Comparison of responses to methacholine and cold air in patients suspected of having asthma.

In 140 adult patients with FEV1 greater than or equal to 60 percent predicted referred because of suspected asthma, we compared responses to methacholine and isocapnic cold-air hyperventilation. Most challenges were accomplished on the same day, cold air always being done first. The cold-air test employed a single episode of hyperventilation (target, 30 times the FEV1), and subsequent FEV1 changes were noted, a decrease of 10 percent being defined as a positive test result. For methacholine, subjects inhaled aerosols of increasing concentrations and the dose associated with a 20 percent decline in FEV1 (PC20) was noted; positive tests were defined as a 20 percent decrease at concentrations less than or equal to 8 mg/ml. Of the 140 patients, 65 had negative results on both challenges. Twelve patients had positive results on cold-air testing but negative responses to methacholine, and 17 had the opposite result. Among patients with positive results to either test, there was a significant correlation (p less than 0.001) between change in FEV1 with cold air and log PC20, but there was considerable scatter, the results of one test accounting for 25 percent of the variability in the other. Some scatter may have been related to the methods we used, but much was probably due to the patients themselves. Neither test should be used on an exclusive basis to make the diagnosis of asthma.

Ventilatory response to sustained hypoxia: effect of methysergide and verapamil.

The biphasic nature of the ventilatory response to sustained (30 min) hypoxia may be explained by the central accumulation of a neurochemical with net inhibitory effect or, alternatively, peripheral chemoreceptor adaptation. To determine the role of serotonin (a putative central neuroinhibitor) and calcium ions (a putative peripheral neurotransmitter) in this response we measured VI and breathing pattern during 30 min of sustained isocapnic hypoxia in 11 normal adults 1 h after the double blind administration of either 2 mg methysergide (serotonin antagonist), 80 mg verapamil (calcium channel blocker), or placebo. Each subject was studied once a day for three days. After placebo the mean VI peaked at 12.5 +/- 3.4 L/min (176% of resting room air VI). VI then declined to a mean of 9.8 +/- 2.3 L/min (138% of room air VI) during 25 min of constant hypoxia. VI during hypoxia was always greater than VI during room air breathing (p less than 0.01), and peak VI during hypoxia was greater than final VI during hypoxia (p less than 0.05). The hypoxic response was not significantly affected by either pharmaceutical. At their maximal safe dosage in humans, methysergide and verapamil suggest no role for serotonin and calcium ions. Not excluded is the possibility that drug levels were inadequate to effect meaningful blockade.

High-frequency oscillatory ventilation may increase airway closure.

In five seated, normal subjects, we measured closing volumes using 133Xe boluses inhaled at residual volume. High frequency oscillatory ventilation (HFOV) (15 Hz, 2 cc/kg) was applied during either inspiration to total lung capacity or the subsequent expiration. Closing volume was increased (P less than 0.001) when HFOV was applied during the latter half of expiration, but not when HFOV was applied during inspiration or the first half of expiration. Subsequently, in seven subjects, we measured the regional distributions of 133Xe boluses delivered during open-glottis breath-hold at 14% vital capacity after equilibration with N2O. HFOV was applied during bolus delivery for about 16 sec. These distributions were compared with those achieved by intravenous injections of 133Xe in saline. Regional perfusion (injected isotope) exceeded regional N2O uptake at the lung bases and this was significantly accentuated by HFOV, compatible with increased basal closure. We conclude that in normal subjects at low lung volumes, HFOV may enhance airway closure, though other explanations are possible.

Depression of hypoxic ventilatory response in humans by somatostatin.

In nine normal subjects we measured the ventilatory response to isocapnic hypoxia with and without an intravenous infusion of 1 mg of somatostatin. Arterial O2 saturation was rapidly lowered to 80 +/- 2% in 2 min and maintained for 30 min. During control experiments, ventilation increased immediately (3-5 min) and then declined so that at 25 min of hypoxia ventilation was little above that in room air. Somatostatin was associated with a small decrease in ventilation while the subjects breathed room air. With hypoxia there was no immediate increase in ventilation for the group as a whole, although an increase was observed in one subject. With somatostatin, after 25 min of hypoxia, mean ventilation was lower than at any other time in the study; as hypoxia was discontinued ventilation increased slightly. Somatostatin causes profound depression of the ventilatory response to hypoxia by a mechanism that is not known but may be central. With somatostatin hypoxia of 25-min duration tends to depress ventilation.

Airway closure with methacholine-induced bronchoconstriction.

