Coughing frequency in patients with persistent cough: assessment using a 24 hour ambulatory recorder.

Cough is an important symptom of many respiratory disorders. We determined the frequency and diurnal variation of cough in normal subjects and in patients with asthma or with persistent cough of unknown cause. We used a portable, solid-state, multiple-channel recorder to record cough sounds over a 24 h period. The audio-signal was recorded from a unidirectional microphone strapped over the chest wall, and electromyographic (EMG) signals from the lower respiratory muscles were simultaneously registered with surface electrodes. The recorded digital data were examined on an IBM-compatible computer, and the typical signals induced by cough (as assessed by voluntary or experimentally-induced cough) were counted. In 12 normal subjects, only 0-16 coughs were recorded over 24 h. In 21 stable asthmatics with a history of chronic cough ("asthma") the median number was 282 (ranges: 45-1,577), and in 14 patients with the predominant symptom of daily dry coughs ("chronic coughers") the median number was 794 (64-3,639). In both groups of patients, there was a diurnal variation of coughs, such that the least numbers occurred between 2 and 5 a.m. (< 3% of total). In the asthma group, there was no significant correlation between forced expiratory volume in one second (FEV1) (% predicted) or diurnal variation of peak expiratory flow and cough frequency. In the chronic coughers, there was a significant correlation between daytime cough numbers and daytime cough symptoms scores but not for the night-time values. Our data show that cough frequency is not determined by the severity of asthma in relatively stable asthmatics on inhaled steroids, and is reduced during sleep in both asthmatics and chronic cough patients. This portable cough recorder may be useful in the assessment of drug therapy for chronic cough.

Exercise ability after Mustard's operation.

Twenty children who were well six to 12 years after undergoing Mustard's operation for transposition of the great arteries were studied. Each child performed a graded maximal treadmill test with measurements of gas exchange and oxygen saturation, and had electrocardiography carried out. Nineteen were also catheterised, and oxygen consumption was measured so that pulmonary and systemic flow could be calculated. Compared with 20 age and size matched controls, seven of the patients had normal exercise tolerance (as judged by a maximal oxygen consumption of greater than 40 ml/kg/min), 10 showed a moderate reduction (30-39 ml/kg/min), and three were more seriously limited. None of the patients with normal exercise tolerance had obstruction of venous return but six of those with mild impairment of exercise ability had partial or complete obstruction of one or both of the vena cavas. More severe limitation was associated with pulmonary vascular disease and fixed ventricular outflow tract obstruction. Formal exercise testing of apparently well children who have undergone Mustard's operation identifies those with haemodynamic abnormalities that may require intervention.

Changes in pulmonary circulation in severe bronchopulmonary dysplasia.

Eight patients with severe bronchopulmonary dysplasia underwent cardiac catheterisation. Seven had a pulmonary vascular resistance greater than 3 mm Hg.l-1 min.m2 (mean 8.9, range 2.2-13.8). All had raised intrapulmonary shunts (mean 25.6%, range 5.4-50%, normal less than 5%). Two had a high alveolar dead space, and two had unsuspected congenital heart disease. Epoprostenol (prostacyclin), but not 100% oxygen, caused a significant fall in pulmonary vascular resistance. Death was associated with a high pulmonary vascular resistance and a high shunt. Morphometric studies in three cases showed normal numbers of airways, but increased thickness of bronchial muscle. The numbers of alveoli were reduced and the walls thickened. There was increased medial thickness in small pulmonary arteries with distal extension of muscle. In the oldest child some vessels were obliterated by fibrosis. We speculate that measurements of pulmonary vascular resistance and shunt may have prognostic value; that a trial of pulmonary vasodilators other than oxygen might be worthwhile in patients with poor prognosis; and that abnormalities of the pulmonary circulation contribute to the difficulties of managing patients with bronchopulmonary dysplasia.

Preoperative measurement of pulmonary vascular resistance in complete transposition of the great arteries.

Transposition of the great arteries is frequently complicated by the early onset of pulmonary vascular disease. It is difficult to measure pulmonary blood flow by the Fick principle because the pulmonary arteriovenous oxygen content difference is small and bronchial blood flow is increased in this condition. In eight patients (mean age 7.7 years, range 3 months to 29 years) with transposition of the great arteries mass spectrometry was used to measure oxygen uptake and predict pulmonary end capillary blood oxygen content. The effects of the bronchial circulation were studied by computer modelling. There was close agreement between pulmonary end capillary and pulmonary vein blood oxygen contents but the resultant percentage difference in arteriovenous content difference was significant (mean (SE of difference)) (14.5(3.8)%). The effect of the bronchial circulation was to give spuriously high estimates of pulmonary blood flow. The error was greatest when oxygen consumption was low and aortic blood was very desaturated.

