Blood Gas Changes in Nonasthmatic Rhinitis during and after Nonspecific Airway Challenge 1, 2 ROBERTO W. DAL NEGRO, PAOLA A. TURCO, and WIGI ALLEGRA

Introduction

Lung volumes and mechanics in bronchial asthma have been extensively studied, but blood gas changes in this disease have not received the same degree of attention, few reports being available either in humans (1-4) or in animals (5-7). Continuous noninvasivemonitoring of gas composition can now be achieved by means of electrodes for transcutaneous P02 and Pc02 (Ptc02 and PtcC02) measurement. This technique, which provides an accurate means of monitoring gasexchange trends, has been used only recently in the study of spontaneous (8) or induced (9) bronchoconstriction in asthmatic subjects. No changes in lung function are detectable in atopic rhinitic subjects who have never suffered from bronchial asthma. Furthermore, blood gas assessment has never been employed to detect a possible bronchial response to challenge in nonasthmatic atopic subjects. The aim of our study was to assess whether a bronchial challenge could be used to detect a hyperreactive response pattern in never wheezy rhinitic subjects through changes in transcutaneously monitored blood gases. The bronchial challenge used is inhalation of ultrasonically nebulized distilled water (UNDW), which is an effective bronchoconstrictor in adult asthmatic subjects (10-12). The method is simple and reproducible and is characterized by a high degree of specificity (9). We, therefore, investigated whether the magnitude and time course of transcutaneously monitored blood gas changes during and after UNDW are capable of discriminating between nonasthmatic atopic rhinitic and normal subjects and whether such monitoring can detect changes in lung function that are not revealed by lung volumes or mechanics and thus constitute an accurate diagnostic and, perhaps, prognostic test. Methods Subjects A total of 104 young atopic adults (49 males and 55 females, mean age 24.5 ± 0.9 yr (SEM,

SUMMARY Noninvasive blood gas monitoring Is a new, simple, and reliable method for assessing hyperreactlvlty associated with bronchial asthma. In this study, 104 atopic rhlnltlc subjects with no history of wheezing and 104 healthy volunteers were challenged with Ultrasonically nebulized distilled weter (UNDW). Blood gases were monitored transcutaneously (PtCO, and Ptcco,) over 42 min (20 min for electrode stabilization, 3 min for monitoring a steady baseline, 5 min during UNDW, and 14 min after UNDW). Mean baseline PtCO,and Ptcco, values were comparable In the two groups. In rhlnltlc subjects only, a sudden decrease in PtcCO, (starting Immediately after the beginning of the challenge and maximal 34.7 ± 0.4 mm Hg SEM versus baseline 41.8 ± 0.2 SEM mm Hg at the third minute of UNDW exposure) wes Induced by the challenge and proved significant (p < 0.001). In the same SUbJects, a slightly delayed decrease In PtCO, (starting Immediately after the end of UNDW Inhalation and maximal 64.5 ± 1.1 mm Hg SEM versus baseline 78.3 ± 0.7 SEM mm Hg at 4 min post-UNDW) was also Induced by the challenge and proved highly significant (p < 0.001). The effects of UNDW Inhalation on blood gases In normal subjects were negligible and nonsignificant. UNDW In nonasthmatlc rhinitis but not In normal subJecta gives rise to a sudden hyperventilation and to gas-exchange abnormalities presumably reflecting a ventilation-perfusion mismatching, which, however, Is of shorter duration In rhlnltlc than In asthmatic sUbJecta. AM REV RESPIR DIS 1992; 145:337-339

standard error of the mean), range 14.3to 34.1 yr), all nonsmokers suffering from allergic rhinitis but with no history of wheezing, were selected for the study. All patients presented a normal clinical and functional condition from the respiratory point of view,were not on maintenance treatment with adrenergic drugs, systemic or inhaled steroids, antihistaminic agents, antibiotics, or nonsteroidal antiinflammatory drugs, and had not taken any local medication during the previous 12 h. The rhinitic subjects were compared with a control group of 104 healthy, nonsmoking volunteers (56 males and 48 females, mean age26.2 ± 1.1 yr SEM, range 14.7to 36.9yr). All subjects weretested after obtaining their informed consent.

