamine, a powerful vasoconstrictor is released from mast cells clustered primarily around the pulmonary vasculature. Despite this evidence, much uncertainty exists about the role of histamine as a chemical mediator of compensatory pulmonary vasoconstriction.’
The aims of this study were: a) to examine the Va/Q distributions in moderately severe asthmatic subjects using the multiple inert gas elimination technique, b) to assess the presence of hypoxic compensatory pulmonary vasoconstriction by measuring changes to Va/Q distributions after breathing 100 percent oxygen, and c) to test the hypothesis that histamine is a mediator of compensatory pulmonary vasoconstriction in asthmatic subjects. This was done by administering an intravenous antihistamine (clemastine) and measuring any increase in the dispersion of the Va/Q distribution which may be compatible with the counteraction of compensatory pulmonary vasoconstriction.
Materials and Methods
Ten patients with moderately severe asthma were chosen, seven men and three women. They all signed their informed consent forms prior to the experiment, which had been approved by the Medical Ethics Committee of the Royal Prince Alfred Hospital. Anthropometric data are presented in Table 1. The lung volumes were measured while patients were on full therapy, and are shown to further characterize the patient population. All subjects were taking regular aerosol bronchodilator therapy and four subjects were steroid dependent. Another three subjects had taken oral steroids intermittently but were not taking steroids at the time of the study. Only one subject (No 5) was not atopic, apd one subject (No 1) had hypertension for which she was taking prazosin. All medications, except steroids and the prazosin, were stopped 12 hours before the study. Lung volumes were measured by closed-circuit helium dilution (Pulmotest, Godart, Utrecht, Holland). The forced expiratory volume in one second (FEVj) and forced vital capacity (FVC) were measured by a Minato Autospirometer A51-700 (Osaka, Japan) or a Vitalograph (Buckingham, England). Normal predicted values for lung volumes in adults were taken from the data of Goldman and Becklake. Asthma is a dangerous disease damaging not only adults but children as well. To know more about how to protect yourself from this disorder you may here More info about diseases and hot news – Canadian health&care Mall – healthcaremall4you.com.
The application of the multiple inert gas infusion technique we used to measure continuous distributions of Va/Q ratios in human subjects has been described in detail by Wagner et al. A No 7 balloon flotation catheter (USCI, Massachusetts) was inserted percutaneously under local anesthesia into an antecubital vein, the tip positioned in the pulmonary artery under electrocardiographic and pressure monitoring (Bell and Howell 4-327-L223 transducer, Philips XV1505 recorder). The subjects were then placed in a comfortable position (reclining at about 30° above the horizontal) for the rest of the procedure. The reference point for calibrating the pressure transducer was the fourth intercostal space in the midaxill-ary line. Tfoo short polythene cannulae were then inserted in the other arm under local anesthesia, one in the radial artery and one in a peripheral vein. The radial and pulmonary artery catheters were used to sample systemic arterial and mixed venous blood respectively, while the peripheral venous line was used to infuse the sterile dilute solution of six inert gases (sulphur hexafluoride [SF6]), ethane, cyclopropane, halothane, di-ethyl ether and acetone) in 0.9 perent saline solution. The solution was infused at a constant rate of 3 to 5 mL/min in the manner described by Wagner et al. Each patient wore a nose clip and breathed through a one way valve box with a functional dead space of 15 ml. The expired gas passed through a copper pipe enclosed in an insulated box to allow time for intrabreath mixing, so that mixed expired gas could be collected into glass syringes at the end of the copper pipe via a three-way stopcock. Ibe entire expired gas conducting system, to the point of syringe collection, was wrapped in electrical heating tape to keep it above body temperature to avoid condensation which would dissolve the more soluble inert gases in the expirate. The gas was then conducted through a gas meter and the volume expired every minute manually recorded using a stopwatch. The temperature in the gas meter was also recorded for subsequent conversion of the ventilation to BTPS conditions. Each patient breathed through this apparatus for at least five minutes before blood and gas samples were taken. A lag volume of 15 liters was allowed to wash through before the expired gas corresponding to a particular blood sample was taken. This was the volume of the system as determined by detecting a plateau in expired C02 with a mass spectrometer at the sampling site after the subject started to breathe through the valve.
Subsequent analysis of blood and gas samples for the pressure of each of the inert gases was also performed by the methods described by Wagner et al, with minor modifications already described.
Spirometry, pulmonary artery pressures, arterial and mixed venous blood gases, total ventilation, cardiac output and ventilation, and perfusion distributions were measured in each physiologic state. Two sets of measurements were done in the control state breathing air. The subjects were then given 100 percent oxygen for 20 minutes and the measurements were repeated. TWenty minutes after ceasing the 100 percent oxygen a third control set of measurements was made. Then, between 2 to 4 mg of clemastine was injected intravenously. Measurements were made 5 minutes later and between 20 and 60 minutes later. Clemastine was the chosen antihistamine because of its lack of anticholinergic and antiserotonin actions.
Histamine skin tests were done before the clemastine was administered and then 5,20 and 60 minutes later to test the effectiveness of the antihistamine. Each test consisted of placing four drops of histamine acid phosphate solution in four separate areas on the skin of the flexor surface of the forearm. A 26-gauge needle was used to prick the skin lightly, making sure that no bleeding resulted from the prick. Ten minutes later, the wheals were measured and the average diameter of the four wheals was used as the result. Arterial and mixed venous blood gas tensions were measured by a Coming analyzer (Coming 175, Massachusetts).
Calculations of the Va/Q distributions from the inert gas data were performed on a digital computer using the enforced smoothing approach with a scalar smoothing factor of 40. This is the same factor used by Evans et al as the coefficients of variation for replicate measurements of inert gas concentrations in our laboratory are similar to those previously determined in their laboratory.
The multiple inert gas technique requires that subjects are in a steady state of gas exchange. This was ensured by measuring a stable ventilation rate for five minutes before taking samples. The inert gas data fit to the Va/Q distribution model was satisfactory for each distribution reported, thus providing further evidence for steady state conditions.
Table 1—Anthropometric and Pulmonary Function Data
|Subject||Age||Sex||Steroids*||TLC||% Predicted§ VC IC FRC||KV|