Eur J Pediatr (1991) 150 : 854-857 034061999100185J
European Journal of
Pediatrics
9 Springer-Verlag 1991
Ipratropium bromide for symptomatic preterm infants B. Yuksel and A. Greenough Department of Child Health, King's College Hospital, London SE5 9RS, United Kingdom Received November 27, 1990 / Accepted April 11, 1991
Abstract. Twelve p r e t e r m infants, m e d i a n gestational age 31.5 weeks, were entered into a randomised, placebocontrolled trial of b r o n c h o d i l a t o r therapy. Their postnatal age was a m e d i a n of 17.5 m o n t h s and all suffered f r o m recurrent respiratory symptoms. T h e infants received either inhaled placebo or 40 gg of ipratropium b r o m i d e (active therapy) three times a day utilising a coffee cup as a spacer device. E a c h t h e r a p y was administered for 2 weeks. The s y m p t o m score during the active period was r e d u c e d by 59% c o m p a r e d to the placebo period (P < 0.01) and this was associated with 38% imp r o v e m e n t in lung function in the active period compared to a 20% change in functional residual capacity over the placebo period (P < 0.01). W e conclude inhaled ipratropium b r o m i d e appears to be an effective treatm e n t for s y m p t o m a t i c infants at follow up.
Key words: P r e t e r m - B r o n c h o d i l a t o r - Functional residual capacity
Introduction R e c u r r e n t or persistent wheezing is very c o m m o n a m o n g p r e t e r m infants in the first 2 years of life [1, 17, 18], the incidence appearing to be twice that f o u n d in full-term infants [7]. W e have previously d e m o n s t r a t e d in a nonr a n d o m i s e d study that inhaled b r o n c h o d i l a t o r utilising a simple spacer device m a y be an effective t h e r a p y for certain s y m p t o m a t i c p r e t e r m infants [24]. A d m i n i s t r a t i o n of terbutaline was associated with a reduction in symptoms and on overall i m p r o v e m e n t in lung function, but the m a g n i t u d e of response varied [24]. It is possible our results might have b e e n better if we had used an anticholinergic agent such as ipratropium b r o m i d e as this is a m o r e effective b r o n c h o d i l a t o r than [3-adrenergic agents in w h e e z y infants b o r n at term [8, 11]. T h e r e is resting vagal tone in adults t h r o u g h o u t the tracheobronchial tree, but the dilating action of aerosolized particles seems confined to the large airways [3]. InOffprint requests to." A. Greenough Abbreviations: FRC = functional residual capacity; TGV =
thoracic gas volume; FRC: TGV = functional residual capacity : thoracic gas volume ratio
halation of a n o n - a b s o r b a b l e atropine p r e p a r a t i o n can result in a 50% reduction in airways restistance [3]. Anticholinergic drugs have a greater effect on m o r e proximal airways than [3-adrenergic stimulants, as shown by the finding that their administration results in a larger increase in anatomical dead space [10]. A t follow up, preterm infants have evidence of proximal airways d a m a g e , indicated by an elevated airways resistance [23], thus anticolinergic agents m a y be particularly effective in this group of infants. T h e aim of this study was to determine the efficacy of ipratropium b r o m i d e in treating p r e t e r m infants, s y m p t o m a t i c at follow up. To avoid possible bias due to the timing of administration of the bronchodilator, the infants were enrolled into a r a n d o m i s e d placebo-controlled trial.
Patients and methods Twelve infants, 6 boys and 6 girls, median birth weight 1385g (range 682-1780g), gestational age 31.5 weeks (range 24-34 weeks) were enrolled into the study. All but 1 had required ventilation for respiratory distress syndrome in the neonatal period. The median duration of neonatal ventilation was 5 days (range 0.1-42) and of oxygen dependency 8 days (range 1-180). Although 3 infants had had neonatal chronic lung disease (that is an oxygen requirement at i month of age), none had suffered from bronchopulmonary dysplasia [5]. Their median postnatal age was 17.5 months (range 6-40 months), only 2 were older than 2 years. Seven infants had a family history of asthma and six sets of parents smoked. The infants all attended the paediatric respiratory clinic at King's College Hospital and had either coughed and/or wheezed on at least 4 days per week for the last month. No infant was receiving treatment for wheeze at the time of entry into the study. Permission for the study was granted by the King's College Hospital Ethics Committee and parental consent was also obtained. The study period consisted of 4 weeks. The infants received, in random order, either 2 weeks of placebo therapy or 2 weeks of active therapy. The active therapy was two puffs (20 Ixg per puff) of ipratropium bromide aerosol inhalation. Both the parents and the investigator who analysed the lung function data (see later) were blind to the nature of the therapy being administered. Placebo or active therapy was administered as two puffs three times a day from an inhaler utilising a coffee cup as spacer device [6]. At study entry and at the end of each 2 week period a clinical history was taken from the parents. The child was examined and the height, weight and respiratory function measured. During each 2 week period the parents completed a diary card regarding the nature and frequency of respiratory symptoms: 1) runny nose, off
855 feeds, unwell; 2) daytime and 3) night cough; 4) daytime and 5) night wheeze. Each symptom category was scored from 0-3 (none 0, mild 1, moderate 2, bad 3), thus the maximum score for each 2 week period was 210. The infant's diary card was subsequently analysed by a clinician blind to the order in which therapy had been given. Lung function was assessed by measurement of functional residual capacity (FRC) by a helium gas dilution technique, which has been described previously in detail [6]. Measurement of FRC was always made before and 20min after 40~tg of ipratropium bromide. The reproducibility of the measurement had been previously assessed in 20 children of a similar gestational and postnatal age range to the study population. The mean of the differences between the 20 paired measurements was 2.0ml/kg. The coefficient of variation of the measurements was 7.3%, thus, a clinically important change in FRC was defined as an increase in FRC of more than 14.6% [7]. An increase in FRC was taken to indicate an improvement as in two previous studies [6, 25] since an increase rather than a decrease has been associated with a reduction in symptoms. We have previously measured FRC at follow up in 12 preterm infants of similar gestational age to the study group (median 30 weeks, range 27-33 weeks). These infants, however, had requried no form of respiratory support in the neonatal period. Their median FRC was 28 ml/kg (range 26-35).
