Reproducibility of histamine challenge tests in asthmatic children.

The measurement of bronchial reactivity by histamine challenge testing is of increasing clinical importance in paediatrics. By means of a simple tidal breathing technique for the measurement of histamine sensitivity (expressed as PC20--the concentration of histamine which produces a 20% fall in peak flow rate) in childhood asthma, the reproducibility of pairs of tests was estimated over one hour and 24-hour intervals in 22 children. Under carefully controlled conditions the 95% confidence limits of PC20 were 0.8-1.25 X baseline PC20 after one hour and 0.36-2.8 X baseline PC20 after 24 hours.     

Multiple exercise and histamine challenge in asthmatic patients

We studied the effects of repeated exercise and histamine challenge in asthmatic patients to determine the frequency and degree to which a state of refractoriness was induced by these stimuli. Twenty-nine patients performed three exercise tests, and on a separate day 16 of these patients had three histamine inhalational challenge tests. Forty minutes separated each challenge. Changes in airways resistance were measured using the peak expiratory flow rate (PEFR). The fall in PEFR (expressed as a percentage of the pre-challenge value) was used to quantify the response to challenge. Significant “protection” was defined as a fall in PEFR after a repeated challenge less than 50% of the fall observed on the first challenge. All patients had a fall in PEFR greater than 22% on the first challenge of the day. With repeated exercise 28 out of 29 patients had a fall in PEFR less than that observed on the first test and 12 had significant “protection”. The fall in PEFR after the third exercise challenge was not significantly different to the second challenge and a “plateau” effect was observed. There was no significant difference in the fall in PEFR after the first and second histamine challenge although two of the 16 patients were significantly protected. After the third histamine challenge five of the 16 patients were significantly protected from the effects of the same dose of histamine. The degree to which repeated exercise challenge induces a diminished response is variable. With repeated challenge the response to histamine remains relatively constant in most patients though 30% may be expected to be refractory after a third challenge.     

Increased responsiveness to methacholine and histamine after challenge with ultrasonically nebulised water in asthmatic subjects.

Responsiveness to inhaled methacholine was compared before and 40-60 minutes after a challenge with ultrasonically nebulised water (UNH2O) in 16 asthmatic patients. The sensitivity to methacholine increased after UNH2O challenge (p less than 0.001). The mean dose of methacholine producing a 20% fall in forced expiratory volume in one second was 0.4 (95% confidence limits 0.2, 0.8) mumol, compared with 0.9 (95% confidence limits 0.5, 1.6) mumol in the first methacholine challenge. When the study was repeated in six asthmatic patients with histamine substituted for methacholine, five of the patients were significantly more sensitive to histamine after UNH2O challenge. It is concluded that challenge with UNH2O produces an increase in airway responsiveness.     

Reduction in exhaled nitric oxide immediately after methacholine challenge in asthmatic children

BACKGROUND: The measurement of exhaled nitric oxide (NO) has recently been proposed as a useful technique for the evaluation of airway inflammation in asthma. The purpose of this study was to determine the effect of methacholine bronchial provocation on the levels of exhaled NO in asthmatic children. METHOD: Exhaled NO was measurement immediately before and after methacholine provocation in 51 children with mild to moderate asthma. RESULTS: A significant decrease occurred in the level of exhaled NO (p<0.0001) after methacholine bronchial provocation which was not correlated with the percentage fall in forced expiratory volume in 1 second (FEV(1)). CONCLUSIONS: The methacholine test should not be used immediately before measurement of exhaled NO in children with asthma.     

Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects.

In order to determine the effect of drugs on bronchial hyperreactivity in subjects with asthma, 12 atopic asthmatic volunteers underwent bronchial challenge with either histamine or methacholine on three separate days. Before the challenges no medication was given on the first day, on the second 400 microgram of aerosol fenoterol and on the third 5 mg of oral fenoterol were administered. The aerosol fenoterol caused the dose response curves to both histamine and methacholine to be shifted to the right in all subjects. The oral dose produced no significant change from the control values. The slope of the dose response curves was not altered by either the oral or the aerosol drug. It is concluded that aerosol but not oral fenoterol in the clinical dosage, causes a change in the sensitivity but not in the reactivity of the airway of patients with atopic asthma.     

Neostigmine after spontaneous recovery from neuromuscular blockade

The effect of neostigmine on neuromuscular function was examined after spontaneous recovery from an atracurium-induced neuromuscular blockade, which reached a train-of-four ratio of either 0.5 or 0.9. Two doses of neostigmine 2.5 mg were given 5 minutes apart. Neuromuscular recovery was assessed with train-of-four and tetanic stimuli. The first dose of neostigmine antagonised the neuromuscular blockade. The second dose diminished tetanic height and increased tetanic fade. The train-of-four measured mechanically was adversely affected to a small degree, but when measured with the electromyograph no significant change occurred. Neostigmine may adversely affect neuromuscular function after spontaneous recovery from a non-depolarising block. This is unlikely with a single modest dose and any effects are probably short-lived.     