Allergen Skin Testing Skin tests were performed by the prick method (13) in response to 16 allergens (Lofarma Allergeni, Milan, Italy), namely Alternaria, Aspergillus mix, milk, egg white,wheat, house dust, Dermatophagoidespteronissinus,Dermatophagoides farinae, cat, dog, horse, feathers, wool, tree mix, grass mix, and ragweed, plus 1:100 histamine and saline control. Wheals> 2 mm larger than those of negative control subjects wereregarded as positive reactions. Reactions were read at 10 min, and wheals were measured in two perpendicular directions. Experimental Procedure All subjects were connected to a monoelectrode for the combined monitoring of Ptc02

and Ptcc02 (14-16) over a total period of 42 min (20 min to obtain electrode stability, 3 min for monitoring a steady baseline, 5 min during exposure to UNDW (9, 12),and 14min after the end of UNDW exposure). The electrode was placed on the anterior side of the chest on the right midclavicular line at the levelofthe third rib and was heated to 45° C. Mean Ptc02 and PtcC02 values ± SEM were calculated at each of the followingexperimental times: once per minute in the 3-min steady baseline period; after 1, 3, and 5 min of UNDW exposure; and every 2 min after the end of UNDW exposure up to 14 min postUNDW (monitoring and recording system: Gasthmati&'; Burke & Burke SpA, Milan, Italy) using a combined 02/C0 2 electrode manufactured by Biochem Inc. (Milwaukee, WI). Since a normal transcutaneous CO2value in healthy subjects runs higher than Paco2, this device has a built-in adjustment factor that lowers the value to close to that of arterial. The adjustment factor used in the device is the so-called in vivo calibration, which con-

(Received in original form June 20, 1990 and in revised form July 23, 1991) 1 From the Department of Clinical Respiratory Physiology, Bussolengo General Hospital, Verona, and the Institute for Respiratory Diseases, University of Milan, Milan, Italy. 2 Correspondence and requests for reprints should be addressed to Prof. L. Allegra, Institute for Respiratory Diseases, 2 Via F. Sforza 35, 220122 Milan, Italy.

337

338

DAL NEGRO, TURCO, AND ALLEGRA

..

TABLE 1

UNDW

f

co J:

E

E E

E ,.

Pao. AND Paco. BASELINE VALUES AND 4 MIN AFTER END OF UNDW EXPOSURE IN ATOPIC RHINITIS: COMPARISON WITH P1co. AND Ptcco. IN THE SAME 17 PATIENTS' Baseline Pao. P1co. Paco. P1cco.

, I. 51. •

10

tt

'4

_

Fig. 1. Transcutaneous Peo. (Ptcco.) and Po. (Ptco.) time courses (means ± SEM) in normal subjects (open squares, n = 104)and in atopic rhinitis SUbjects (closed squares, n = 104)during and after UNDW inhalation. Trend analysis: comparison of forms (p < 0.001), linear components (p < 0.001), and quadratic components (p < 0.001) for both P1cco. and Ptco•. el. st. = electrode stabilization.

sistsof dividingthe transcutaneous valueby 1.33 and then subtracting 3.0from the resulting value (15). In 17 of 104 consenting rhinitic subjects, arterial blood samplesweredrawn (from the left radial artery) under strict anaerobicconditions immediately before the start of UNDWexposureand 4 min after the end of exposureand analyzedfor arterial Pao, and Paco, (ABL30 Radiometer, Copenhagen, Denmark). Spirograms and flow-volume curves were obtained in all subjects before and after the monitoring period (Vicatest" 5; Mijnhardt, Bunnik, Netherlands). The predictedvalues for sex, age, and height were in line with the EuropeanCoaland Steel Community(ECSC) reference values (17). Statistical Analysis The polynomialPtco, and Ptccn, trends for rhiniticversus healthysubjects and the respective curve forms were compared statistically by means of analysis of variance for trends (18). A paired t test was used to compare volumes and flows as well as arterial Po, (Pao,) and Pco, (Paco,) values and p < 0.01 wastaken as the statisticalsignificance level. Results

Baseline Values Mean basal Ptco, and Ptcco, and mean basal FEV!, maximal midexpiratory flow (MMEF), and V,5 were all within the expected normal range in both healthy and rhinitic subjects. There were also no significant differences in these baseline variables between the two groups of subjects. In the 17 rhinitic subjects submitted to arterial blood gas analysis, baseline Pao, and Paco, were also within the expected normal range.

Response to UNDW In rhinitic patients, both mean Ptco, and

Ptcco, were reduced during and after UNDW inhalation. Ptcco, decreased immediately after the start of UNDW exposure, this decrease proving maximal at the third minute of UNDW challenge. The Ptcoo.Ievel started to pick up again immediately after the end of exposure, initially with a rapid recovery rate, followed by a slower recovery phase beginning 4 min after the end of UNDW. The Ptc02 time course was quite different, the decrease beginning at the third minute of UNDW inhalation and the lowest value reached 4 min after the end of UNDW exposure (with a 6-min shift compared to the maximum decrease in PtCC02)' From this point on, the recovery rate was roughly linear and recovery was almost complete 14min after the end of UNDW (figure 1). The phenomenon thus shows a different time course in rhinitic than in normal control subjects, as demonstrated by the significance of the difference between the linear components (p < 0.001). Furthermore, the significance of the difference between the quadratic components (p < 0.001) shows that these morphologic differences between the two time courses are not causal.