Table 1. Change in individual components of the symptom score (scores for each component are shown for the study group as whole) Placebo period n
Active period
Reduction in symptom score (%)
12
12
Runny nose/unwell
345
106
69
Wheeze
Day Night
168 168
48 54
71 68
Cough
Day Night
195 192
69 61
65 68
Statistical analysis Differences b e t w e e n the two, 2 w e e k periods were assessed for statistical significance using the paired Wilcoxon rank sum test.
Trial size The m e a n s y m p t o m score of the infants included in our previous study [24] during the placebo period was 60 (SD 19.5). A d m i n i s t r a t i o n of b r o n c h o d i l a t o r resulted in a 65% reduction in this score. R e c r u i t m e n t o f 12 infants into the present study gave us the ability to detect a similar reduction in s y m p t o m score with at least 90% p o w e r at the 5% level.
Results T h e overall s y m p t o m score was r e d u c e d by a median of 58.7% during the active period (median 75; range 3 2 125) c o m p a r e d to the placebo period (median 31; range 4 - 5 4 ) P - < 0 . 0 1 ) . T h e greatest reduction in s y m p t o m score was in daytime wheeze (Table 1). T h e m e d i a n F R C increased f r o m 22.8ml/kg (range 19.6-35.4) over the 2 w e e k active period to 31.4ml/kg (range 22.7-42.9) ( P < 0 . 0 1 ) , (Fig. l) c o m p a r e d to a decrease in the m e d i a n F R C f r o m 28.2ml/kg (range 19.3-42.9) to 27.6ml/kg (range 1 9 . 6 - 3 8 . 7 m l / k g ) over the 2 weeks of the placebo period (nonsignificant (Table 2, Fig. 2). T h e r e was no statistically significant relationship b e t w e e n the change in F R C in response to b r o n c h o dilator t h e r a p y and the child's age (Table 2). T e n of the 12 infants had a clinically i m p o r t a n t change in F R C over the active period c o m p a r e d to only 2 of 12 over the placebo period ( P < 0.01).
FRC changes-PLACEBO Period
FRC changes-ACTIVE Period 45
45"
35 35
E L~ rtu.
Fig.1. FRC results at the start (pre) and at the end of the active period (post). [] Clinically important change in FRC, 9 non-clinically important change in FRC
LL 25 84
25-
Fig. 2. FRC results at the start (])re) and the end of the placebo period (post). Individual patients' data points are linked. [] Clinically important change in FRC, 9 non-clinically important change in FRC
15
1
Pre
Post
2
Pre
Post
856 Table 2. Individual lung function results at the beginning and end of each treatment
Patient number
Age (months)
FRC - active period pre post (2 weeks)
FRC - placebo period pre post (2 weeks)
Order of therapy
1 2 3 4 5 6 7 8 9 10 11 12
6 7 8 16 16 17 18 18 23 24 34 40
32.4 20.7 35.4 22.2 31.8 20.6 19.6 27 22.6 23 20.2 35
37.9 19.3 42.9 26.1 36.8 41 22.7 30 26.3 26 26.4 40.7
A P A A P A P P P A P A
37.9 33 42.9 26.1 41.4 41 22.7 26 28.2 26 30.8 40.7
34.2 20.7 35.4 28.7 31.8 28.1 19.6 27 22.6 24.7 20.2 38.7
A, active therapy received first; P, placebo received first
FRC increased after the acute administration (20 min later) of ipratropium bromide. This increase was significant at both the start and end of the active treatment and placebo period ( P < 0 . 0 5 ) . At the start of the active period the median FRC increased from 22.8 ml/kg (range 19.6-38.7) to 29.6 ml/kg (range 19.7-38) and at the end of the active period from a median of 31.4 ml/kg (range 22.7-42.9) to 39.7ml/kg (range 22.2-55.0) 20min post bronchodilator. At the start of the placebo period the median FRC increased from 28.7ml/kg (range 19.342.9) to 37.1ml/kg (range 20.6-49.4) and at the end of the placebo period from 27.6 ml/kg (range 19.6-38.7) to a median of 31.gml/kg (range 19.6-44.0) 20min after bronchodilator administration. Discussion An increase in FRC was taken to demonstrate an improvement in lung function. We considered this justified as both in this study and our previous trial [24], an increase in F R C was associated with a reduction in symptom score. Although five infants, following 2 weeks of placebo therapy, had an FRC which might be considered "hyperinflated" when related to reference ranges for term infants [21], this increase in FRC was associated with a median reduction in the symptom score of the five infants of 70% (range 5 6 % - 9 4 % ) . We therefore maintain that even in these five infants, the elevation in FRC over the active period did indicate an improvement. Amongst asthmatic children aged 2-5 years, relief of symptoms has also been associated with a increase rather than a decrease in FRC [6]. The magnitude of F R C measured by helium gas dilution is dependent on the accessibility of the lung units. Prior to bronchodilator therapy, areas of lung with relatively long time constants might have had limited access to helium. Amongst the preterm infants included in the present and the previous study [24], bronchodilator therapy seems likely to have improved access to helium, reducing gas trapping, which would result in an increase in FRC in association with symptomatic relief. This hypothesis is supported by our
