Churg-Strauss syndrome associated with montelukast.

Churg-Strauss syndrome (CSS) has recently been reported in patients with asthma receiving leukotriene receptor antagonists (LTRAs). In this paper a case of CSS after treatment with montelukast is described. As in other LTRA treated cases, prior withdrawal of maintenance oral steroid may have unmasked a previously occult CSS in the patient, but a dramatic improvement in his eosinophilia after withdrawing montelukast implied that the drug also had a direct effect in activating this condition.

Diaphragm weakness in Charcot-Marie-Tooth disease.

Two patients are described with Charcot-Marie-Tooth disease and chronic peripheral neuropathy. Both had dyspnoea, orthopnoea, and evidence of severe diaphragm weakness. Expiratory muscle function was well preserved and abnormalities of gas exchange during sleep were only minor.

Atenolol and sustained release nifedipine alone and in combination in hypertension. A randomised, double-blind, crossover study.

In this randomised, double-blind, crossover trial, the efficacy in hypertension of atenolol and nifedipine as single agents or in combination was compared. 81 patients with mild to moderate essential hypertension (sitting diastolic blood pressure 100-120 mm Hg, aged 20-70 years) from 6 outpatient clinics entered the study. By use of a Latin-square design, patients received, in randomised fashion, sustained release nifedipine 20mg twice daily, atenolol 50mg in the morning and then placebo in the evening, or sustained release nifedipine 20mg plus atenolol 50mg in the morning and then placebo in the evening. Each schedule was followed for 4 weeks. All treatments lowered systolic and diastolic blood pressure in the supine and standing positions compared with pretreatment values. The combination regimen significantly reduced supine and standing systolic (p less than 0.01 and p less than 0.001, respectively) and diastolic (p less than 0.001) blood pressure compared with nifedipine alone, and it also significantly reduced supine and standing systolic (p less than 0.01 and p less than 0.03, respectively) and diastolic (p less than 0.01) blood pressure compared with atenolol alone. Heart rate was significantly decreased by atenolol and the combination compared with nifedipine alone. 15 patients withdrew because of side effects: 9 during nifedipine treatment, 2 during atenolol treatment and 4 during combination treatment. Side effects were typical of those associated with nifedipine or atenolol. Flushes and hot sweats, which were frequent with nifedipine, were significantly less (p less than 0.001) with atenolol or the combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and tolerability of atenolol, nifedipine and their combination in the management of hypertension.

This randomised, double-blind, crossover study investigated the haemodynamic effects of a beta-blocker (atenolol 50mg) and a calcium antagonist (sustained release nifedipine 20mg) given either separately or in combination in 3 groups of patients with mild to moderate essential hypertension. Each treatment was administered twice daily. The fixed combination given twice daily for 4 weeks produced reductions in blood pressure which lasted for at least 12 hours after administration of the final dose. The control of blood pressure by the combination was superior to that achieved by its individual components. Side effects normally associated with nifedipine therapy were less frequent when it was administered with atenolol. Compliance with treatment was good, but it was best when the drugs were given together rather than separately. A fixed combination of atenolol and nifedipine may prove useful in treating hypertensive patients inadequately controlled on beta-blocker therapy alone.

The efficacy and tolerability of atenolol, nifedipine, and their combination in the management of hypertension.

In this randomized, double-blind, cross-over study we investigated the haemodynamic effects of a beta-blocker (atenolol 50 mg) and a calcium antagonist (nifedipine SR 20 mg) given either separately or in combination in three groups of hypertensive patients. Each treatment was administered twice daily. The fixed combination given twice daily for four weeks produced reductions in blood pressure which lasted for at least 12 h after administration of the last dose. The control of blood pressure by the combination was superior to that achieved by its individual components. Adverse effects normally associated with nifedipine were less frequent when it was given with atenolol. Compliance with treatment was good, but best when the drugs were given together rather than separately. A fixed combination of atenolol and nifedipine may prove useful in treating hypertensive patients inadequately controlled on beta-blocker therapy alone.

