Pediatric Pulmonology 10:36-39 (1991)
Do Wheezy Infants Recovering From Bronchiolitis Respond to Inhaled Salbutamol? Peter D. Sly, Celia J. Lanteri, and Joan M. Raven Summary. Wheezy infants, less than 6 months of age, were given either inhaled salbutamol or saline in a double-blind study. A significant change in maximal flow at functional residual capacity (Vmax), was defined as being greater than twice the coefficient of variation of the baseline measurements. There was no difference in the infants’ response to saline or salbutamol. Wheezy infants, less than 6 months of age, do not have an increase in VmaxFRCfollowing a single dose of inhaled salbutamol. Pediatr Pulmonol 1991; 10:36-39. Key words: Maximal expiratory flow at FRC, chest compression, individual variability of measurement; placebo-controlled,double-blind study.
INTRODUCTION
The response of wheezy infants to inhaled bronchodilators is controversial. Clinical studies have demonstrated an improvement in clinical status as judged by a composite score.’ However, studies that have measured respiratory function gave differing results. Soto et a1.* reported that 30% of infants in the recovery phase from acute viral bronchiolitis had an increase in specific airway conductance following inhaled salbutamol. Other studies have either revealed no benefit from inhaled ~albutamol,~ or a decrease in lung f ~ n c t i o n , ~depend-~ ing on the measurement used. All these have either used a predetermined change in the measured parameter, defined from the coefficient of variation of repeated measurements performed at a single time, or used grouped data to determine a response. Furthermore, none of these s t ~ d i e have s ~ ~included ~ a control group. A wide variation exists in lung function of individual infants, and we recently demonstrated that the coefficients of variation of the commonly used measures of infant lung function approximately doubled if the infant was moved between sets of measurements.6 We, therefore, hypothesized that the variable results reported in the literature may be due to an inappropriate measure of response. To test this hypothesis we studied infants recovering from acute viral bronchiolitis, using a doubleblind, placebo-controlled protocol in which a significant change was defined as being greater than twice the coefficient of variation of the baseline measurements.
MATERIALS AND METHODS
Twenty-two infants, less than 6 months of age (mean, 3.0 1 1.2 [SD] months), in the recovery phase from
0 1991 Wiley-Liss, Inc.
acute viral bronchiolitis, caused by the respiratory syncytial virus were studied. The studies were performed prior to discharge from hospital when the infants were clinically stable and no longer required supplemental oxygen. The infants were under sedation with chloral hydrate (70-100 mg/kg) and lying supine with their heads supported in the midline, so that their necks were slightly extended. A face mask (30331; Respironics Inc., Kawloon, Hong Kong) covered the nose and mouth, and silicone putty was used to form an airtight seal. A pneumotachograph (Fleisch No. 1) attached to the face mask measured flow (V). Pressure in the face mask was measured using a HP270 pressure transducer (Hewlett-Packard). The pressure and flow signals were amplified, lowpassed filtered using eight-pole bessel filters (902LPF; Frequency Devices, Haverhill, MA), with the corner frequency set at 20 Hz, sampled at 100 Hz using a 12-bit analogue-to-digital converter (DT280 1-A; Data Translation, Marlborough, MA) and stored on computer. Flow was numerically integrated to give volume (V). Maximum flow at functional residual capacity (Vmax,,,) was measured from forced expirations produced with an inflatable bag placed over the chest and
From the Department of Thoracic Medicine, Royal Children’s Hospital, Melbourne, Victoria Australia. Received June 20, 1990; (revision) accepted for publication August 23, 1990. This study was supported in part by a grant from the Royal Children’s Hospital Research Foundation. Address correspondence and reprint requests to P.D. Sly, Department of Thoracic Medicine, Royal Children’s Hospital, Flemington Rd., Parkville, Victoria 3052, Australia.