finding of an acute increase in FRC after both the placebo and active period, when F R C was measured before and 20min after administration of ipratropium bromide. In a subsequent study [unpublished data] we found that adminstration of a nebulised bronchodilator resulted in an increase in FRC from a median of 28 ml/ kg (range 18-42) to a median of 37 ml/kg (range 23-48) and this was associated with a decrease in T G V , bringing the F R C : T G V ratio closer to unity. These data also support the hypothesis that preterm infants suffered from pulmonary trapping. All 12 infants responded to ipratropium bromide as evidenced by a reduction in symptom score. In the majority this was associated with a statistically significant change in lung function. In wheezy infants born at term and less than 1 year of age, ipratropium bromide given either via a metered dose inhaler [14] or via a nebuliser [9, 15] improved symptom scores. Henry et al. [9], however, did not find that nebulised ipratropium bromide caused any improvement in lung function. This apparent unresponsiveness may be explained by the lack of severity of the lung function abnormalities in the infants studied [9]. Several groups have examined the effect of other bronchodilators in wheezy term infants and suggested they may be of benefit. Nebulised albuterol resulted in a significant reduction in the accessory muscle score and improvement in oxygen saturation amongst infants who had wheeze and other signs and symptoms of bronchiolitis [18]. The response to therapy was similar in infants both younger and those older than 6 months of age. Salbutamol inhalation has also been shown to be useful in infants and toddlers with asthma [20]. Fenoterol given via a metered dose inhaler [14] or by nebulisation [15] improved symptom score but was associated with an increase in heart rate [16]. Several of these studies [14, 15] have suggested that fenoterol may be more effective than ipratropium bromide. We found that the improvement in F R C following ipratropium bromide was slightly smaller than that caused by terbutaline administration [24], despite similar lung function in both groups at the
857 start of the study, As the two trial designs differed, it is inappropriate to conclude f r o m these two studies that i p r a t r o p i u m b r o m i d e is less effective than terbutaline in improving lung function a m o n g s t p r e t e r m infants at follow up. As we have n o w d e m o n s t r a t e d that maintenance t h e r a p y with inhaled i p r a t r o p i u m b r o m i d e is effective in p r e t e r m infants s y m p t o m a t i c at follow up, a r a n d o m i s e d trial c o m p a r i n g i p r a t r o p i u m b r o m i d e and a b e t a - a d r e n e r g i c agonist might n o w be useful to determine which is the m o s t efficacious therapy. I n children u n d e r 3 years of age successful u n a i d e d use of a m e t e r e d dose inhaler is unpredictable, especially during w h e e z y attacks [2]. T h e r e are n o w commerically available spacers which allow y o u n g children to receive inhaled drugs f r o m a m e t e r e d dose inhaler without the n e e d for h a n d - m o u t h co-ordination [4]. A variety of " h o m e - m a d e " spacer devices have also b e e n used effectively and include a disposable 11 plastic bottle [22], plastic freezer bags [12] and coffee cups [8]. T h e v o l u m e of the spacer is critical in determining its efficacy [13], and a v o l u m e of 750 ml was r e c o m m e n d e d for asthmatics with a m e a n age of 5.2 years [22]. H e n r y et al. [8], however, f o u n d administration of a b r o n c h o d i l a t o r via a smaller v o l u m e spacer, such as a disposable coffee cup, to be effective. T h e infants included in this study, being b o r n very p r e t e r m , were even smaller than the infants studied by H e n r y et al. [8]. Thus, despite possible suboptimal aerolisation [13], an a d e q u a t e a m o u n t of drug might be administered to our very small patients. T h e disposable coffee cup is non-expensive and light for m o t h e r s to carry a r o u n d . These results suggest it is an effective spacer device for p r e t e r m infants as administering b r o n c h o d i l a t o r via the coffee cup resulted in b o t h a reduction in s y m p t o m score and i m p r o v e m e n t in lung function. These results confirm [24] that inhaled b r o n c h o dilator t h e r a p y utilising a simple spacer device is an effective t h e r a p y for p r e t e r m infants with recurrent respiratory symptoms. In this study, unlike our previous trial [24], infants received active or placebo medication in r a n d o m order, thus the reduction in s y m p t o m score was likely to be a true reflection of response to t h e r a p y rather than an effect of time. T h e s y m p t o m score was reduced in all infants and the m a g n i t u d e of response was not greatest in the older infants. W e conclude that regular inhaled i p r a t r o p i u m b r o m i d e t h e r a p y appears to be a useful t h e r a p y for p r e t e r m infants of even less than 2 years o f age w h o have recurrent s y m p t o m s at follow up.
