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! ACUTE EFFECT OF PASSIVE SMOIQNG ON LUNG FUNCTION AND AIRWAY RESPONSIVENESS IN ASTHMATIC CHILDREN & Maike Oldigs MD, Rudolf Jorres MS, Helgo Magnussen MD Krankenhaus Grosshansdorf Zentrum f{ir Pneumologie und Thoraxchirurgie LVA Freie und Hansestadt Hamburg Running title: Passive smoking in childhood asthma Correspondence: Helgo MAGWSSE.'~1 Krankenhaus Grosshansdorf Wohrendamm 80 2070 Grosshansdorf FRG m ~ Telephone: FRG 4102 - 601 150 O) r11 ~ , Supported by Forschungsgesellschaft Rauchen und Gesundheit, Hamburg, FRG. Mr

Oldigs et aL: Acute effect of passive smoking.... 1 I SUMMARY In 11 children with bronchial asthma (age range 8-13 yr, 10 boys, I girl) we studied the effect of an 1 hour exposure at rest during passive cigarette smoking (20 ppm CO) or Sham. Exposure was performed in an environmental chamber. Before and immediately after exposure, lung function and symptom scores were determined. After exposure, a histamine inhalation challenge was performed to determine the concentrations which caused a 100% increase in SRaw, PCtOOSRaw, and a 20% fall in FEVt, PC20FEV1. Mean (SD) SRaw before and after Sham was 8.7 (3.6) and 9.0 (3.2) cmHZ0*s, mean FEV1 (SD) was 1.97 (0.32) and 1.98 (0.40) 1, respectively. Before and after cigarette smoking, mean SRaw (SD) was 10.4 (5.3) and 9.4 (3.3) cmH2O*s, mean FEVl (SD) was 1.95 (0.37) and 1.94 (0.35) 1, respectively. Geometric mean (SD) PC1ppSRaw and PCZpFEV1 after Sham was 1.39 (3.0) and 0.70 (2.7) mg/ml, after passive smoking 1.65 (2.5) and 0.96 (2.3) mg/ml, respectively. There was no statistical difference in lung function and PC- values between Sham and passive cigarette smoking. The main symptoms during passive smoking were eye and nasopharyngeal irritation. Our observations suggest that in children with mild bronchial asthma one hour of passive cigarette smoking does not cause airway obstruction or changes in bronchial responsiveness. KEY WORDS: Passive Smoking, Lung Function, Bronchial Hyperresponsiveness, Childhood Asthma

Oldigs et aL: Acute effect of passive smoking....2 INTRODUCrlON Subjects with bronchial asthma are characterized by airway hyper- responsiveness to a variety of stimuli. Cigarette smoke is considered to be a common stimulus which may affect subjects with asthma (1-3). In children, the adverse effect of chronic passive smoking on respiratory symptoms has received increasing attention (4-7). In some of these investigations an association between parental smoking habits and acute lower respiratory illness (8-12), respiratory symptoms (13-16), prevalence and severity of asthma (13,17,18), impaired lung function and bronchial responsiveness (10,12,13,16,17,19-23) could be demonstrated. In contrast to chronic exposure, little is known on the acute effect of passive smoking in children. We therefore studied symptoms, lung function and airway responsiveness of children with bronchial asthma before and after one hour exposure to cigarette smoke as compared to control conditions.

j Oldigs et aL: Acute effect of passive smoking....3 MATERIAL AND METHODS Patients We investigated 11 children with allergic bronchial asthma (10 boys, 1 girl) ranging in age from 8 to 13 years (mean (SD) 10.4 (1.4) yr). Individual patient characteristics are given in table 1. In all children the diagnosis of bronchial asthma was made up within at least 1 year before entering the study and patients had been followed up for a longer period of time on an out-patient basis. Diagnosis was based on typical symptoms, reversible airflow obstruction, bronchial hyperresponsiveness to histamine and a positive prick skin test to at least one common allergen (Allergopharma, Reinbek, FRG). Six out of 11 patients showed an increase in total IgE (>150 IE/ml), and 6 children an increase of eosinophils in peripheral blood (>300/mm3). In- all subjects the severity of asthma required a long-term therapy, which had to be continued in 9 of 11 children during the study period. All children on therapy received disodium cromoglycate, two puffs two to four times per day. Each puff of disodium cromoglycate (1 mg) was combined with 0.05 mg fenoterol (DitecR) or 0.5 mg reproterol (AaraneR) as a Q2-agonist. One subject took two additional puffs of 200 µg beclomethasone dipropionate. In all children, this therapeutic regime was sufficient to control the disease and allow normal activities. This is also reflected by the magnitude of morning (before therapy, PEFr,,;n) and maximum daytime peak flow values (PEF,t,ax), which were measured regulary (table 1). In the 9 asthmatic children receiving regular therapy, the activity of the disease allowed to discontinue inhalation therapy at least six hours prior to