Effect of aerosol particle size on bronchodilatation with nebulised terbutaline in asthmatic subjects.

The bronchodilatation achieved by the beta 2 agonist terbutaline sulphate given as nebulised aerosol from different devices has been measured in seven patients with mild asthma (mean FEV1 76% predicted) over two hours after inhalation. The subjects were studied on four occasions. On three visits they received 2.5 mg terbutaline delivered from three different types of nebuliser, selected on the basis of the size distribution of the aerosols generated; and on a fourth (control) visit no aerosol was given. The size distributions of the aerosols expressed in terms of their mass median diameter (MMD) were: A: MMD 1.8 microns; B: 4.6 microns; C: 10.3 microns. The aerosols were given under controlled conditions of respiratory rate and tidal volume to minimise intertreatment variation. Bronchodilator response was assessed by changes in FEV1, forced vital capacity (FVC), peak expiratory flow (PEF), and maximal flow after expiration of 50% and 75% FVC (Vmax50, Vmax25) from baseline (before aerosol) and control run values. For each pulmonary function index all three aerosols gave significantly better improvement over baseline than was seen in the control (p less than 0.05) and had an equipotent effect on FEV1, FVC, and PEF. Aerosol A (MMD 1.8 microns) produced significantly greater improvements in Vmax50 and Vmax25 than did B or C (p less than 0.05). These results suggest that for beta 2 agonists small aerosols (MMD less than 2 microns) might be advantageous in the treatment of asthma.     

Propranolol inhalation challenge in relation to histamine response in children with asthma.

The relation between airway responsiveness to propranolol and histamine was studied in 32 asthmatic children. Propranolol and histamine were given by nebuliser to a maximum dose of 16 mg/ml and 32 mg/ml respectively and the response was measured as the provocative concentration of agonist causing a 20% fall in FEV1 (PC20). A PC20 histamine value of less than 32 mg/ml was obtained in 24 of the 32 children, of whom 15 had a measurable PC20 propranolol (less than 16 mg/ml). In these 24 children the geometric mean PC20 histamine was 4.5 mg/ml and 14.4 mg/ml respectively in those with and without a measurable PC20 propranolol (p = 0.023). There was a linear relationship between histamine and propranolol PC20 values (r = 0.60), and between PC20 histamine and FEV1 % predicted (r = 0.43), but not between PC20 propranolol and FEV1 % predicted (r = 0.38). In an open time course study in 12 children with asthma recovery of FEV1 after inhaled propranolol was incomplete in seven of the children after 90 minutes. When inhaled propranolol was followed by inhaled ipratropium bromide in a further 11 children FEV1 had returned to baseline in all children after 60 minutes. Thus propranolol inhalation can be used in children with asthma to assess the contribution of the beta adrenergic system to the regulation of bronchial smooth muscle tone. The test has several disadvantages in comparison with histamine provocation-long duration, the prolonged action of propranolol, and the fact that only the children with substantial hyperreactivity to histamine react to propranolol.     

Changes in bronchial responsiveness to histamine at intervals after allergen challenge.

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.     

Repeatability of methacholine challenge in asthmatic children measured by change in transcutaneous oxygen tension.

BACKGROUND: The airway response to bronchial provocation may be evaluated by monitoring the fall in transcutaneous oxygen tension (PtcO2) but the repeatability of this method has not been rigorously assessed. METHODS: To determine the repeatability of this indirect method of assessment, bronchial challenge was performed with methacholine in nine children with stable asthma (age range 6-12 years) and was repeated 24 hours later. The response was determined by the fall both in forced expiratory volume in one second (FEV1) and in PtcO2. A modified tidal inhalation protocol was used in which quadrupling concentrations of methacholine were given, thereby reducing the time taken for the full challenge by almost half. The concentrations of methacholine that provoked a 20% decrease in FEV1 (PC20FEV1) and 15% and 10% falls in PtcO2 (PC15PtcO2, PC10PtcO2) were calculated. RESULTS: Repeatability measures, assessed as the 95% range for a single determination, were +/- 0.96 and +/- 1.12 doubling concentration differences respectively for PC15PtcO2 and PC10PtcO2 and +/- 0.80 for PC20FEV1. CONCLUSION: This challenge method using quadrupling concentrations and an indirect assessment of the response by PtcO2 was sufficiently repeatable for clinical use and compared favourably with repeated challenge assessed by FEV1. The PtcO2 method is simple and effort independent, and should prove particularly useful for measuring bronchial reactivity in young children.     

Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients.

The effect of a single oral dose (800 mg) of zileuton (A-64077), a specific 5-lipoxygenase inhibitor, on the early and late airway responses to inhaled allergen was studied in a randomised, double blind, placebo controlled, and crossover trial in nine subjects with atopic asthma. Leukotriene generation was also assessed in vivo by measuring urinary leukotriene (LT) E4 excretion, and ex vivo by measuring calcium ionophore stimulated whole blood LTB4 production. Zileuton almost completely inhibited ex vivo LTB4 production but reduced urinary excretion of LTE4 by only about half. There was a trend for the early asthmatic response to be less on the day of zileuton treatment, but this did not reach statistical significance (p = 0.08). The zileuton induced reduction in maximum fall in FEV1 in the early asthmatic response was, however, significantly related to the reduction in urinary LTE4 excretion (r = 0.8), but not to the reduction in LTB4 generation ex vivo. There was no significant change in the allergen induced late asthmatic response, or in the increase in airway responsiveness to methacholine following antigen. The results provide some support for the hypothesis that the cysteinyl leukotrienes have a role in the allergen induced early asthmatic response. More complete in vivo inhibition of 5-lipoxygenase may be needed to produce a significant reduction in airway response to allergen challenge.     

Use of a special inhaler attachment in asthmatic children.

Asthmatics often find difficulties in using an aerosol inhaler correctly as they are unable to co-ordinate the release of a bolus of drug to coincide with an inspiratory effort. This is especially the case with children. The addition of a special attachment to an ordinary inhaler overcame this problem. Twelve asthmatic children produced significantly better PEFR measurements when 0.25 mg terbutaline sulphate was administered via an inhaler with the attachment than when an ordinary inhaler was used alone.     

Refractory period following bronchoconstriction provoked by histamine in asthmatic subjects.

To determine whether refractoriness to histamine induced bronchoconstriction occurs, 20 asthmatic subjects aged 19-50 years were tested. Subjects underwent two histamine challenge tests (1 and 2) on the same day, the second one being given 45-60 minutes after the first, once the FEV1 after test 1 had returned spontaneously to within 90% of baseline. A further "control" histamine challenge test was carried out on a different day at the same time (+/- 2 hours) as test 1. Bronchial responsiveness was recorded as the cumulative dose (microgram) of histamine provoking a 20% fall in FEV1 (PD20), and the ratio PD20 test 2:PD20 test 1 was used to assess refractoriness. The median value of this ratio (2.20) was significantly greater than 1 (p = 0.003), indicating refractoriness at the time of test 2. By contrast the median ratio PD20 control:PD20 test 1 of 1.03 was not significantly different from 1. Refractoriness could not be accounted for by failure to regain the initial baseline FEV1, though such failure may have exaggerated the effect. An increase in PD20 with the second test was observed uniformly in subjects with moderate or high initial PD20 values but not in those with low values. This suggests that there may be a PD20 threshold of the order 25-100 micrograms for refractoriness to occur. Refractoriness could exert an important confounding effect in investigations in which repeated histamine tests are carried out at short intervals.     

Effects of histamine on lung permeability in normal and asthmatic subjects.

The permeability of respiratory mucosa, as measured by clearance of diethylenetriamine penta-acetate (DTPA) labelled with technetium 99m, was similar in seven normal and nine asthmatic subjects. Histamine induced bronchoconstriction was associated with a 50% increase in permeability in both groups of subjects. In normal subjects inhaled salbutamol, given as 1 mg acutely or as 200 micrograms four times daily for two weeks, had no effect on pulmonary permeability. Salbutamol, given before histamine challenge, prevented bronchoconstriction, but did not affect the increase in permeability seen in normal subjects. Low doses of histamine, sufficient to cause bronchoconstriction in the asthmatic subjects, produced little bronchoconstriction in normal subjects but caused increases in lung permeability similar to those seen in asthmatic subjects. These studies suggest that these two effects of inhaled histamine, bronchoconstriction and increased permeability, are independent.     