Salbutamol in Wheezy Infants
upper abdomen anteriorly and surrounded by a nonexpandable jacket. Infants were studied with the jacket loosely applied and with their arms out. A compressive force of 20 cmH,O was applied to the bag at end-inspiration by rapidly opening the bag to a pressure reservoir, and the flow at FRC was measured. FRC was defined as the end-expiratory position of the breaths preceding the forced expiration. Bag pressure was increased progressively in 5 cmH,O steps to a maximum of 60 cmH,O until the forced expiratory flow at FRC reached a maximum (Vmax,,). After the bag pressure that gave the maximum flow was determined, at least five technically satisfactory forced expirations were performed at that pressure. The mean and standard deviation of the baseline Vmax,,, was determined. The coefficient of variation of the baseline measurements was calculated by dividing the standard deviation by the mean. Following the baseline measurements, the infants were randomly allocated in a double-blind fashion to receive either salbutamol (5 mg in saline) or saline. Four milliliters of either solution was nebulized using a Hudson Updraft nebulizer driven at 8 L/min by a clinical air pump. This nebulizer system produces an aerosol with a mass-median diameter of approximately 3.5 km. Aerosol was delivered to the face mask for 10 min and the measurements of Vmax,, repeated 5 , 10, and 15 min following completion of the nebulization. Repeated measures analysis of variance was performed on grouped data to determine whether there was a different response to salbutamol compared to placebo and to examine the time course of any changes in Vmax,,,. For each individual infant's data, a significant change from baseline was defined as a mean value of Vmax,, that differed from the baseline measurements by more than twice the coefficient of variation. Informed consent was obtained from at least one parent, and the study protocol was approved by the institution's ethics committee.
RESULTS No differences were found between the active and placebo groups with respect to age, height, weight, and baseline VmaxFRC(Table 1). The two groups were not different in their response to the aerosol received. On grouped data, the change in VmaxFRCwas not different between the infants receiving salbutamol and those receiving placebo (Table 2). There was no tendency for Vmax,,, to increase or decrease in the 15 min following either salbutamol or placebo inhalations (Table 2). Examination of individual infants' data did not reveal any differences between the infants treated with salbutamol and those who received placebo (Table 2). Six had no significant change in VmaxFR, following inhaling
TABLE 1-Anthropometric Placebo Groups
37
Data of the Medicated and
Age (months)
Height (cm)
Weight (kg)
(% pred.)"
6.0 3.5 2.3 3.0 3.0 4.3 5.0 2.0 1.3 2.0 2.8 3.2 (1.4)
67.0 64.5 60.0 61.5 62.5 61.5 51.0 59.5 51.0 57.0 57.5 59.9 (4.3)
8.4 6.7 5.8 5.6 6.4 4.8 4.6 5.4 2.9 4.6 4.5 5.4 (1.4)
19 65 63 36 34 62 25 81 30 45 29 44.5 (20.2)
11
4.5 2.8 3.5 4.0 1.o 2.5 2.5 2.0 2.3 4.0 2.0
61.8 57.0 60.0 61 .O 50.5 61.5 56.0 61.5 56.5 65.0 56.5
4.1 5.6 4.8 5.2 3.9 6.1 4.3 5.0 4.8 7 .O 4.5
29 54 49 73 50 21 34 26 61 48 68
Mean (SD)
2.8 (1.1)
58.8 (4.0)
5.1 (1.0)
47.2 (16.5)
Subject No. Salbutamol 1 2 3 4 5 6 7 8 9 10 11 Mean (SD) Placebo I 2 3 4 5 6 7 8 9 10
Vmax,,,
"Calculated using the formula of Tepper et al.: VmaxFRC(mUsec) = (4.5 X height) - 123.'
salbutamol, whereas three had an increased \jmaxFRC and 2 had a decreased VmaxFKC.Four infants had no change following saline inhalation, 5 had an increased and 2 a decreased VmaxFR,. DISCUSSION There is no agreement in the literature regarding the response of young wheezy infants to inhaled bronchodilators. Clinical studies have suggested that these infants do benefit from treatment with inhaled bronchodilators. However, studies using objective measures of pulmonary function have failed to demonstrate such benefit3 or have found a detrimental r e ~ p o n s e ~to- ~inhaled sympathomimetics. A significant change in pulmonary function has traditionally been determined from repeated measures, made at a single testing. A coefficient of variation is determined for each individual and then the group mean coefficient of variation calculated. We have recently published data demonstrating that the coefficient of variation for the commonly used tests of infant pulmonary function approximately doubles if the infant is moved between sets of measurements.6 In this respect, replacing
Sly et al.