Oldigs et al.: Acute effect of passive smoking....4 1 i each study session without precipitating symptoms or deteriorating lung function (subject 6 continued beclomethasone inhalation during the study period). Spirometry, measured at least six hours after inhaling a bronchodilator was within normal limits. In all children the provocative concentration of inhaled histamine necessary to decrease FEVt by 20% as compared to baseline was less than 8 mg/ml (table 1), thus demonstrating airway hyperrespon- siveness (see Histamine inhalation challenge). During the study period and within the two weeks preceeding the study no child suffered from an upper respiratory tract infection, experienced an uncommon burden of allergen or reported on any other trigger which may worsen asthma; therefore all included children were considered to be currently clincallv stable. None of the children had ever actively smoked cigarettes, six of them were exposed to cigarette smoke at home (table 2). Children and parents were informed about the aim of the study and gave their consent. Cigarette smoke exposure Exposure chamber The study was performed in a 24 m3 exposure chamber. To ensure homogenous concentration of cigarette smoke the air was moved by fans in a spiral form. Sampling ports were distributed within the chamber to check for gradients of gas concentrations and partide density. Cigarette smoke was

I Oldigs et aL: Acute effect of passive smoking....5 generated by a smoking machine designed in our laboratory which took 1 puff per cigarette per minute (according to DIN 10240). To achieve the target concentration of about 20 ppm CO, on average 2 cigarettes were smoked simultaneously. We used filter cigarettes of a leading brand with a nicotine content of 0.9 mg and tar content of 13 mg per cigarette. Measurement of exposure conditions The level of cigarette smoke exposure was determined by measuring CO, NO,, partide density, nicotine, acetaldehyde, formaldehyde, aaolein and ammonia. Concentration of CO was measured continuously by an infrared gas analyzer (Unor 6N, Maihak AG, Hamburg, FRG) whose calibration was checked daily by a certified span gas (Linde AG, Unterschleii3heim, FRG). Concentration of NO,, was measured by a chemiluminescence nitrogen oxides analyzer (8840, Monitor Labs Inc., San Diego, CA, USA) which was calibrated regularly by a permeation tube calibrator (Model 8550, Monitor Labs Inc., San Diego, CA). Particle density was monitored continuously by measuring optical particle density (RAM-l, GCA/Environmental Instruments, Bedford, Mass., USA) using a 4 µm precollector. Calibration of optical particle density was done in regular intervals gravimetrically by taking filter probes (Millipore, FALP 03700, Typ FA) from total sampling volumes of 17-73 litres of air. Nicotine, acetaldehyde, formaldehyde, aaolein and ammonia were determined using commercially available sample tubes and filters at sampling volumes ranging between 3 and 100 litres of air. Analysis was done by gas chromatography (nicotine), by HPLC (acetaldehyde, formaldehyde, acrolein) and by the indophenol method VDI 2461

i I Oldigs et al.: Acute effect of passive smoking....6 (ammonia). Temperature and relative humidity were measured at the beginning and at the end of each exposure. Estimation of chronic smoke exposure To estimate chronic passive smoke exposure at home, urinary cotinine concentrations were determined in triplicate from morning urine spedmens collected at the second study day. Urine was stored at -20 OC until assayed. Cotinine was measured by a radioimmunoassay procedure (24). Assessment of symptoms Before and immediately after exposure the chest of each subject was auscultated by one of us (M.O.). To estimate severity of symptoms induced by exposure, the children and their parents were instructed to check an ordinal scale ranging from 0 to 10 in order to determine severity of eye, nose irritation, throat irritation, cough, chest tightness and headache. Zero indicated no perceptible symptom, 10 almost intolerable severity of the respective symptom. Lung Function Measumment Airway resistance (Raw) during breathing at 1 Hz and thoracic gas volume (TGV) were measured by a volume-constant body plethysmograph (Bodytest, E. Jaeger, Wurzburg, FRG) connected to a Computer (PDP 11 /04, Digital

