, 1979, Volume9, pages 575-583

Comparison of histamine bronchial challenges with the Wright nehulizer and the dosimeter

A. BEAUPRE and J. L. MALO Service de Pneumologie. Hopital du Sacre-Coeur, Montreal. Canada (Received 27 February 1979; acceptedfor publication 12 March 1979)

Summary

In twenty adult asthmatics studied in a stable state, histamine bronchial challenges were carried out at one-week intervals with the Wright nebulizer and with the dosimeter-DeVilbiss apparatus. Dose-response curves were analysed for sensitivity, defined as the minimal histamine dose causing a 20% fall in FEV] (PC20). and for reactivity, defined as the slope of the dose-response curve once the reaction starts to occur. A significant relationship (r = 0-80) was found for the sensitivity obtained with the two nebulizers. PC20 was indeed reproducible within a two folds concentration of histamine in sixteen of the twenty patients. A significant difference (/»< 001) was found in the reactivity to the two different apparatus, reactivity being greater with the Wright nebulizer in twelve out of fifteen patients so tested. Sensitivity and reactivity showed a borderline relationship {r = 0-47) with the Wright nebulizer but not with the dosimeter. A significant correlation {P< 005) was found to exist between the initial FEV| (in % of the predicted value) and the observed sensitivity and reactivity as assessed with the Wright nebulizer, but not as assessed with the dosimeter. We conclude that histamine bronchial challenges with the Wright nebulizer and with the dosimeter yield reproducible results if the threshold of a 20% fall in FEV, is taken as positive. However, the two methods produce different results in terms of reactivity. Introduction

In the past few years, the need for standardized procedures to perform bronchial provocation tests has been emphasized. Two such standardized procedures have been issued recently. One originated from the United States and recommended the use of a special apparatus called a dosimeter (Chai et ai, 1975). The other was described by Canadian investigators and suggested the use of the Wright nebulizer which is widely used in the United Kingdom. (Cockcroft et ai, 1977). We decided to study the reproducibility of these two different procedures in asthmatics. Correspondence: Dr J. L. Malo, Service de Pneumologie, Hopital du Sacre-Coeur. 5400 Gouin Ouest Montreal, Canada H4J IC5. 0009-9090/79/1100-0575502.00

© 1979 Blackwell Scientific Publications

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A. Beaupre and J. L. Malo

Patients and methods Histamine inhalation tests were carried out in twenty adult asthmatics attending the Respiratory Allergy Clinic at the Hopital du Sacre Coeur de Cartierville, in Montreal. The patients were well-known asthmatics, meeting the definition of the American Thoracic Society (A.T.S., 1962). AH were in a reasonably 'stable state' since their asthma had been well controlled during the previous 2 months. They denied having any recent respiratory infection. Each patient completed an asthmatic and respiratory questionnaire before the tests. All the patients denied having any cardiac or coronary symptoms, arterial hypertension, or migraine. As suggested by the investigators of the Asthma and Allergic Diseases Center (Chai et ai, 1975). medications were withheld; beta adrenergic stimulating agents withheld for at' least 8 hr; sustained release medications of the beta adrenergic stimulator and/or phosphodiesterase inhibitor type, 12 hr; cromolyn sodium, 24 hr; antihistamine agents, 48 hr; alpha adrenergic blocking agents or anticholinergic agents, 8 hr. Corticosteroid drugs were continued as usual and the patients were challenged in a constant relationship to the last dose. All the patients were studied on two different occasions, with a different aerosol delivery system each time. On the first visit, half the subjects were assigned to the Wright nebulizer, while the other half were challenged with the dosimeter nebulizer. The two tests were performed at the same time of day. There was an interval of one week between the two tests. The forced expiratory volume at 1 second (FEVi) of the patients was similar on each occasion, the difference always being less than 10",,. The subjects were asked to perform a forced expiratory manoeuvre to assess their initial EEV, and their forced vital capacity (FVC). They were then first challenged with a diluent solution composed of 0 5% sodium chloride, 0 275% sodium bicarbonate, and 0 4"; phenol (pH 7 0). Histamine phosphate solutions in increasingconcentrations were then given. Forced expiratory manoeuvres were done at 30,90, and 180 seconds, twice each time, after the end of each nebulization. At the last dose used, FEV, was also measured at 300 seconds. In order to assess bronchial reactivity, the tests were generally stopped when a fall of FEV, around 35% was reached, or when the top dose had been given. The subjects were then given two inhalations of salbutamo! aerosol. The FEVi was measured ten min later and in all subjects it had returned to the initial value. The percentage fall in FEVi was calculated according to the method suggested by Cockcroft et ai (1977), from the lowest post diluent FEVi (FEVA) and the lowest post histamine phosphate FEV, (FEVB), as follows: 100 X ( F E V A - F E V B ) / F E V A

All the measurements were taken on a Vitalograph apparatus (Vitalograph Ltd.). The procedure was different depending on the aerosol delivery system used. In the case of the Wright nebulizer, aerosols were generated with 5 ml of test solution in the nebulizer container at a constant oxygen flow of 7 I/min. The aerosols were delivered into an oronasal mask. The only modification to the technique suggested by Cockcroft et al. (1977) was the addition of a rebreathing bag which is more generally recommended for inhalation challenges (Pepys & Hutchcroft, 1975). The subject was asked to inhale through the mouth, with the nose clipped, by tidal volume breathing for 2 min. The histamine phosphate concentrations used were 0 03, 0 06, 0-125, 0-5, 1, 2, 4, and 8 mg/ml.