Effects of almitrine bismesylate 100 mg daily for four weeks on respiratory regulation in patients with chronic bronchitis.

The effects on respiratory regulation of giving almitrine bismesylate (100 mg daily) orally for four weeks in twelve patients with chronic airflow obstruction were assessed in a double-blind placebo-controlled study. The drug caused significant increases in ventilation and the ventilatory response to hypoxia, associated with partial relief of arterial hypoxaemia and a fall in arterial CO2 tension. No consistent changes occurred with placebo. The results are in accord with a sustained action of almitrine bismesylates sensitising peripheral chemoreception.

Increased respiratory chemosensitivity induced by oral almitrine in healthy man.

Cardiorespiratory effects of 50 mg and 100 mg doses of almitrine and placebo given orally on separate test days to twelve healthy volunteers were assessed in a double-blind crossover study. The drug caused no significant changes in ventilation, mixed venous CO2 tension, metabolic rate, heart rate or blood pressure while they were resting and breathing room air. With progressive hypercapnia, however, the ventilatory response increased by 5% after the 50 mg dose (NS) and by 27% after the 100 mg dose (P less than 0.05). There were greater increases in the response to progressive hypoxia by 78% after 50 mg of almitrine (P less than 0.01) and by 120% after 100 mg (P less than 0.01), which was also significantly greater than the increase after the 50 mg dose (P less than 0.01). In contrast there were only minor and inconsistent changes in chemosensitivity after administering placebo. The findings are consistent with an agonist action of almitrine in the peripheral chemoreceptors and suggest that it may have clinical value in managing respiratory failure due to hypoventilation.

Increased respiratory chemosensitivity induced by infusing almitrine intravenously in healthy man.

The respiratory effects of intravenously infused almitrine were evaluated in healthy volunteers. In the dose range 0.25-1.0 mg/kg/hour it caused large and dose-dependent increases in hypoxic chemosensitivity, which were longlasting and more persistent than the drug's retention in the plasma. Increases in sensitivity to hypercapnia were much less and were detected only when the plasma almitrine exceeded 200 ng/ml. Small increases in resting ventilation and metabolic rate with a decrease in mixed venous carbon dioxide tension occurred only at the highest infusion rate. The findings accord with an action of almitrine in the peripheral chemoreceptors, which may be of therapeutic value in managing some cases of respiratory failure.

Effects of almitrine bismesylate on chemosensitivity in patients with chronic airways obstruction.

The effects of 100 mg doses of almitrine bismesylate given orally were compared with placebo on separate test days in twelve hypoxaemic patients with chronic airways obstruction. The drug caused significant increases in ventilation and arterial O2 tension with a fall in CO2 tension. Assessed by rebreathing techniques it augmented their ventilatory response to hypercapnia and even more to hypoxia. Only minimal changes occurred with placebo. The results are consistent with the drug's known action of sensitising the peripheral chemoreceptors.

Airway function in sarcoidosis.

Airway function was studied in 18 patients with sarcoidosis, aged 18 to 49 years. Eleven of the patients were smokers. All patients had the characteristic functional changes of restrictive lung disease: decreased lung volumes and single breath diffusing capacity, and increased static transpulmonary pressures. Abnormal airway function was demonstrated in every patient by at least one test, and nearly always by multiple tests. Specific airway conductance was abnormally low in two patients. The ratio of the 1 second forced expiratory volume to the forced vital capacity was decreased in six patients. Frequency dependence of dynamic compliance was demonstrated in eight patients. The ratio of closing volume to vital capacity was increased above age-corrected predictions in all but two patients. Upstream airway resistance was abnormally increased in 16 of the patients. These results suggest that airway dysfunction is not uncommon in sarcoidosis.

Fragile lung in the Marfan syndrome.