Acknowledgements. Dr. B. Yuksel (Research Fellow) is supported by the Joint Research Council. We thank Ms. Sue Williams for secretarial assistance.
References 1. Bowman E, Yu V (1989) Continuing morbity in extremely low birthweight infants. Early Hum Dev 18:165-174 2. Conner WT, Dolovich MB, Frame RA, Newhome MT (1989) Reliable salbutamol administration in 6 to 36 months children by means of a metered dose inhaler and aerochamber with mask. Pediatr Pulmonal 6 : 263-267
3. DeTroyer A, Yernault J-C, Rodenstein D (1979) Effects of vagal blockade as lung mechanics in normal man. J Appl Physio146 : 217-226 4. Ellul-Micallel R, Moren F, Wetterlin K, Hidingen KL (1980) Use of a special inhaler attachment in asthmatic children. Thorax 35 : 620-623 5. Greenough A (1990) Personal practice - bronchopulmonary dysplasia. Arch Dis Child 65 : 1082-1088 6. Greenough A, Pool JB, Price JF (1989) Changes in functional residual capacity in response to bronchodilator therapy among young asthmatic children. Pediatr Pulmonol 7:8-11 7. Greenough A, Maconochie I, Yuksel B (1990) Recurrent respiratory symptoms in the first year of life following preterm delivery. J Perinat Med 18 : 489-494 8. Henry RL, Milner AD, Davies JG (1983) Simple drug delivery system for use by young asthmatics. Br Med J 286 : 2021 9. Henry RL, Hiller E J, Milner AD, Hodges IGS, Stokes GM (1984) Nebulised ipratropium bromide and sodium cromoglycate in the first two years of life. Arch Dis Child 59 : 54-57 10. Hensley MJ, O'Cain CF, McFadden ER, Ingrain RH (1978) Distribution of bronchodilation in normal subjects: beta agonist versus atropine. J Appl Physiol 45 : 778-782 11. Hodges IGC, Groggins RC, Milner GM (1981) Bronchodilator effects of inhaled ipratropium bromide in wheezy toddlers. Arch Dis Child 56 : 729-732 12. Lee HS, Evans HE (1984) Aerosol bag for administration of bronchodilator to young asthmatic children. Pediatrics 73: 230-232 13. Levison H, Reilly PH, Worsley GH (1985) Spacing devices and metered dose inhaler in childhood asthma. J Pediatr 107: 662-668 14. Mallol J, Barrueto L, Girardi G, Toro O (1987a) Bronchodilator effect of feneterol and ipratropium bromide in infants with acute wheezing. Pediatr Pulmonol 3 : 352-356 15. Mallol J, Barrueto L, Girardi G, Munoz R, Puppo H, Ulloa V, Toro O, Queredo F (1987b) Use of nebulised bronchodilators in infants under one year of age: analysis of four forms of therapy. Pediatr Pulmonol 3 : 298-303 16. Mallol J, Munoz R, Puppo H, Ulloa V, Toro O, Girardi G, Barrueto L (1987c) Effects of nebulished fenoterol associated with ipratropium bromide or steroids on the heart rate of infants under one year of age with acute wheezing. Pediatr Pulmonol 3 : 83-85 17. Sauve RS, Singhal N (1985) Long term morbidity of infants with bronchopulmonary dysplasia. Pediatrics 76:725-733 18. Schuh S, Canny G, Reismann JJ, Kerem E, Brentur L, Petric M, Levison H (1990) Nebulized albuterol in acute broncbiolitis. J Pediatr 117 : 633-637 19. Smyth JA, Tobachnik E, Duncan WJ, Reilly B J, Levison H (1981) Pulmonary function and bronchial hyperreactivity in long term survivors of bronchopulmonary dysplasia. Pediatrics 68 : 336-340 20. Tal A, Levy N, Bearman JE (1990) Methylprednisolone therapy for acute asthma in infants and toddlers: a controlled clinical trial. Pediatrics 86 : 350-356 21. Taussig LM, Harris TR, Lebowitz MD (1977) Lung function in infants and young children, functional residual capacity, tidal volume and respiration. Am Rev Respir Dis 116:233-239 22. Teo J, Kwang LW, Yip WCL (1988) An inexpensive spacer for use with metered dose bronchodilators in young asthmatic children. Pediatr Pulmonol 5 : 244-246 23. Yuksel B, Greenough A (1991a) Lung function abnormalities at six months of age following neonatal intensive care. Arch Dis Child 66 : 472-476 24. Yuksel B, Greenough A, Maconochie I (1990) Effective bronchodilator therapy by a simple spacer device for wheezy premature infants in the first two years of life. Arch Dis Child 65 : 728-785
European Journal of
Pediatrics
9 Springer-Verlag 1991
Ipratropium bromide for symptomatic preterm infants B. Yuksel and A. Greenough Department of Child Health, King's College Hospital, London SE5 9RS, United Kingdom Received November 27, 1990 / Accepted April 11, 1991
Abstract. Twelve p r e t e r m infants, m e d i a n gestational age 31.5 weeks, were entered into a randomised, placebocontrolled trial of b r o n c h o d i l a t o r therapy. Their postnatal age was a m e d i a n of 17.5 m o n t h s and all suffered f r o m recurrent respiratory symptoms. T h e infants received either inhaled placebo or 40 gg of ipratropium b r o m i d e (active therapy) three times a day utilising a coffee cup as a spacer device. E a c h t h e r a p y was administered for 2 weeks. The s y m p t o m score during the active period was r e d u c e d by 59% c o m p a r e d to the placebo period (P < 0.01) and this was associated with 38% imp r o v e m e n t in lung function in the active period compared to a 20% change in functional residual capacity over the placebo period (P < 0.01). W e conclude inhaled ipratropium b r o m i d e appears to be an effective treatm e n t for s y m p t o m a t i c infants at follow up.
