Prostaglandin synthesis blockade by ketoprofen attenuates respiratory and cardiovascular responses to static handgrip.

We investigated the effects of prostaglandin synthesis blockade on the changes in breathing pattern, mean blood pressure (MBP), and heart rate (HR) elicited by 3 min of static handgrip at 30% of the maximum voluntary contraction in 12 healthy volunteers. Before each handgrip trial, subjects were treated with intravenous administration of either saline placebo (control) or 1 mg/kg of ketoprofen. Muscle tension and integrated electromyographic activity of exercising muscles remained fairly constant during each trial. In agreement with our earlier findings, during control handgrip minute ventilation progressively increased (P < 0.01) due to a rise in tidal volume and, to a lesser extent, in respiratory frequency. Mean inspiratory flow, MBP, and HR also increased (P < 0.01). End-tidal PCO2 decreased (P < 0.05) during the late phases of control handgrip bouts. Ketoprofen administration reduced serum thromboxane B2 levels (from 57.5 +/- 7.0 to 1.6 +/- 0.4 pg/ml; P < 0.01) and significantly attenuated mean increases in minute ventilation (40.25 +/- 0.60%), tidal volume (37.78 +/- 7.48%), respiratory frequency (55.94 +/- 17.92%), inspiratory flow (42.66 +/- 5.11%), MBP (22.33 +/- 6.82%), and HR (11.04 +/- 2.75%) during the 3rd min of handgrip. End-tidal PCO2 remained close to normocapnic levels. In agreement with previous animal investigations, the present results show that arachidonic acid metabolites are involved in the regulation of the cardiovascular responses to static efforts in humans, possibly through a stimulatory action on muscle receptors. Furthermore, they provide the first experimental evidence that products of the cyclooxygenase metabolic pathway play a role in the mediation of the respiratory adjustments elicited by this form of exercise.

Respiratory and cardiovascular responses to static handgrip exercise in humans.

We studied the time course of respiratory and cardiovascular responses by evaluating changes in the breathing pattern, mean blood pressure (MBP), and heart rate elicited by 3 min of static handgrip at 15, 25, and 30% of the maximum voluntary contraction (MVC) in 15 healthy volunteers. Muscle tension and integrated electromyographic activity remained fairly constant during each trial. During 15% MVC bouts, initially only mean inspiratory flow increased; then, tidal volume and minute ventilation (VI) also rose progressively. No significant changes in MBP and heart rate were observed. During 25 and 30% MVC bouts, not only did mean inspiratory flow, VT, and VI increase but MBP and heart rate increased as well. A slight and delayed rise in respiratory rate was also observed. Unlike 15 and 25% MVC handgrip, 30% MVC handgrip caused a small decrease in end-tidal PCO2. Changes in the pattern of breathing occurred more promptly than those in cardiovascular variables in the majority of subjects. Furthermore, we found a positive correlation between changes in VI and those in cardiovascular variables at the end of 25 and 30% MVC trials. This study indicates that respiratory and cardiovascular responses to static handgrip exercise are controlled independently.

Aspirin effect on early and late changes in acute lung injury in sheep.

OBJECTIVE: There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B2 (TxB2) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep. DESIGN: 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i.v.) 30 min before OA, the others saline as placebo. MEASUREMENTS AND RESULTS: Pulmonary and tissue gas exchange, pulmonary and systematic hemodynamics, respiratory system mechanics, TxB2 and 6-keto-PGF1 alpha, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB2 generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at approximately 1 in ASA-group compared to its fall to approximately 0.7 in controls. CONCLUSION: Our findings suggest that ASA: 1) is only effective to treat the very transient TxB2-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB2; 2) has a transient protective effect on the TxB2-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO2.

Changes in respiratory activity induced by mastication in humans.

We studied the influence of mastication on respiratory activity in nine healthy volunteers who were requested to masticate a 5-g chewing gum bolus at a spontaneous rate (SR) for 5 min and "at the maximum possible rate" (MPR) for 1 min. Significant increases in respiratory frequency were induced by SR mastication due to a decrease in both the inspiratory and expiratory time. Tidal volume displayed slight nonsignificant decreases, but minute ventilation and mean inspiratory flow significantly increased. The duty cycle (TI/TT) did not change significantly. Total airway resistance significantly increased. Both peak and rate of rise of the integrated electromyographic activity of inspiratory muscles presented marked increases, accompanied by the appearance of a low level of tonic muscular activity. Similar but more intense effects on respiratory activity were induced by MPR mastication; in addition, a significant decrease in tidal volume and a significant increase in TI/TT were observed. Rhythmic handgrip exercise performed at metabolic rates comparable to those attained during SR or MPR mastication induced similar changes in the drive and time components of the breathing pattern, although accompanied respectively by nonsignificant or significant increases in tidal volume. Furthermore, the frequency of SR mastication significantly entrained the respiratory rhythm. The results suggest that mastication-induced hyperpnea does not merely represent a ventilatory response to exercise but also reflects complex interactions between respiratory and nonrespiratory functions of the upper airway and chest wall muscles.