93.6 77.7 40.3 41.2

± ± ± ±

0.9 0.7 0.6 0.6

p Value

< 0.001 < 0.001 NS NS

4 Min Post UNDW 75.9 58.6 40.1 40.9

± ± ± ±

1.1 0.9 0.8 0.4

Definition of abbreviations: Plco, and Ptcco, • transcutaneous Po, and Pco,: UNDW • ultrasonically nebulized distilled water; NS • not significant. • Values are mean ± SEM in mm Hg. Significance determined by paired t test.

In contrast to rhinitic subjects, the only change observed in normal subjects appears to be a minor (nonsignificant) decrease in PtcC02 during UNDW challenge (figure 1). In 17 rhinitic subjects, a comparison of transcutaneous and arterial blood gas values at baseline and at the point of maximal Ptco, decrease (4 min postUNDW) was possible: the baseline values presented a significant confirmatory drop (p < 0.001) in both mean Ptco, and Pa02, but only nonsignificant changes in both Ptcoo, and Paco2 were detected at this observation time (table 1). Mean FEV h MMEF, and V25 values showed no changes at the end of the monitoring period compared with preexposure baseline values in either rhinitic or normal subjects (table 2). Furthermore, at the time of the spirometric measurements, all transcutaneous values had returned to baseline. Nevertheless, with this experimental design, simultaneous changes in mechanics at the time of maximal fall in Ptco, cannot be ruled out. Discussion Airway reactivity is lower in allergic rhinitis than in asthma but is still greater

TABLE 2 FEV" MMEF, AND it•• BASELINE VALUES AND VALUES AFTER UNDW EXPOSURE IN NORMAL AND ATOPIC RHINITIC SUBJECTS' Baseline

Rhinitic subjects Normal subjects

Post UNDW

FEV,

MMEF

it••

FEV,

MMEF

it••

97.6±1.5 99.6 ± 1.2

92.5 ± 1.5 95.3 ± 1.0

92.3 ± 1.3 94.5 ± 0.8

-2.4 ± 0.6 -1.5 ± 0.7

-2.5 ± 1.1 -1.2 ± 0.5

-3.1 ± 1.0 -1.6 ± 0.6

Definition of abbreviations: MMEF = maximal midexpiratory flow; II" = maximal flow at 25% of vilal capacity; UNDW = ultrasonically nebulized distilled water. • Values are mean ± SEM (%). Significance determined by paired t test. No values are significant.

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BLOOD GAS CHANGES IN NONASTHMATIC RHINITIS

than that observed in normal subjects (19-21).

A challenge like UNDW induces bronchoconstriction in most symptomatic and asymptomatic asthmatic subjects but in general does not induce any significant spirographic or mechanical changes in normal or in rhinitic subjects with no history of asthma, although, using other means, a minor degree of airwayhyperreactivity has been demonstrated in a small percentage of allergic rhinitic subjects (22). In the present study, noninvasiveblood gas monitoring was performed for the first time in a group of never-asthmatic rhinitic subjects to evaluate their bronchial reactivity during and after UNDW exposure. In a previous study, a significant transient hypocapnia induced by UNDW was demonstrated in asymptomatic asthmatic subjects, suggesting an immediate, transient hyperventilation; a minor, nonsignificant degree of transient hypocapnia was also demonstrated in normal subjects (9). This latter trend was confirmed in the present study, in which a systematic high degreeof hypocapnia during UNDW challenge was also demonstrated in rhinitic subjects. The degree and time course of the hypocapnia were significantly different from those observed both in normal and in asthmatic subjects, however, suggesting that UNDW-induced hyperventilation is not necessarily correlated with bronchoconstriction. Furthermore, as in asthmatic subjects (9), a significant hypoxia, albeit of shorter duration, was also present in the rhinitic subjects after UNDW, with a later onset and shifted maximum effect, indicating the occurrence of significant disturbances in the peripheral distribution of the alveolar ventilation and a consequent ventilation-perfusion mismatch. This phenomenon was not present in normal subjects. Airway reactivity is not an "all-ornothing" phenomenon: it is distributed in a continuous fashion, and the dividing line between normal and increased reac-

tivity is by no means sharp (23, 24); new and/or more carefully standardized tests must be employed to increase the possibility of detecting hidden hyperreactivity. In this study wedemonstrated that the borderline area between normal and hyperreactive subjects (when studied by means of newly applied and/or carefully monitored tests) includes nonasthmatic rhinitic subjects who exhibit a blood gas pattern similar to, although ofshorter duration than that which constitutes the hallmark of asthma. In conclusion, these results suggest that this kind of simple, noninvasive monitoring allows the identification of a neglected pattern of hyperreactivity and proves helpful in clinical research aimed at discriminating "susceptible" individuals (or early stages of airway disease) to pinpoint the transition between normality and the asthmatic range of bronchial reactivity.

Acknowledgment The writers are grateful to Adam Wanner and William Abraham of the Mount Sinai Medical Center, Miami Beach, for their invaluable technical collaboration in terms of facilities, help, and biologic expertise during the development of the basic animal model essential to our ongoing research program.

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