Key words: P r e t e r m - B r o n c h o d i l a t o r - Functional residual capacity
Introduction R e c u r r e n t or persistent wheezing is very c o m m o n a m o n g p r e t e r m infants in the first 2 years of life [1, 17, 18], the incidence appearing to be twice that f o u n d in full-term infants [7]. W e have previously d e m o n s t r a t e d in a nonr a n d o m i s e d study that inhaled b r o n c h o d i l a t o r utilising a simple spacer device m a y be an effective t h e r a p y for certain s y m p t o m a t i c p r e t e r m infants [24]. A d m i n i s t r a t i o n of terbutaline was associated with a reduction in symptoms and on overall i m p r o v e m e n t in lung function, but the m a g n i t u d e of response varied [24]. It is possible our results might have b e e n better if we had used an anticholinergic agent such as ipratropium b r o m i d e as this is a m o r e effective b r o n c h o d i l a t o r than [3-adrenergic agents in w h e e z y infants b o r n at term [8, 11]. T h e r e is resting vagal tone in adults t h r o u g h o u t the tracheobronchial tree, but the dilating action of aerosolized particles seems confined to the large airways [3]. InOffprint requests to." A. Greenough Abbreviations: FRC = functional residual capacity; TGV =
thoracic gas volume; FRC: TGV = functional residual capacity : thoracic gas volume ratio
halation of a n o n - a b s o r b a b l e atropine p r e p a r a t i o n can result in a 50% reduction in airways restistance [3]. Anticholinergic drugs have a greater effect on m o r e proximal airways than [3-adrenergic stimulants, as shown by the finding that their administration results in a larger increase in anatomical dead space [10]. A t follow up, preterm infants have evidence of proximal airways d a m a g e , indicated by an elevated airways resistance [23], thus anticolinergic agents m a y be particularly effective in this group of infants. T h e aim of this study was to determine the efficacy of ipratropium b r o m i d e in treating p r e t e r m infants, s y m p t o m a t i c at follow up. To avoid possible bias due to the timing of administration of the bronchodilator, the infants were enrolled into a r a n d o m i s e d placebo-controlled trial.
Patients and methods Twelve infants, 6 boys and 6 girls, median birth weight 1385g (range 682-1780g), gestational age 31.5 weeks (range 24-34 weeks) were enrolled into the study. All but 1 had required ventilation for respiratory distress syndrome in the neonatal period. The median duration of neonatal ventilation was 5 days (range 0.1-42) and of oxygen dependency 8 days (range 1-180). Although 3 infants had had neonatal chronic lung disease (that is an oxygen requirement at i month of age), none had suffered from bronchopulmonary dysplasia [5]. Their median postnatal age was 17.5 months (range 6-40 months), only 2 were older than 2 years. Seven infants had a family history of asthma and six sets of parents smoked. The infants all attended the paediatric respiratory clinic at King's College Hospital and had either coughed and/or wheezed on at least 4 days per week for the last month. No infant was receiving treatment for wheeze at the time of entry into the study. Permission for the study was granted by the King's College Hospital Ethics Committee and parental consent was also obtained. The study period consisted of 4 weeks. The infants received, in random order, either 2 weeks of placebo therapy or 2 weeks of active therapy. The active therapy was two puffs (20 Ixg per puff) of ipratropium bromide aerosol inhalation. Both the parents and the investigator who analysed the lung function data (see later) were blind to the nature of the therapy being administered. Placebo or active therapy was administered as two puffs three times a day from an inhaler utilising a coffee cup as spacer device [6]. At study entry and at the end of each 2 week period a clinical history was taken from the parents. The child was examined and the height, weight and respiratory function measured. During each 2 week period the parents completed a diary card regarding the nature and frequency of respiratory symptoms: 1) runny nose, off
855 feeds, unwell; 2) daytime and 3) night cough; 4) daytime and 5) night wheeze. Each symptom category was scored from 0-3 (none 0, mild 1, moderate 2, bad 3), thus the maximum score for each 2 week period was 210. The infant's diary card was subsequently analysed by a clinician blind to the order in which therapy had been given. Lung function was assessed by measurement of functional residual capacity (FRC) by a helium gas dilution technique, which has been described previously in detail [6]. Measurement of FRC was always made before and 20min after 40~tg of ipratropium bromide. The reproducibility of the measurement had been previously assessed in 20 children of a similar gestational and postnatal age range to the study population. The mean of the differences between the 20 paired measurements was 2.0ml/kg. The coefficient of variation of the measurements was 7.3%, thus, a clinically important change in FRC was defined as an increase in FRC of more than 14.6% [7]. An increase in FRC was taken to indicate an improvement as in two previous studies [6, 25] since an increase rather than a decrease has been associated with a reduction in symptoms. We have previously measured FRC at follow up in 12 preterm infants of similar gestational age to the study group (median 30 weeks, range 27-33 weeks). These infants, however, had requried no form of respiratory support in the neonatal period. Their median FRC was 28 ml/kg (range 26-35).