Two cases of the Marfan syndrome presented with spontaneous pneumothorax. Both had chest radiographs showing bilateral bullae in the upper lung zones and pulmonary function tests consistent with mild emphysema. There were dereases in forced expiratory flow rates at low lung volumes, carbon monoxide transfer factor, and lung elastic recoil. It is suggested that pneumothorax and bullous emphysema in this syndrome are caused by a weakness in the pulmonary connective tissue framework.

Electromyographic response of respiratory muscles during elastic loading.

The response of respiratory motor neurons to graded elastic loading was assessed in anesthetized dogs by recording the electromyogram (EMG) from the diaphragm (ED) and the intercostal muscle (EIC). Elastic loads were applied for 1-20 breaths. The effects of changes in PCO2 on respiratory motor neuron output was assessed by applying loads during the course of CO2 rebreathing. On the first loaded breath, ED and EIC increased reflexly due chiefly to prolongation of inspiration. Vagotomy or vagal cooling to block the Hering-Breuer reflex eliminated the increase in ED and diminished the increase in EIC. During the second to fifth breath, the level of EMG activity was disproportionately high for the level of PCO2, suggesting an additional reflex component over and above the reflex activity present on the first loaded breath.

Effects of hypercapnia on mouth pressure during airway occlusion in conscious man.

The effects of hypercapnia and inspiratory flow-resistive loading on mouth pressure during periods of arrested airflow were studied in conscious human subjects to determine the usefulness of inspiratory muscle force in the assessment of respiratory neural efferent activity. Hypercapnia increased the peak end-inspiratory mouth pressure (Ppeak) during complete airway occlusion and the pressures at 100, 200, and 300 ms after the onset of inspiration (P100, P200, P300). During rebreathing without added mechanical loads, P100 and Ppeak increased linearly with the electrical activity of the diaphragm and changes in P100 and Ppeak during hypercapnia correlated well with ventilatory responses to PCO2 (DELTA V/DELTA PCO2) suggesting that occluded mouth pressures are reliable measures of respiratory activity. In individuals with the greatest reduction in delta V/DELTA PCO2 during inspiratory flow-resistive loading, changes in P100 and Ppeak with PCO2 increased only minimally. In contrast, there was a much greater increase in occluded mouth pressures with hypercapnia in the presence of mechanical loading when inspiratory flow-resistive loading failed to depress delta V/DELTA PCO2. In all subjects, occluded mouth pressures were greater at any given PCO2 during mechanical loading than during free breathing. Mechanical loading resulted in augmented respiratory neural efferent activity unexplained by alterations in chemical stimulation.

Effects of hypercapnia and flow-resistive loading on tracheal pressure during airway occlusion.

To determine whether the isometric force of concentration of the inspiratory muscles could be used to assess respiratory efferent neural activity, the tracheal pressure generated by the inspiratory muscles during airway occlusion (occluded tracheal pressure) was measured during progressive hypercapnia in anesthetized dogs breathing normally and breathing against added flow-resistive loads. Hypercapnia increased the peak end-inspiratory tracheal pressure and the occluded tracheal pressures generated 100, 200, and 300 ms after the onset of inspiration. The duration of the occluded inspiratory effort generally remained unchanged and the configuration of the pressure tracing was not affected. During normal breathing occluded tracheal pressures increased linearly with tidal volume and with the electrical activity of the diaphragm and the external intercostal muscles both before and after vagotomy. Inspiratory flow-resistive loading reduced the ventilatory response to CO2 but did not affect occluded tracheal pressures at any given PCO2 or the change in pressures with hypercapnia both before and after vagotomy. Similarly, expiratory flow-resistive loading failed to affect occluded tracheal pressures. These results suggest that occluded tracheal pressures measure respiratory efferent neural activity and can be used as indices of CO2 responsivity even during mechanical loading in anesthetized animals.

Effect of hypoxia on the pressure developed by inspiratory muscles during airway occlusion.