Do asymptomatic school children have normal haemodynamics 6-13 years after Mustard's operation?

Twenty asymptomatic school children who had undergone Mustard's operation for simple complete transposition (concordant atrioventricular and discordant ventriculo-arterial connexions) were catheterised electively 6-13 years later. The studies were carried out under general anaesthesia in air and in 100% O2. Oxygen consumption was measured and end-tidal gases were monitored using respiratory mass spectrometry. There was significant left ventricular outflow tract obstruction in 2 patients. Cardiac output in air was normal in 15 and decreased in 5 patients. The pulmonary vascular resistance was normal in 18 of 19 cases, but grossly elevated in one patient. Baffle dysfunction was present in 11 patients: 10 with important gradients between the venous pathways and the systemic venous atrium, and 5 with a leak identified either by a left-to-right shunt or by the course of the catheter. Balloon dilatation was attempted in the inferior caval venous channel in 6 and in the superior caval venous channel in 2. Mean gradient before the dilatation fell after the procedure. No pulmonary venous obstruction was identified. Even in this group of children selected as asymptomatic, approximately half had a detectable haemodynamic abnormality.

Interactions between alveolar hypercapnia and epoprostenol on the pulmonary circulation: clinical and pharmacological implications.

Hypoxic vasoconstriction has been the subject of many studies, but little is known about the interaction of hypercapnia and the pulmonary circulation. We performed two haemodynamic studies on each of three patients with pulmonary vascular disease secondary to congenital heart disease. On the first occasion ventilation was inadequate due to technical problems, and the patients were therefore hypercapnic (arterial pCO2 greater than 5.3 kPa). On the second occasion, they were normocapnic. Pulmonary vascular resistance was measured on each occasion while the patients were breathing 100% oxygen (alveolar hyperoxia) and while epoprostenol (prostacyclin) was infused at doses of 5-20 ng/kg/min. Pulmonary vascular resistance was elevated in the presence of hypercapnia and, despite oxygen and epoprostenol, could not be reduced to the levels observed in the normocapnic study. We conclude that hypercapnia causes significant vasoconstriction in infants; and that epoprostenol is a relatively ineffective pulmonary vasodilator in infants who are hypercapnic due to inadequate ventilation. Where possible, respiratory acidosis should be corrected before using oxygen or epoprostenol as a pulmonary vasodilator.

Comparison of the cardiovascular and pulmonary effects of oral celiprolol, propranolol and placebo in normal volunteers.

1. The effects on heart rate, blood pressure and pulmonary function of single oral doses of celiprolol hydrochloride (400 mg), and propranolol (40 mg) were compared with placebo in 12 healthy volunteers, in a double-blind three-period crossover study. 2. Celiprolol had no effect on heart rate while propranolol caused a significant reduction compared with placebo. Systolic blood pressure was reduced by propranolol but not celiprolol, whereas standing diastolic blood pressure was lowered by both drugs. 3. The maximal expiratory flow at 50% vital capacity (MEF.50), was significantly lower after propranolol compared with placebo and celiprolol. Celiprolol had no effect on the flow-volume loop parameters. 4. Effective pulmonary blood flow was significantly increased by celiprolol, but reduced by propranolol. 5. A high incidence of subjective side-effects were experienced on celiprolol (10/12; particularly unpleasant in 5). Side-effects were experienced to a lesser extent on placebo (8/12). Only one volunteer experienced a side-effect on propranolol. 6. Oral celiprolol exerts its hypotensive effect by vasodilatation without reflex tachycardia. It does not cause airways obstruction in healthy subjects.

Multiple pulmonary arteriovenous fistulas in childhood.

Three cases of multiple pulmonary arteriovenous fistulas are described in children who presented at five months, two and nine years of age. Mass spectrometry was used to measure pulmonary blood flow and, in two cases, the intrapulmonary right-to-left shunt. The shunt fractions were 51% and 35%, with no significant change on breathing 100% oxygen. In one case, effective pulmonary blood flow was measured during cardiac catheterisation by the argon-freon rebreathing method and agreed closely with that found from the Fick, principle with measured oxygen consumption. Treatment consisted of surgical ligation of a lower lobe pulmonary artery in the youngest child, balloon embolisation in the second, and initial surgical oversewing of a single large fistula followed twenty months later by steel coil embolisation in the third. The last and oldest child is well and no longer cyanosed. The first two children died seven months after treatment with evidence of progression of their pulmonary arteriovenous fistulas. The first of these, who also had an atrial septal defect and discordant thoraco-abdominal arrangement, died of heart failure. Autopsies on both children confirmed extensive involvement of both lungs by arteriovenous fistulas. In one case who had a diffuse, telangiectatic form of pulmonary arteriovenous fistulas, microscopic serial reconstructions of lung tissue revealed that anastomoses occurred between arteries accompanying terminal bronchioles and intra-acinar arteries and adjacent veins. Occlusion of the pulmonary arteries supplying the fistulas led to extensive fibrosis within them, and was associated with enlargement of the corresponding bronchial arterial circulation.