Comparison of neostigmine-induced recovery with spontaneous recovery from mivacurium-induced neuromuscular block

In 24 ASA I–II adults anaesthetized with thiopentone,fentanyl and nitrous oxide in oxygen, we studied neuromusculartransmission with isometric adductor pollicis monitoring. Patientsreceived mivacurium 0.2 mg kg^–1 followed by an infusionlasting at least 60 min and adjusted to maintain twitch heightat 1–5%. After termination of the mivacurium infusion,when twitch height spontaneously regained 25% of its controlvalue, the patients were allocated to two groups of 12 patientseach. In group NEO patients received neostigmine 40 µgkg^–1 and atropine 15 µg kg^–1 and in groupSPO neuromuscular transmission was allowed to recover spontaneously.Twitch height was measured every 10 s and train-of-four (TOF)(2Hz) every 3 min. After 15 min, residual force after tetanicstimulation (50 and 100 Hz, 5-s duration (RF50_HZ, RF100_Hz),1 min apart) were recorded sequentially. At 15 min, mean TOFratio was greater in group NEO (0.94 (SEM 0.01)) than in groupSPO (0.87 (0.02)) (P < 0.01). All patients in group NEO recoveredto a TOF ratio greater than 0.7 after 6 min compared with 15min in group SPO (P < 0.005). A TOF ratio greater than 0.9was observed in all patients in group NEO compared with onlysix in group SPO (P < 0.025). Nevertheless, RF50_HZ and RF100_HZdid not differ significantly (0.92 (0.01) (group NEO), 0.91(0.01) (group SPO) and 0.83 (0.02) (group NEO), 0.78 (0.03)(group SPO), respectively). We conclude that although therewas a high degree of spontaneous recovery, administration ofneostigmine-atropine accelerated the rate of recovery of neuromusculartransmission after mivacurium and greatly increased the numberof patients satisfying the criteria for complete recovery ofneuromuscular transmission (TOF ratio < 0.9) within 15 min.     

Early MR abnormality indicating functional recovery from spontaneous intracerebral hemorrhage.

Magnetic resonance (MR) imaging as an indicator of recovery from hemiparesis was evaluated in 60 patients with spontaneous intracerebral hemorrhage. T2-weighted MR images revealed early MR abnormality (EMA) of the corticospinal tract within 1 week of ictus. Most patients without EMA recovered beyond Brunnstrom's Recovery Stage 3 while only a few patients with EMA did so. Patients with EMA cannot regain motor function because EMA is almost always followed by complete tract degeneration. EMA in the brainstem and poor motor function recovery are closely correlated.     

Assessment of postsurgical recovery after discharge using a pen computer diary

We assessed patients after their return home following gynaecological surgery, using a daily electronic diary. Thirty-two females aged 27-77 years took part. After a hospital stay of 1-6 days (mean 2.3), they were given a pen-based electronic diary and asked to record symptoms and other data over one month. They also completed a questionnaire at the end of the study. Substantial effects on quality and duration of sleep, pain during both the night and day, interference with daily activities, energy, and ability to concentrate were recorded, mostly during the first week of treatment. Symptoms reported in the final questionnaire correlated significantly with diary data. Most patients found the electronic diary easy to use, and none found it difficult. Daily electronic diaries are an acceptable method of obtaining better information on the extent and duration of symptoms and other difficulties after discharge following surgery.     

Effect of endobronchial aspirin challenge on inflammatory cells in bronchial biopsy samples from aspirin-sensitive asthmatic subjects.

BACKGROUND: The aspirin-induced bronchoconstriction in patients with aspirin-sensitive asthma is caused by cysteinyl leukotriene release. The cellular source of the leukotrienes is unknown. The inflammatory cell infiltrate in bronchial biopsy samples from seven aspirin-sensitive asthmatic (ASA) subjects and eight non-ASA subjects before and after local challenge with lysine aspirin was therefore examined. METHODS: Using flexible bronchoscopy, airway mucosal biopsy samples were taken and lysine aspirin solution was placed directly onto a carina of the contralateral lung. Twenty minutes later a second series of biopsy samples was taken from the site of the local endobronchial lysine aspirin challenge. The biopsy samples were double immunostained with a rabbit polyclonal antibody to the enzyme 5-lipoxygenase and monoclonal antibodies to mast cells (AA1), neutrophils (NP57), macrophages (EBM11), T lymphocytes (anti-CD3), and total (BMK13) and activated eosinophils (EG2). RESULTS: A decrease in both absolute mast cell numbers staining with mast cell tryptase (AA1) and the percentage of mast cells co-immunostaining with 5-lipoxygenase was seen in the ASA patients after lysine aspirin challenge compared with the non-ASA control group. There was also an increase in the numbers of activated eosinophils (EG2) in the ASA subjects compared with the non-ASA group. No changes were observed in the total numbers of macrophages (EBM11), neutrophils (NP57), total eosinophils (BMK13), and T lymphocytes (anti-CD3) after challenge with lysine aspirin. CONCLUSIONS: The decrease in numbers of mast cells staining for tryptase and the increase in activated eosinophils after endobronchial challenge with lysine aspirin may represent degranulation of these cell types, and may be an early event associated with aspirin-sensitive reactions in ASA subjects.