The effect of progressive isocapnic hypoxia on the pressure generated by the inspiratory muscle during airway occlusion was studied in 10 awake subjects during normal and obstructed breathing. Isocapnic hypoxia was produced by rebreathing a gas mixture of 6% CO2 in air while the expired gas was passed through a CO2 scrubber so as to maintain PACO2 constant (42.6 mmHg +/- 2.2 SE). Occlusion of the airway was performed randomly for a single breath at FRC. In all 10 subjects maximal pressure (Ppeak) and the pressures measured 100, 200, 300, and 400 ms after the onset of inspiration increased during hypoxia. Furthermore, good correlation was noted between the occlusion pressure response to hypoxia (delta P/DELTA[1/PO2-32]) and simultaneous changes in ventilatory response to hypoxia (delta VI/DELTA[1/PO2-32]). The occlusion pressure response to hypoxia therefore seems to be a reliable measure of respiratory center output. When rebreathing was repeated during inspiratory resistive loading, the occlusion pressure at any given PO2 and delta P/DELTA(1PO2-32) measured in the first 400 ms of inspiration increased in 9 of 10 subjects. Since PACO2 and PAO2 during both control and loaded experiments were the same, the increase in occlusion pressure in the presence of flow-resistive loading appeared to represent a neurally mediated increase in inspiratory motoneuron activity.

Effect of liver failure on the ventilatory response to hypoxia in man and the goat.

1. The ventilatory responses to transient and steady-state hypoxia were measured in ten patients with hepatic cirrhosis and in ten healthy control subjects. Successive measurements of these responses were also obtained in six goats before and after the experimental production of liver failure. Changes in the effect of steady-state hypoxia on the ventilatory response to hypercapnia were evaluated by successive studies in another goat. 2. In spite of a respiratory alkalosis during liver failure, the response to transient hypoxia was greater in the patients than in the control subjects. This response was increased after the onset of liver failure in all the goats. 3. In healthy humans and goats the responses to transient and steady-state hypoxia were similar in magnitude. During liver failure there was a disparity between the size of these responses, since the ventilatory increment evoked by steady-state hypoxia was unchanged in spite of the increase in response to transient hypoxia. Steady-state hypoxia consistently enhanced the ventilatory response to hypercapnia in a healthy goat, but frequently depressed the response to hypercapnia during liver failure. 4. The findings suggest that liver failure heightens the sensitivity of the peripheral chemoreceptors to the hypoxic stimulus, but may increase the tendency of the medullary centres to become depressed in hypoxia.

Effect of liver failure on the cerebral circulatory and metabolic responses to hypoxia in the goat.

1. Six unanaesthetized goats were used to evaluate the effect of liver failure on the hypoxic responsiveness of cerebral blood flow. The animals breathed air and several different hypoxic gas mixtures enriched with sufficient CO2 to maintain an isocapnic state. The cerebral metabolic rate for O2 (CMRo2) was also measured in four of these goats. 2. In baseline studies there was a linear relationship between cerebral blood flow and arterial O2 saturation (Sa,o2) measured at different levels of isocapnic hypoxia. The slopes of the cerebral blood flow/Sa,o2 response lines were used to quantify the response of cerebral blood flow to hypoxia. In the healthy goat, CMRo2 was not depressed by hypoxia until the O2 tension (Po2) in arterial and cerebral venous blood had fallen below critical threshold values of approximately 3-2 and 2-2 kPa (24 and 16 mmHg) respectively. 3. Liver failure was accompanied by a fall in cerebral blood flow and CMRo2. There was also a depression in the response of cerebral blood flow to hypoxia and a disproportionate reduction of cerebral O2 delivery in hypoxia. CMRo2 was further reduced at arterial and cerebral venous Po2 values, which were much higher than the critical threshold values for producing hypoxic CMRo2 depression in health. 4. It is concluded that the brain becomes more vulnerable to the adverse effects of hypoxia during liver failure. This may be of practical importance in the management of patients with arterial hypoxaemia or other complications (e.g. anaemia or shock), which may reduce cerebral oxygen delivery.