We examined airway closure with methacholine-induced bronchoconstriction in eight normal seated adults at a mean lung volume of 39% total lung capacity. Closure was evaluated in two ways. Regional closure was examined by comparing the regional distributions of 133Xe boluses distributed according to N2O uptake with those distributed by pulmonary perfusion; regions that exhibited less N2O uptake than perfusion were interpreted as having airway closure. In addition, we measured single-breath washouts of the same boluses; differences between the washouts indicated closure that was not necessarily regional. Basal airway closure increased with methacholine inhalation from 21 +/- 3 to 46 +/- 4% (means +/- SE; P less than 0.001). This was due to both decreased basal N2O uptake and a relative increase of basal perfusion. Washout curves of boluses distributed by perfusion did not change with bronchoconstriction. Before bronchoconstriction, washouts of boluses distributed by N2O uptake did not differ significantly from those distributed by perfusion. During bronchoconstriction, single-breath washouts of boluses distributed by N2O uptake showed increased concentration differences (P less than 0.015) that were significantly greater than those resulting from boluses delivered by perfusion. Changes in basal closure did not correlate with washout changes. We conclude that methacholine inhalation induced bronchoconstriction-increased basal airway closure and also increased airway closure in other lung regions in a way that did not relate to basal closure.

Effect of volume history on distribution of inspired gas in asthmatics.

Twelve stable adult asthmatics slowly inhaled boluses of He at 20, 40, or 60% vital capacity (VC); these volumes were achieved either by expiring from total lung capacity (TLC) or by inspiring from residual volume (RV). Inspirations were continued to TLC and then were followed by slow expirations to RV while expired He was measured as a function of expired volume. At 20% VC slopes of alveolar plateaus (phase III) were positive, at 40% VC they were flat, and at 60% VC they were negative; at 20 and 60% VC the slopes were steeper than those in normals. When boluses were administered at 40 and 60% VC, He washout curves were independent of lung volume history. However at 20% VC the slope of phase III was significantly less positive when boluses were given after inspiration from RV than after expiration from TLC. In eight subjects, who were given inhaled beta-agonists, slopes of all He washouts decreased and became independent of volume history at 20% VC. We conclude that in asthmatics at low lung volumes the airways that determine ventilation distribution behave as though they have less hysteresis than the lung parenchyma probably due to increased airway tone.

Changes in regional emptying sequence need not change maximum expiratory flow.

Nine normal young men inhaled boluses of He at the onset of slow vital capacity (VC) inspirations. During the subsequent VC expirations, we measured expired flow, volume, and He concentrations. Expirations consisted of full or partial maximum expiratory flow-volume (MEFV) maneuvers. Full maneuvers were forced expirations from total lung capacity (TLC). Partial maneuvers were accomplished by expiring slowly from TLC to 70, 60, 50, and 40% VC and then initiating forced expiration. Expired He concentrations from full and partial maneuvers were compared with each other and with those resulting from slow expirations. At comparable volumes less than 50% VC, flow during partial and full MEFV maneuvers did not differ. Expired He concentrations were higher during partial maneuvers than during full ones; at the onset of partial maneuvers upper zone emptying predominated, whereas this was not the case at the same lung volumes during maneuvers initiated at TLC. We observed substantial differences in regional emptying sequence that did not influence maximum expiratory flow.

Responses to large doses of salbutamol and theophylline in patients with chronic obstructive pulmonary disease.

To assess additive effects of therapy with salbutamol and theophylline, we examined 16 patients (5 women, 11 men) with a mean age of 67.6 +/- 6.9 (SE) yr, long-standing chronic obstructive pulmonary disease, an FEV1 of 0.73 +/- 0.05 (SE) L, and a smoking history of 38.4 +/- 4.1 (SE) pack-years. On 2 consecutive days they were given large doses of either salbutamol followed by theophylline or vice versa. In the group as a whole, responses to salbutamol alone averaged 24% of the baseline FEV1 and responses to theophylline alone were 17% of baseline. Similar increases were observed when either drug was given after the other; responses to the 2 agents were additive. Responses to salbutamol were larger (p less than 0.05) than those to theophylline. Responses to salbutamol and theophylline were correlated. In 8 patients whose FEV1 increased after salbutamol by more than both 20% and 0.2 L, adding theophylline produced responses that were also large (32% baseline and 0.22 L). In the remaining 8 nonresponsive patients, salbutamol and theophylline were also additive, but the small (mean 10% or 0.06 L) increases in FEV1 with theophylline raised the question of the risk benefit ratio of high-dose theophylline therapy in such patients.