Effect of infused adenosine on cardiac output and systemic resistance in normal subjects.

1. The purine nucleoside adenosine relaxes smooth muscle in vitro and is a vasodilator in animals, but its effects on cardiac output and systemic vascular resistance have not been measured in normal conscious human subjects. 2. We have studied the effects of infused adenosine in doses of 0.005, 0.03 and 0.07 mg kg-1 min-1 on pulmonary blood flow and systemic vascular resistance in eight healthy volunteers, using a non-invasive, inert gas method and mass spectrometry. 3. At a dose of 0.07 mg kg-1 min-1, there was a rise in effective pulmonary blood flow (which is approximately equivalent to cardiac output) of 0.52 +/- 0.08 l min-1 m-2 (mean +/- s.e. mean) and a fall in estimated systemic vascular resistance of 357 +/- 44 dyn s cm-5. Despite this marked systemic vasodilation, there was no significant change in mean heart rate. 4. The effects of this dose of adenosine were maximal 2 min after starting the infusion, and had disappeared within 5 min of stopping it. 5. Adenosine may be therapeutically useful in the reduction of left ventricular afterload, where the absence of reflex tachycardia may be advantageous. We suggest that adenosine in doses of 0.03 mg kg-1 min-1 should be evaluated as a selective pulmonary vasodilator.

Effects of infusion of prostacyclin on anatomical intrapulmonary right to left shunt: a useful model of human hypoxic vasoconstriction?

1. Eleven infants and children (mean age 4.3 years, range 0.2-12 years) with pulmonary vascular disease secondary to congenital cardiac anomalies (n = 6) or bronchopulmonary dysplasia (n = 5), were studied during cardiac catheterization while ventilated on 100% oxygen. 2. All had a raised pulmonary vascular resistance (mean 11.8 units, range 4.1-26.0 units, normal value less than 3 units) and a raised anatomical intrapulmonary right to left shunt (mean 22%, range 8-50%, normal value less than 5%). The elevated shunt was attributed to the effects of 100% oxygen and general anaesthesia causing alveolar collapse, with only partial compensation for impairment of gas exchange by compensatory local hypoxic vasoconstriction. 3. When prostacyclin was infused, pulmonary vascular resistance fell by 3.2 +/- 1.8 units (mmHg litre-1 min m2), and pulmonary blood flow rose by 1.0 +/- 0.7 litre min-1 m-2 (mean +/- 95% confidence intervals). 4. Intrapulmonary right to left shunt fraction increased in eight of 11 patients, with a maximal rise for the group of 5.9 +/- 4.6% (mean +/- 95% confidence intervals). However, even at doses of prostacyclin sufficient to cause systemic vasodilatation and tachycardia, there was no evidence for a selective increase in shunt fraction. 5. We suggest that studying the effects of therapeutic interventions on intrapulmonary shunt fraction may be a useful model in vivo of human hypoxic pulmonary vasoconstriction.

Comparison of the haemodynamic effects of epoprostenol (prostacyclin) and tolazoline.

The haemodynamic effects of infusion of epoprostenol (prostacyclin) and bolus injection of tolazoline were compared in a crossover study in 11 children with pulmonary hypertension caused by pulmonary vascular disease. The children were studied during cardiac catheterisation, while they were anaesthetised, paralysed, and ventilated with 100% oxygen. The order of drug administration was not randomised because tolazoline has a half life of hours whereas epoprostenol has a half life of a few minutes. Both drugs caused pulmonary and systemic vasodilatation, and there were no significant differences between the two. The 95% confidence intervals suggest that tolazoline did not have a clinically important haemodynamic advantage over epoprostenol. Previous reports suggest that serious side effects are common when tolazoline is used in repeated doses; epoprostenol has only a few minor side effects that are rapidly reversible when the infusion is stopped. Epoprostenol is more expensive than tolazoline but this study suggests that epoprostenol is a more suitable pulmonary vasodilator if more than a single dose is required.