Two methods of histamine challenge

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The dosimeter apparatus is a device developed at Johns Hopkins and designed to deliver a consistent amount of solution from a connected DeVilbiss nebulizer, by limiting the inspiratory time of nebulization. Instead of the DeVilbiss nebulizer number 42, we had to use the DeVilbiss nebulizer number 646, since the former is no longer available. The modification was suggested by Dr Richard R. Rosenthal from Johns Hopkins. The nebulizer is triggered by inhalation. Compressed air at 20 p.s.i. was connected to the input valve and the timing adjustment of the dosimeter was 0 6 second. All breaths of diluent and histamine phosphate solutions were delivered from functional residual capacity to total lung capacity. The subjects were asked to take five breaths of each of the histamine phosphate concentrations, without any apnea period between each breath. The histamine phosphate concentrations used with the dosimeter apparatuswereOO3. 0 06, 012. 0 25, 10. 2 5, 5 0, and 10 mg/ml. Informed consent was obtained from each patient and the entire project was approved by a medical ethies committee. Results Clinical and functional data of our subjects are listed in Table 1. The twenty subjects included thirteen females and seven males. Their age range was from 17 to 62

Table i. Clinical and physiological data

Reactivity Sensitivity (PC20) FEVi/FVC Patient Age Sex Atopy Treatment Obs %P (%) Wright Dosimeter Wright Dosimeter FEVI

t 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

44 30 28 25 44 17 20 18 50 44 45 30 52 62 44 27 18 24 36 25

M M F F M F F F M F M F M

F F F F F M F

-t-1-

+

+ + -1-

+ -

+ — + -\—

2 2 76

79

2 406 102 3 1 1 2 4 1 3 2 4 3

3 3 3 3 3 1 3 3

3 09 1 95 3-25 390 2-22 282 341 I 89 2 49 2-76 2-76 1 89 2'22 233 1 73 325 2-55 2-76

118 67 83 121 72 98 106 87 64 95 76 Ul 89 86 64 116 64 106

68 91 77 65 62 89 69 88 69 59

58 94 76 66 79 69 84 86 59 84

160 1-00 275 0-55 2 60 3-30 055 075 600 0-18 0-08 1 10 6 50 080 1 30 3-40 018 5-00 0-45 800

205 7-79 1 30 17-25 014 24-98 9358 Oil 325 10-63 7^95 6-50 0-38 65-70 1-20 25-10 2-05 4-39 0-06 84-70 0-06 294-00 22-57 0-60 10-00 4-32 080 3570 100 13-91 110 0-14 10-00 090 8 00

6'87 7-44 243'60 18-07 3-79 3-25 38-70 10-10 7'43 6290 87-50 11-15 1-71 123-00 12-26

Atopy: -I- if 2 or more positive skin prick tests to a routine battery of 15 common inhaled antigens; Treatment: 1, beta-adrenergic stimulants or phosphodiesterase inhibitors PRN; 2, beta-adrenergic stimulants or phosphodiesterase inhibitor or sodium cromoglycate continuously; 3, aerosolized beclomethasone continuously; 4, oral corticosteroids continuously; FEVi, initial forced expiralory volume in the first second; FVC, initial forced vital capacity; sec text for definitions of sensitivity and reactivity.

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(mean = 35 2. s.d. = 14) years. Fifteen out of twenty were atopies, showing at least two positive skin prick reactions to a routine battery of 15 inhaled antigens. Only one of the twenty subjects was a smoker. The patients were on the following medications: four were using beta adrenergic agents and/or phosphodiesterase inhibitor type medication only when needed; four were taking beta adrenergic agents and/or phosphodiesterase inhibitor type medication and/or sodium cromoglycate on a daily basis; ten were using aerosolised beclomethasone with a beta adrenergic agent or a phosphodiesterase inhibitor type medication permanently; two were on aerosolised beclomathasone and oral corticosteroid drugs. On the basis of the ratio between initially observed and predicted FEVi. the patients could be divided into four groups: nine over 90",,; four between 80 and 89",,; three between 70 and 79",,; and four under 70",,. On the basis of the ratio between initial FEV, and FVC. the patients could be divided into four groups: two over 90",,, give between 80 and 89",,; three between 70 and 79",, and ten under 70%. The results of the dose response curves for each patient with the Wright nebulizer and the dosimeter apparatus were studied for sensitivity and reactivity as defined by Orehek & Gayrard (1976). Sensitivity is the histamine phosphate concentration needed to obtain a 20°,, fall in FEV,, represented by the abbreviation PC:o (provocative concentration). Reactivity is the slope of the dose response curve once the reaction starts to occur. Recently, it has been shown that such curves are linear if assessed for a fall in F E V I between 15 and 35",.. Figure 1 shows such curves obtained from four different patients with the Wright nebulizer. These curves were linear with a statistically significant P value. It can be seen that these curves have different slopes, representing different reactivities. Individual results of sensitivity and reactivity with the Wright and dosimeter nebulizers are listed in Table I. A significant correlation between the sensitivity with the Wright nebulizer and the dosimeter apparatus was found, the r value being 0 80 (Fig. 2). In only four patients was the threshold dose different by more than two folds with the two delivery systems. In fifteen patients out of twenty, we were able to assess the reactivity. In the other five patients, less than 3 points were available to assess the slope of the dose response