Table 1. Change in individual components of the symptom score (scores for each component are shown for the study group as whole) Placebo period n
Active period
Reduction in symptom score (%)
12
12
Runny nose/unwell
345
106
69
Wheeze
Day Night
168 168
48 54
71 68
Cough
Day Night
195 192
69 61
65 68
Statistical analysis Differences b e t w e e n the two, 2 w e e k periods were assessed for statistical significance using the paired Wilcoxon rank sum test.
Trial size The m e a n s y m p t o m score of the infants included in our previous study [24] during the placebo period was 60 (SD 19.5). A d m i n i s t r a t i o n of b r o n c h o d i l a t o r resulted in a 65% reduction in this score. R e c r u i t m e n t o f 12 infants into the present study gave us the ability to detect a similar reduction in s y m p t o m score with at least 90% p o w e r at the 5% level.
Results T h e overall s y m p t o m score was r e d u c e d by a median of 58.7% during the active period (median 75; range 3 2 125) c o m p a r e d to the placebo period (median 31; range 4 - 5 4 ) P - < 0 . 0 1 ) . T h e greatest reduction in s y m p t o m score was in daytime wheeze (Table 1). T h e m e d i a n F R C increased f r o m 22.8ml/kg (range 19.6-35.4) over the 2 w e e k active period to 31.4ml/kg (range 22.7-42.9) ( P < 0 . 0 1 ) , (Fig. l) c o m p a r e d to a decrease in the m e d i a n F R C f r o m 28.2ml/kg (range 19.3-42.9) to 27.6ml/kg (range 1 9 . 6 - 3 8 . 7 m l / k g ) over the 2 weeks of the placebo period (nonsignificant (Table 2, Fig. 2). T h e r e was no statistically significant relationship b e t w e e n the change in F R C in response to b r o n c h o dilator t h e r a p y and the child's age (Table 2). T e n of the 12 infants had a clinically i m p o r t a n t change in F R C over the active period c o m p a r e d to only 2 of 12 over the placebo period ( P < 0.01).
FRC changes-PLACEBO Period
FRC changes-ACTIVE Period 45
45"
35 35
E L~ rtu.
Fig.1. FRC results at the start (pre) and at the end of the active period (post). [] Clinically important change in FRC, 9 non-clinically important change in FRC
LL 25 84
25-
Fig. 2. FRC results at the start (])re) and the end of the placebo period (post). Individual patients' data points are linked. [] Clinically important change in FRC, 9 non-clinically important change in FRC
15
1
Pre
Post
2
Pre
Post
856 Table 2. Individual lung function results at the beginning and end of each treatment
Patient number
Age (months)
FRC - active period pre post (2 weeks)
FRC - placebo period pre post (2 weeks)
Order of therapy
1 2 3 4 5 6 7 8 9 10 11 12
6 7 8 16 16 17 18 18 23 24 34 40
32.4 20.7 35.4 22.2 31.8 20.6 19.6 27 22.6 23 20.2 35
37.9 19.3 42.9 26.1 36.8 41 22.7 30 26.3 26 26.4 40.7
A P A A P A P P P A P A
37.9 33 42.9 26.1 41.4 41 22.7 26 28.2 26 30.8 40.7
34.2 20.7 35.4 28.7 31.8 28.1 19.6 27 22.6 24.7 20.2 38.7
A, active therapy received first; P, placebo received first
FRC increased after the acute administration (20 min later) of ipratropium bromide. This increase was significant at both the start and end of the active treatment and placebo period ( P < 0 . 0 5 ) . At the start of the active period the median FRC increased from 22.8 ml/kg (range 19.6-38.7) to 29.6 ml/kg (range 19.7-38) and at the end of the active period from a median of 31.4 ml/kg (range 22.7-42.9) to 39.7ml/kg (range 22.2-55.0) 20min post bronchodilator. At the start of the placebo period the median FRC increased from 28.7ml/kg (range 19.342.9) to 37.1ml/kg (range 20.6-49.4) and at the end of the placebo period from 27.6 ml/kg (range 19.6-38.7) to a median of 31.gml/kg (range 19.6-44.0) 20min after bronchodilator administration. Discussion An increase in FRC was taken to demonstrate an improvement in lung function. We considered this justified as both in this study and our previous trial [24], an increase in F R C was associated with a reduction in symptom score. Although five infants, following 2 weeks of placebo therapy, had an FRC which might be considered "hyperinflated" when related to reference ranges for term infants [21], this increase in FRC was associated with a median reduction in the symptom score of the five infants of 70% (range 5 6 % - 9 4 % ) . We therefore maintain that even in these five infants, the elevation in FRC over the active period did indicate an improvement. Amongst asthmatic children aged 2-5 years, relief of symptoms has also been associated with a increase rather than a decrease in FRC [6]. The magnitude of F R C measured by helium gas dilution is dependent on the accessibility of the lung units. Prior to bronchodilator therapy, areas of lung with relatively long time constants might have had limited access to helium. Amongst the preterm infants included in the present and the previous study [24], bronchodilator therapy seems likely to have improved access to helium, reducing gas trapping, which would result in an increase in FRC in association with symptomatic relief. This hypothesis is supported by our