Rebreathing method for the simultaneous measurement of oxygen consumption and effective pulmonary blood flow during exercise.

This paper describes a rebreathing method for the simultaneous measurement of oxygen consumption (VO2) and effective pulmonary blood flow (QP. eff) at rest and during exercise. Subjects rebreathed a test gas consisting of 35% oxygen, 3.5% chlorodifluoromethane (freon-22), and 10% argon in nitrogen for 30 seconds or until the respired oxygen tension fell to below 13.3 kPa. Sixty normal subjects were studied on a motorized treadmill, the Bruce protocol being used. The rebreathing manoeuvre was performed at three minute intervals, and was initially practised sitting down. Measurements were then made with the subjects standing at rest, and subsequently during the last minute of each stage of the Bruce exercise protocol until the subjects were exhausted. Heart rate was recorded from the electrocardiogram. Oxygen uptake plotted against calculated power (watts) showed a discontinuity between resting and exercise values, probably because power output during treadmill exercise is underestimated. The arbitrary addition of 30 watts to the exercise power output abolished this discontinuity. There was good agreement between rebreathing estimates of oxygen consumption and values measured during a second exercise test by the conventional open circuit argon dilution method. Coefficients of variation of oxygen consumption and effective pulmonary blood flow measured by rebreathing were usually less than 10% even during maximal exertion. At rest mean (SD) effective pulmonary blood flow corrected for body surface area was 2.2 (0.46) l/min/m2. Effective pulmonary blood flow rose linearly with oxygen consumption. At rest the arteriovenous oxygen content difference for pulmonary blood (VO2/QP eff) was 9.1 (1.6) ml/dl, rising to a maximum of 16.4 (1.8) ml/dl. The stroke volume index was 27.5 (6.8) ml/m2, rising to a maximum of 46.5 (7.1) ml/m2 during exertion.

Cardiovascular function at rest and on exercise in patients with cryptogenic fibrosing alveolitis.

Cardiovascular complications are common in fibrosing alveolitis, but there have been few physiological studies of the pulmonary circulation in this condition, and those that have been carried out have usually depended on right heart catheterisation. This paper reports non-invasive measurements of effective pulmonary blood flow, oxygen uptake, pulmonary arteriovenous oxygen content differences, and estimates of mixed venous oxygen saturation in 20 patients with histologically proved cryptogenic fibrosing alveolitis at rest and while exercising on a motorized treadmill. Results were compared with those of 20 age and sex matched normal subjects, at rest and at an arbitrarily chosen oxygen uptake of 0.75 l/min. The latter results were obtained by linear interpolation. Effective pulmonary blood flow was normal at rest, but oxygen dispatch to the tissues (blood flow x blood oxygen content) was significantly reduced at rest (mean reduction 190 (SD 68) ml/l/min; p less than 0.01) and at an oxygen uptake of 0.75 l/min (mean reduction 128 (50) ml/l/min; p less than 0.02), reflecting the presence of systemic arterial hypoxaemia. Pulmonary arteriovenous oxygen content differences were similar in patients and normal subjects, but mixed venous saturation was lower in the patients at rest (mean % reduction 6.8 (2.6); p less than 0.02) and at an oxygen uptake of 0.75 l/min (mean % reduction 9.6 (2.9); p less than 0.002). It is concluded that the supply of oxygen potentially available to the tissues is reduced at rest and during exercise in patients with fibrosing alveolitis and hence, by analogy with normal people exercising under hypoxic conditions, that pulmonary blood flow is inappropriately low in this condition. The low mixed venous oxygen saturation may contribute to the development of pulmonary hypertension in some patients. The rebreathing technique used in this study may be of use in monitoring treatment; it could be applied many times to the same patient, and might be a suitable way of following the response to pulmonary vasodilators.

Correlations of lung morphology, pulmonary vascular resistance, and outcome in children with congenital heart disease.

Pulmonary vascular resistance was measured in air, oxygen, and after administration of vasodilators in 14 children with pulmonary hypertension and congenital heart disease. Lung morphology was examined by light microscopy and assessed quantitatively. In this selected group of patients (a) medial muscle thickness of greater than 20% in the intra-acinar arteries and Heath-Edwards changes of I or II were significantly associated with perioperative death from pulmonary complications after cardiac surgery; (b) children with lower percentage medial muscle thickness had a higher baseline resistance (r = -0.84) associated with Heath-Edwards grade III or higher changes (most of these patients were not offered corrective surgery); (c) when the lowest pulmonary vascular resistance was less than 3 units, Heath-Edwards grading was I or II (n = 4). When the pulmonary vascular resistance was greater than 6 units, however, there was no direct correlation with Heath-Edwards grading (n = 9). Four patients with a resistance of greater than 6 units had only grade I or II changes. Three had a medial muscle thickness above 20%, and were among those who died at or soon after operation. It is concluded that (a) patients with a lowest pulmonary vascular resistance of greater than 6 units have a bad prognosis whatever their lung morphology; and (b) some patients with Heath-Edwards grade I or II will have a high resistance (this group has a high medial muscle mass and a poor prognosis and would not be detected by Heath-Edwards grading alone).