-

20

Histamine phoshate {mg/ml)

Fig. I. Individual dose-response curves in four asthmatics. From 3 to 5 points (n) have been used for each patient and they are statistically shown to be linearly correlated. The slope of these lines represents reactivity.

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r=o-ao

Fig. 2. Relationship between sensitivity (PC:o) defined as ihe dose which produces a 20",, fall in FEVi and assessed by the dosimeter on the abcissa and sensitiviiy assessed by the Wright on Ihe ordinate. The line of identity (doited) and the line of regression (continuous) are shown.

curve. Using the paired / test, we found a significant difference between the reactivity measured by the Wright and dosimeter nebulizers (0001 < / ' < 0 01). The reactivity was greater with the Wright nebulizer in twelve out of fifteen patients. We were further interested in the relationships between the sensitivity and reactivity of our subjects. With the Wright nebulizer these parameters were nearly correlated (r = 0-468). while with the dosimeter they were not statistically correlated. We also looked for correlations between the initial FEVi in percentage of predicted value and observed sensitivity. We found a significant correlation with the Wright nebulizer, with a r value of 0-46. There was no significant correlation between these parameters when using the dosimeter apparatus. Relationships were also studied for the initial FEVi in percentage of predicted value and observed reactivity. We found a significant correlation when using the Wright nebulizer (/• = 0 54), but not when using the dosimeter apparatus. Discussion Many variables must be taken into account in order to obtain quantitative information from bronchial provocation tests. Because of this, the need for standardized procedures has been emphasized. In 1975. the National Institute of Allergic and Infectious Diseases of the National Institute of Health issued recommendations for the U.S.A. (Chai et al, 1975). In 1977, a different procedure was suggested by Canadian workers from McMaster University in Hamilton (Cockroft et ai, \911), These two procedures differed in many ways, especially in the way in which to generate the aerosols (a DeVilbiss nebulizer powered by a dosimeter apparatus for Chai. and a Wright nebulizer for Cockcroft), and in the way in which to administer these aerosols (five maximal inspiratory manoeuvres for Chai. slow tidal breathing during 2 min for Cockcroft). From a practical pointof view, we found that the two procedures were equally easy to perform, both for the patients and the technician. Using a dosimeter apparatus was a little quicker than a Wright nebulizer, because with the latter there was a two minute delay for inhalation ofthe aerosols. No significant discomfort was experienced by any of the patients, even though a 50"., fall in FEV i was reached in seven out of the forty

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A. Beaupre and J. L. Malo

procedures. It was possible to monitor a progressive fall in FEV i without inducing too big sudden changes. In every patient the FEVi returned to its initial value 10 min after two inhalations of salbutamol. FEVi was the parameter which was used to assess the bronchial response in our study. This choice was made because this physiological index is probably the most readily available to assess bronchial obstruction. Although more sophisticated tests have also been advocated in the past few years (Stanescu & Brasseur. 1975; Grimaud et ai, 1976; Gonsior, Kruger & Meier-Sydow, 1978), it is obvious that the increased sensitivity of these tests may lead to a decreased specificity. Indeed Orehek ei a/. (1977) have shown that a 50% fall in specific airway conductance was necessary to differentiate between the normal and asthmatic reactions to carbachol. These investigators have suggested that when such changes in specific airway conductance are obtained, a significant fail in FEVi is also demonstrated. It is also known that the use of maximal expiratory manoeuvres, like the FEVi, has the advantage over non-forced manoeuvres in emphasizing the distinction between normal and asthmatic populations, by causing greater obstruction in asthmatics (Orehek et ai, 1975a). Finally, it has also recently been shown that the use of FEV| in bronchial provocation tests permits linear dose response curves (Orehek et ai, 1978) to be drawn. Thus it is possible to assess sensitivity as well as reactivity. In our study, we clearly differentiated the two notions of sensitivity and reactivity of the bronchial response to inhalation challenge. This is particularly advocated by workers in Marseilles (Orehek et al, 1977) who insist that these two parameters represent different aspects of bronchial hyperresponsiveness. Sensitivity is defined as the minimal histamine dose necessary to cause a significant airway obstruction (Viz: a 20% fall in FEVi). Reactivity is the slope of the dose response curve obtained once the reaction starts to occur. It is important to recognize that this distinction is not always made, and that most of the studies done on this subject only evaluated sensitivity and that both words were used without making this distinction. We found a significant relationship (r = 0-80; P