38
TABLE 2-VmaxF,, or Placeboa Subject No.
(mL/s) Following Inhaled Salbutamol
‘
Baseline
5 Min
10 Min
15 Min
34.3 107.8 92.5 54.7 53.6 96.2 33.5 117.5 32.0 59.7 40.1
40.7 100.5 81.8 50.2 34.0 98.3
41.5 94.0 73.5 44.4 33.1 105.5 64.0 168.7 8.7 105.6 37.2
40.5 90.0 51.8 48.2 36.3 127.8 63.0 243.5 10.2 77.6 33.0
44.3 71.9 72.2 110.9 51.8 41.9 43.4 40.6 79.3 80.6 89.4
52.8 86.8 67.6 104.3 52.8 36.3 60.2 31.9 93.6 107.7 85.1
53.9 68.5 97.5 100.7 75.6 32.0 60.0
58.4 81.1 Y0.6 105.4 76.8 44.3 57.5 33.1 77.2 115.2 92.6
Salbutamol 1 2 3 4
5 6 7 8 9 10 11
Placebo I 2 3 4 5 6 7 8 9 10
I1
the clinical studies demonstrating benefit from treatment with salbutamol’ and the ‘‘physiological’’ studies that do not”-5 is that the clinical response is generally assessed
-
134.2 22.1 84.5 38.8
92.3 116.3 63 .0
“Missing values represents technical difficulty in obtaining data.
the infant’s face mask caused as much variability in the measurement as removing and repositioning the infant on the test site, taking care to position the head and neck in the same way. From these observations we reasoned that a significant change in lung function determined from group data may not be appropriate for judging an individual’s response to a therapeutic intervention. In the present study we defined a significant change of Vmax,,, as one that differed from the mean of the baseline measurements by more than twice the coefficient of variation of the baseline measurements. By this definition of a significant change, the responses to saline or salbutamol were not different. Most infants did not show any change, and as many infants responded with a significant change to inhaled saline as to inhaled salbutamol. Traditionally, a change in VmaxFRC greater than 35% of the baseline measurement has been taken as a significant change. If this definition of significant change was used in the present study, 6 infants had no change in Vmax,,, following inhaled salbutamol, 3 had an increase in flows, and 2 had a decrease in VmaxFRC.In the placebo group, seven had no change in VmaxFRC,5 had an increase, and 2 had a decrease. It is worth noting that in variance with other reports4.’ no tendency for a paradoxical response in VmaxFRc following inhaled salbutamol was observed. One possible explanation for the discrepency between
after a period of treatment, whereas the functional studies are performed before and after a single treatment. If mucosal edema and mucous secretion contribute significantly to the airway obstruction in these infants, more than one dose of salbutamol may be required to enlarge airway caliber. Another possible explanation for the differences seen between the clinical and “physiological” studies is that the latter are almost invariably performed under sedation with chloral hydrate. Although it has been established that chloral hydrate does not alter respiratory mechanics in healthy infants,879no data exist on the effect of chloral hydrate on respiratory mechanics in infants with respiratory disease. Also, it remains possible, although unlikely, that chloral hydrate may interfere with the pharmacologic action of salbutamol. Some “physiological” studies have reported a fall in VmaxFRC following inhaled salb~tamol.’-~Hughes et al. speculated that salbutamol decreases bronchomotor tone thus making the airways more prone to collapse on forced expiration. Le Souef et aL7 have demonstrated the so-called negative-effort dependence phenomenon: if the pressure in the “squeeze” bag is higher than that required to produce maximal flow at FRC the shape of the expiratory limb of the flow-volume curve may be altered and result in a lower Vmax,,,. The reports of a fall in VmaxFRCfollowing inhaled s a l b ~ t a m o l ”do ~ not specify whether the same pressures were used to produce forced expiration before and after salbutamol. If