finding of an acute increase in FRC after both the placebo and active period, when F R C was measured before and 20min after administration of ipratropium bromide. In a subsequent study [unpublished data] we found that adminstration of a nebulised bronchodilator resulted in an increase in FRC from a median of 28 ml/ kg (range 18-42) to a median of 37 ml/kg (range 23-48) and this was associated with a decrease in T G V , bringing the F R C : T G V ratio closer to unity. These data also support the hypothesis that preterm infants suffered from pulmonary trapping. All 12 infants responded to ipratropium bromide as evidenced by a reduction in symptom score. In the majority this was associated with a statistically significant change in lung function. In wheezy infants born at term and less than 1 year of age, ipratropium bromide given either via a metered dose inhaler [14] or via a nebuliser [9, 15] improved symptom scores. Henry et al. [9], however, did not find that nebulised ipratropium bromide caused any improvement in lung function. This apparent unresponsiveness may be explained by the lack of severity of the lung function abnormalities in the infants studied [9]. Several groups have examined the effect of other bronchodilators in wheezy term infants and suggested they may be of benefit. Nebulised albuterol resulted in a significant reduction in the accessory muscle score and improvement in oxygen saturation amongst infants who had wheeze and other signs and symptoms of bronchiolitis [18]. The response to therapy was similar in infants both younger and those older than 6 months of age. Salbutamol inhalation has also been shown to be useful in infants and toddlers with asthma [20]. Fenoterol given via a metered dose inhaler [14] or by nebulisation [15] improved symptom score but was associated with an increase in heart rate [16]. Several of these studies [14, 15] have suggested that fenoterol may be more effective than ipratropium bromide. We found that the improvement in F R C following ipratropium bromide was slightly smaller than that caused by terbutaline administration [24], despite similar lung function in both groups at the
857 start of the study, As the two trial designs differed, it is inappropriate to conclude f r o m these two studies that i p r a t r o p i u m b r o m i d e is less effective than terbutaline in improving lung function a m o n g s t p r e t e r m infants at follow up. As we have n o w d e m o n s t r a t e d that maintenance t h e r a p y with inhaled i p r a t r o p i u m b r o m i d e is effective in p r e t e r m infants s y m p t o m a t i c at follow up, a r a n d o m i s e d trial c o m p a r i n g i p r a t r o p i u m b r o m i d e and a b e t a - a d r e n e r g i c agonist might n o w be useful to determine which is the m o s t efficacious therapy. I n children u n d e r 3 years of age successful u n a i d e d use of a m e t e r e d dose inhaler is unpredictable, especially during w h e e z y attacks [2]. T h e r e are n o w commerically available spacers which allow y o u n g children to receive inhaled drugs f r o m a m e t e r e d dose inhaler without the n e e d for h a n d - m o u t h co-ordination [4]. A variety of " h o m e - m a d e " spacer devices have also b e e n used effectively and include a disposable 11 plastic bottle [22], plastic freezer bags [12] and coffee cups [8]. T h e v o l u m e of the spacer is critical in determining its efficacy [13], and a v o l u m e of 750 ml was r e c o m m e n d e d for asthmatics with a m e a n age of 5.2 years [22]. H e n r y et al. [8], however, f o u n d administration of a b r o n c h o d i l a t o r via a smaller v o l u m e spacer, such as a disposable coffee cup, to be effective. T h e infants included in this study, being b o r n very p r e t e r m , were even smaller than the infants studied by H e n r y et al. [8]. Thus, despite possible suboptimal aerolisation [13], an a d e q u a t e a m o u n t of drug might be administered to our very small patients. T h e disposable coffee cup is non-expensive and light for m o t h e r s to carry a r o u n d . These results suggest it is an effective spacer device for p r e t e r m infants as administering b r o n c h o d i l a t o r via the coffee cup resulted in b o t h a reduction in s y m p t o m score and i m p r o v e m e n t in lung function. These results confirm [24] that inhaled b r o n c h o dilator t h e r a p y utilising a simple spacer device is an effective t h e r a p y for p r e t e r m infants with recurrent respiratory symptoms. In this study, unlike our previous trial [24], infants received active or placebo medication in r a n d o m order, thus the reduction in s y m p t o m score was likely to be a true reflection of response to t h e r a p y rather than an effect of time. T h e s y m p t o m score was reduced in all infants and the m a g n i t u d e of response was not greatest in the older infants. W e conclude that regular inhaled i p r a t r o p i u m b r o m i d e t h e r a p y appears to be a useful t h e r a p y for p r e t e r m infants of even less than 2 years o f age w h o have recurrent s y m p t o m s at follow up.