The prominent role of thromboxane A2 formation on early pulmonary hypertension induced by oleic acid administration in sheep.

The early increase of pulmonary artery pressure observed in different models of experimentally induced lung injury have been shown to be associated with the release of vasoconstrictive agents by activated platelets. The aim of this study was to evaluate the pattern of these metabolites, in particular TxA2, and the effects of the inhibition of their production by ASA on the modifications of pulmonary hemodynamics induced by oleic acid administration in sheep. Group I (8 sheep) was infused with oleic acid (0.09 ml/kg at 0.02 ml/min) while in group II (6 sheep) ASA (10 mg/kg i.v.) was administered 30 minutes before oleic acid infusion. In group I pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were significantly higher at the end of the infusion while cardiac output (CO) significantly decreased in comparison to baseline values. A marked increase in plasma TxB2 levels paralleled pulmonary hemodynamic changes. Also plasma 6 keto PGF levels increased after OA infusion. The early increase in PAP and PVR was significantly lower in group II (p less than 0.005) while CO did not undergo any significant change. ASA pretreatment significantly blunted the rise of TxB2 concentrations and prevented the elevation of 6 keto PGFa. These results indicate that early pulmonary hypertension in oleic acid induced injury is mainly related to TxA2 released from platelets and leukocytes and that pulmonary hemodynamic changes are significantly inhibited by ASA pretreatment.

Effect of aminophylline aerosol on the bronchial response to ultrasonic mist of distilled water in asthmatic patients.

To ascertain whether inhaled aminophylline was effective in preventing the bronchial response induced by inhalating of an ultrasonic mist of distilled water (UMDW), we examined 8 asthmatic patients who had previously been shown to be reactive to this agent. Patients were given either 30 mg aminophylline or saline placebo aerosols followed by inhalation of 60 liters of UMDW; measurements of specific airway conductance (sGaw) were made before and after aminophylline or saline administration and after UMDW challenge. UMDW consistently induced a significant decrease in sGaw in all patients; however, in our subjects as a group, the degree of UMDW-induced bronchoconstriction was significantly less after premedication with aminophylline aerosol than after saline (p less than 0.01). Our results suggest that aminophylline is effective in preventing UMDW-induced bronchoconstriction; the possible relationships between bronchial response to UMDW and its modulation by inhaled aminophylline are discussed.

Serum theophylline concentrations and pulmonary function tests after administration of two sustained-release formulations containing theophylline in patients affected by chronic obstructive lung disease.

We compared serum theophylline concentrations in patients treated with one of two commercially available theophylline preparations: a sustained-release aminophylline and a sustained-release theophylline. Two comparable groups of 15 out-patients with stable, chronic obstructive lung diseases were studied: one group was given sustained-release aminophylline while the other took sustained-release theophylline. Both drugs were administered orally for 7 days at a daily dose, equivalent to 12 mg/kg in terms of anhydrous theophylline. Serum theophylline concentrations were always significantly lower after treatment with sustained-release aminophylline than after treatment with sustained-release theophylline, which latter frequently caused undesirable side-effects. Moreover, patients receiving sustained-release aminophylline always showed serum theophylline concentrations lower than 10 mcg/ml. Pulmonary function tests were unaffected by the administration of either drug. We conclude that sustained-release theophylline is more effective than sustained-release aminophylline in terms of induced serum theophylline concentrations. However neither drug was suitable for the treatment of patients with chronic obstructive lung disease without other concomitant therapy.

Histamine-induced bronchial response after administration of placebo, salbutamol and a combination of a beta-2-adrenergic drug (fenoterol) with an anticholinergic agent (ipratropium bromide) in asymptomatic asthma patients.

We examined 12 non-smoking patients affected by extrinsic bronchial asthma in steady state. Histamine PD20 FEV1 was assessed 4 h after the administration of salbutamol 200 micrograms, a combination of fenoterol 200 micrograms and ipratropium bromide 80 micrograms, and placebo. Despite the absence of any relevant bronchodilator effect, both salbutamol and the combination fenoterol + ipratropium bromide showed a strong protective effect against the bronchial response to histamine compared to placebo, the combination being more effective than salbutamol (p less than 0.05). Our data suggest that, when bronchial challenges with histamine are performed, airway response may be a consequence of both a direct action of such an agent on H1 receptors and of an associated cholinergic reflex.

Bronchoprovocation tests in bronchial asthma and other respiratory disorders: a short review and some personal contributions.