Time course of the effects of epoprostenol on effective pulmonary blood flow in normal volunteers.

1. Epoprostenol (prostacyclin) has been widely used as a vasodilator, but its effects on cardiac output are controversial and the time course of its effects little studied. 2. We report its cardiovascular effects in doses of 5 and 10 ng kg-1 min-1 in six healthy volunteers. 3. Each of the two doses caused a mean 20% rise in effective pulmonary blood flow and a 15% rise in heart rate. These effects appeared to reach a maximum within 10 min of starting or increasing the rate of infusion, with no evidence of a rebound effect. 4. When the dose was reduced, heart rate and effective pulmonary blood flow appeared to reach a new steady state within 5 min of reducing or stopping the infusion. Only minor side-effects were encountered, and they were rapidly reversed on stopping the drug. 5. These results should be applied to the therapeutic use of epoprostenol as a vasodilator, particularly when titrating the optimum dose for a given individual.

Cardiovascular effects of tolazoline and ranitidine.

The cardiovascular effects of ranitidine were studied in 12 children with congenital heart disease who had been given tolazoline as a pulmonary vasodilator. Ranitidine was given as prophylaxis against gastrointestinal haemorrhage induced by tolazoline. Tolazoline 1-2 mg/kg caused significant falls in pulmonary and systemic vascular resistances and a rise in heart rate. After intravenous administration of ranitidine 3 mg/kg both resistances rose again and neither resistance then differed significantly from baseline levels. Heart rate also fell and the final heart rate was significantly below baseline levels. We conclude that there may be H2 receptors within the pulmonary and systemic circulations and that tolazoline may mediate some of its effects through these H2 receptors rather than by alpha adrenergic receptor blockade. The safety of H2 blockade in children, particularly those with pulmonary hypertension, needs further investigation.

Effect of long term oxygen treatment at home in children with pulmonary vascular disease.

Inhalation of 100% oxygen by nine children with pulmonary vascular disease increased pulmonary blood flow measured at cardiac catheterisation; there was no significant change in pulmonary artery pressure. Fifteen children with pulmonary vascular disease that was severe enough to preclude corrective cardiac operation were studied to determine the effect of long term oxygen treatment on pulmonary vascular disease. Nine received long term domiciliary oxygen for a minimum of twelve hours a day for up to five years. Though the untreated group closely resembled the treated group their survival was significantly less good. All nine treated children are alive whereas five of the six children who did not receive oxygen have died.

The use of oxygen and prostacyclin as pulmonary vasodilators in congenital heart disease.

We have obtained dose-response curves for the effects of prostacyclin on the pulmonary and systemic circulations of 10 patients with pulmonary hypertension secondary to congenital heart disease. With the subjects breathing air, prostacyclin caused statistically significant, pulmonary and systemic vasodilation. When the patients breathed 100% oxygen, pulmonary blood flow rose and pulmonary vascular resistance fell with no significant change in pulmonary artery pressure. Prostacyclin had a small additional vasodilator effect, but this did not reach statistical significance. Prostacyclin may be of some use in the assessment of the reversibility of an elevated pulmonary vascular resistance when surgery for the underlying congenital heart defect is being contemplated.

Applications of respiratory mass spectrometry to intensive care.

A monitoring and research system based on a respiratory mass spectrometer controlled by a microprocessor has been installed in a paediatric intensive care unit. It provides an opportunity to study up to twelve patients simultaneously at distances up to 30 m from the instrument, can operate for prolonged periods without intervention, and includes a routine for regular calibration checks. There is an automatic sensitivity control which compensates for minor variations in probe patency or in water vapour pressure. Information derived from the system can be displayed centrally or at the bedside and data can be conserved for up to 24 hours; past events can be recalled and displayed for either the previous hour or previous 24 hours. The system can be used to measure respired gas tensions, metabolic gas exchange, lung volume, pulmonary blood flow and pulmonary tissue volume. The clinical value and limitations of the system are discussed.