Oldigs et aL: Acute effect of passive smoking....7 I Equipment Corp., Maynard, MA, USA). Airway resistance was multiplied by the corresponding thoradc gas volume to obtain specific airway resistance (SRaw). Airway resistance was measured during up to 4 breathing cycles. FEVI was assessed by a pneumotachygraph immediately after body plethysmo- graphy. Measurements were repeated 4 times. For analysis, the average of 4 values of SRaw and the average of the two maximum values of FEVI was taken. Histamine Inhalation Challenge Bronchial challenge with histamine was done according to the guidelines of Chai et al. ;25) using a breath-synchronized pressure valve. The aerosols were generated during 0.6 sec. at the beginning of 5 slow inspirations from FRC to TLC, the nebulizer output being 80 µl of solution per 5 nebulizations. Saline solutions of histamine diphosphate (Sigma Chemie, Deisenhofen, FRG) were prepared daily. After inhaling buffer solution, the subjects inhaled doubling concentrations of histamine, starting with 0.05 mg/ml histamine. Lung function was measured 1 and 3 min after inhalation. The inhalation was stopped after at least a 100 % inaease of SRaw and a 20 % fall in FEVt. Dose- response curves were constructed by plotting SRaw and FEVI against log histamine concentration. By linear interpolation, the provocative concentrations of histamine (in mg/ml) were computed necessary to increase SRaw by 100 %(PC1opSRaw) and to decrease FEVI by 20 %(PC20FEV1) as compared to baseline. With this method, hyperresponsiveness was assumed if PC-values were below 8 mg/ml (26).

Oldigs et al.: Acute effect of passive smoking....8 i Experimental Protocol Each subject was studied at three days within a two week period. All investigations were performed at least six hours after the last application of therapy. On the first day recent history was taken and a physical investigation performed. Lung function and airway responsiveness to inhaled histamine were measured. In case of stable clinical conditions, normal lung function and airway hyperresponsiveness, the children and their.parents were instructed in the experimental procedure. They were provided with sampling probes for collecting morning urinary specimens. On the second study day, exposure to ambient air (Sham) and at the third study day exposure to cigarette smoke was performed. On exposure days, subjects rested for 10 minutes after entering the laboratory. After auscultation of the chest, assessment of svmptoms and measurement of baseline lung function, the children entered the exposure chamber. They were always seated at the same place inside the chamber. Five minutes before the end of exposure, symptoms were assessed again. Immediately after exposure, auscultation of the chest and lung function measurement were performed. Histamine inhalation challenge was started 15 minutes after the end of exposure.

Oldigs et aL: Acute effect of passive smoldng....9 i Statistical Analysis Lung function parameters before and after both exposures and control values were compared to each other by the paired t-test after appropriate Bonferroni correcrion for multiplicity of tests (27). Log PC-values after both exposures and control values were also compared by the paired t-test. Statistical significance was assumed for p<0.05. RESULTS Exposure conditions During Sham and cigarette smoke exposure, mean (SD) temperature was 24.1 (1.6) oC and mean relative humidity was 51 (3) %, with no difference between the study days. During passive smoke exposure, mean (SD) total particle density was 2743 (348) µg/m3 and nicotine content was 397 (78) µg/m3. Mean (SD) concentrations of CO were 20.5 (0.5) ppm, NO,, 0.90 (0.09) ppm, formaldehyde 0.13 (0.01) ppm, acetaldehyde 0.50 (0.05) ppm, acrolein 0.081 (0.017) ppm and ammonia 5.69 (3.35) ppm. During exposure with ambient air, mean (SD) CO was 0.1 (0.3) ppm, and mean (SD) total partide density was 17 (57) ug/m3. Symptoms during exposure In all of our children, auscultation of the chest was normal before and after exposure to Sham and cigarette smoke, respectively. Eye irritation was