The purpose of this paper, after a brief review of the main features of bronchoprovocation challenges, was to determine whether the administration of an ultrasonic mist of distilled water can influence the bronchial tone of normal subjects and patients affected by various respiratory disorders, in order to assess the effectiveness of this bronchoprovocation test in discriminating between patients. Of the 129 subjects tested 13 were classified as normal, 60 as extrinsic asthmatics, 21 as intrinsic asthmatics, 25 as allergic rhinitics and 37 as chronic bronchitics. Ultrasonic mist, was administered for 5 min and the bronchial response was evaluated in terms of difference between that after the mist minus baseline values of specific airways conductance. The data suggest that the bronchial challenge with ultrasonic mist, a safe, non-pharmacological and simple test, allows a good discrimination between asthma patients and those affected by other respiratory disorders.

Effects of theophylline-ethylendiamine on chronic pulmonary arterial hypertension secondary to chronic obstructive pulmonary disease.

The use of theophylline in the treatment of chronic lung disease is wide spread thanks to the positive effects on the bronchial tree, on ventilation and on diaphragmatic contractile activity, which are well documented. On the other hand, the cardiovascular effects of this drug have not been studied much, particularly the effects on the hemodynamics of the pulmonary circulation. The latest studies were carried out by Parker (1966 and 1967) and by Jezek (1970) with heart catheterization and by Matthay (1978) with isotopic angiocardiography, but the problem has not been fully explored from the standpoint of pulmonary arterial hypertension. Therefore we are studying the effects of intravenous infusions of aminophylline in patients with chronic obstructive lung disease, trying to examine the effects of this drug on three different groups of patients: the 1st without pulmonary arterial hypertension; the 2nd with latent pulmonary arterial hypertension; the 3rd with evident pulmonary arterial hypertension. We consider pulmonary arterial hypertension as pulmonary arterial pressure greater than 20 mmHg at rest and pulmonary arterial pressure greater than 35 mmHg at the end of 8 min of exercise in the supine position, with 40 W load cycle ergometer. The experimental protocol includes the clinical and functional identification of subjects with chronic obstructive long disease, the performance of right heart catheterization and the cannulation of a peripheral artery, measuring all pressure levels, cardiac output, hemogasanalytic data and theophylline levels in steady state (20-30 min. after the end of invasive manoeuvres) at the 10th, 20th and 30th min after the end of an infusion of 10 mg/kg of aminophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

Classification of respiratory functional impairment in chronic obstructive pulmonary disease.

Starting from a paper published in 1964 by Wilson et al., we explored the possibility of classifying the clinical and functional deficit of patients with chronic obstructive lung disease into six classes, class 0 representing normality and class 5 greatest severity. Each symptom or sign was classified into six degrees of increasing severity. Next, we looked for a possible dependence of the collegially assigned score on anthropometric, clinical, or instrumental data in each case. More particularly, we tried (1) to identify such combinations of variables as would permit classification of the patient with the smallest possible error, and (2) to determine which of the variables reflected the severity of the case more faithfully. The results emerging from this study suggest the possibility of evaluating and classifying respiratory impairment in three different ways, as follows: (1) On the basis of clinical data only. This method is the easiest to use and affords a fairly good determination coefficient (R2 = 0.812). (2) Using only some combinations of laboratory data (static and dynamic pulmonary volumes, blood gases, etc.), with or without the addition of vital statistics and anthropometric data. These subensembles would allow a posteriori estimates in cases where the subject is no longer available for questioning and examination. In that case the best multiple regression affords a determination coefficient R2 = 0.82. (3) Using all clinical and laboratory data available. In that case, the best multiple regression (R2 = 0.899) for predictive purposes is that which includes the sum of clinical data, the pulmonary volumes before and after pharmacological bronchodilation, and the PaCO2 value. For practical purposes, however, the most convenient function is the one that includes the sum of clinical data plus FEV1 and RV (R2 = 0.863). Even with the best of the three functions proposed in this paper, however, the standard error of estimate entails tolerance limits sometimes amounting to one whole class of severity. Still, the probability of making an error exceeding one class of severity occurs in only 3.7% of the cases, an average which seems quite acceptable from the clinical point of view.

[The ventilation-perfusion ratio, with special reference to muscular exercise]. / Il rapporto ventilazione/perfusione, con particolare riguardo al lavoro muscolare

The values of VA/Q obtained at rest in 12 normal subjects undergoing cardiac catheterization in a supine position were between 0.63 and 1.695, with a mean of 1.142 +/- 0.295. The VA/Q values obtained in another 10 healthy subjects tested in a sitting position with a rebreathing method for calculating Q. were somewhat less scattered (between 0.77 and 1.50), and also lower (mean 0.975 +/- 0.210). A highly significant correlation was demonstrated during muscular exercise on the bicycle ergometer (sitting position), both between oxygen consumption and alveolar ventilation and between oxygen consumption and cardiac output. However, since at various submaximal work loads cardiac output increased much less than alveolar ventilation, the overall VA/Q ratio showed a progressive increment with increasing oxygen consumption.