Acknowledgements. Dr. B. Yuksel (Research Fellow) is supported by the Joint Research Council. We thank Ms. Sue Williams for secretarial assistance.
References 1. Bowman E, Yu V (1989) Continuing morbity in extremely low birthweight infants. Early Hum Dev 18:165-174 2. Conner WT, Dolovich MB, Frame RA, Newhome MT (1989) Reliable salbutamol administration in 6 to 36 months children by means of a metered dose inhaler and aerochamber with mask. Pediatr Pulmonal 6 : 263-267
3. DeTroyer A, Yernault J-C, Rodenstein D (1979) Effects of vagal blockade as lung mechanics in normal man. J Appl Physio146 : 217-226 4. Ellul-Micallel R, Moren F, Wetterlin K, Hidingen KL (1980) Use of a special inhaler attachment in asthmatic children. Thorax 35 : 620-623 5. Greenough A (1990) Personal practice - bronchopulmonary dysplasia. Arch Dis Child 65 : 1082-1088 6. Greenough A, Pool JB, Price JF (1989) Changes in functional residual capacity in response to bronchodilator therapy among young asthmatic children. Pediatr Pulmonol 7:8-11 7. Greenough A, Maconochie I, Yuksel B (1990) Recurrent respiratory symptoms in the first year of life following preterm delivery. J Perinat Med 18 : 489-494 8. Henry RL, Milner AD, Davies JG (1983) Simple drug delivery system for use by young asthmatics. Br Med J 286 : 2021 9. Henry RL, Hiller E J, Milner AD, Hodges IGS, Stokes GM (1984) Nebulised ipratropium bromide and sodium cromoglycate in the first two years of life. Arch Dis Child 59 : 54-57 10. Hensley MJ, O'Cain CF, McFadden ER, Ingrain RH (1978) Distribution of bronchodilation in normal subjects: beta agonist versus atropine. J Appl Physiol 45 : 778-782 11. Hodges IGC, Groggins RC, Milner GM (1981) Bronchodilator effects of inhaled ipratropium bromide in wheezy toddlers. Arch Dis Child 56 : 729-732 12. Lee HS, Evans HE (1984) Aerosol bag for administration of bronchodilator to young asthmatic children. Pediatrics 73: 230-232 13. Levison H, Reilly PH, Worsley GH (1985) Spacing devices and metered dose inhaler in childhood asthma. J Pediatr 107: 662-668 14. Mallol J, Barrueto L, Girardi G, Toro O (1987a) Bronchodilator effect of feneterol and ipratropium bromide in infants with acute wheezing. Pediatr Pulmonol 3 : 352-356 15. Mallol J, Barrueto L, Girardi G, Munoz R, Puppo H, Ulloa V, Toro O, Queredo F (1987b) Use of nebulised bronchodilators in infants under one year of age: analysis of four forms of therapy. Pediatr Pulmonol 3 : 298-303 16. Mallol J, Munoz R, Puppo H, Ulloa V, Toro O, Girardi G, Barrueto L (1987c) Effects of nebulished fenoterol associated with ipratropium bromide or steroids on the heart rate of infants under one year of age with acute wheezing. Pediatr Pulmonol 3 : 83-85 17. Sauve RS, Singhal N (1985) Long term morbidity of infants with bronchopulmonary dysplasia. Pediatrics 76:725-733 18. Schuh S, Canny G, Reismann JJ, Kerem E, Brentur L, Petric M, Levison H (1990) Nebulized albuterol in acute broncbiolitis. J Pediatr 117 : 633-637 19. Smyth JA, Tobachnik E, Duncan WJ, Reilly B J, Levison H (1981) Pulmonary function and bronchial hyperreactivity in long term survivors of bronchopulmonary dysplasia. Pediatrics 68 : 336-340 20. Tal A, Levy N, Bearman JE (1990) Methylprednisolone therapy for acute asthma in infants and toddlers: a controlled clinical trial. Pediatrics 86 : 350-356 21. Taussig LM, Harris TR, Lebowitz MD (1977) Lung function in infants and young children, functional residual capacity, tidal volume and respiration. Am Rev Respir Dis 116:233-239 22. Teo J, Kwang LW, Yip WCL (1988) An inexpensive spacer for use with metered dose bronchodilators in young asthmatic children. Pediatr Pulmonol 5 : 244-246 23. Yuksel B, Greenough A (1991a) Lung function abnormalities at six months of age following neonatal intensive care. Arch Dis Child 66 : 472-476 24. Yuksel B, Greenough A, Maconochie I (1990) Effective bronchodilator therapy by a simple spacer device for wheezy premature infants in the first two years of life. Arch Dis Child 65 : 728-785