the mechanism proposed by Hughes et al.3 is correct, negative-effort dependence may explain the lower values of VmaxFRC reported following salbutamol. This phenomenon may contribute to the apparent discrepancy between the clinical and “physiological” studies. We have seen no evidence of negative effort dependence following inhaled salbutamol. Zn conclusion, the present study has failed to demonstrate any benefit from a single dose of inhaled salbutamol in infants during the first 6 months of life, even when using each infant’s individual variability to determine a significant response. Thus the apparent discrepency between the clinical and physiological studies cannot be explained by an inappropriate methodology of assessing the functional response. REFERENCES 1. Mall01 J , Barmeto L, Girardi G, et al. Use of nebulized broncho-
dilators in infants under 1 year of age: Analysis of four forms of therapy. Pediatr Pulrnonol. 1987; 3:298-303. 2. Soto ME. Sly PD, Uren E, Taussig LM, Landau LI. Bronchodilator response during acute viral bronchiolities in infancy. Pediatr Pulmonol. 1985; 2 3 - 9 0 ,
Salbutamol in Wheezy infants 3. Hughes DM, LeSouef PN, Landau LI. Effect of salbutamol on respiratory mechanics in bronchiolitis. Pediatr Res. 1987; 22:8386. 4. Prendiville A, Green S, Silverman M. Paradoxical response to nebulized salbutamol in wheezy infants, assessed by partial expiratory flow-volume curves. Thorax. 1987; 42:86-9 I . 5 . O’Callaghan C, Milner AD, Swarbrick A. Paradoxical deterioration in lung function after nebulized salbutamol in wheezy infants. Lancet. 1986; 2:1424-1425. 6. Mallol J, Hibbert ME, Robertson CF, Olinsky A, Phelan PD, Sly PD. Inherent variability of pulmonary function tests in infants with bronchiolitis. Pediatr Pulmonol. 1988; 5:152-157.
39
7. Le Souef PN, Hughes DM, Landau LI. Effect of compression pressure on forced expiratory flow in infants. J Appl Physiol. 1986; 61:1639-1646. 8. Tepper RS, Morgan WJ, Cota C , Wright A , Taussig LM, GHMA Pediatricians. Physiologic growth and development of the lung during the first year of life. Am Rev Respir Dis. 1988; 138590591. 9. Turner DJ, Morgan SEG, Landau LI, LeSouef PN. Methodological aspects of flow-volume studies in infants. Pediatr Pulmonol. 1990; 8:289-293.
Do Wheezy Infants Recovering From Bronchiolitis Respond to Inhaled Salbutamol? Peter D. Sly, Celia J. Lanteri, and Joan M. Raven Summary. Wheezy infants, less than 6 months of age, were given either inhaled salbutamol or saline in a double-blind study. A significant change in maximal flow at functional residual capacity (Vmax), was defined as being greater than twice the coefficient of variation of the baseline measurements. There was no difference in the infants’ response to saline or salbutamol. Wheezy infants, less than 6 months of age, do not have an increase in VmaxFRCfollowing a single dose of inhaled salbutamol. Pediatr Pulmonol 1991; 10:36-39. Key words: Maximal expiratory flow at FRC, chest compression, individual variability of measurement; placebo-controlled,double-blind study.
INTRODUCTION
The response of wheezy infants to inhaled bronchodilators is controversial. Clinical studies have demonstrated an improvement in clinical status as judged by a composite score.’ However, studies that have measured respiratory function gave differing results. Soto et a1.* reported that 30% of infants in the recovery phase from acute viral bronchiolitis had an increase in specific airway conductance following inhaled salbutamol. Other studies have either revealed no benefit from inhaled ~albutamol,~ or a decrease in lung f ~ n c t i o n , ~depend-~ ing on the measurement used. All these have either used a predetermined change in the measured parameter, defined from the coefficient of variation of repeated measurements performed at a single time, or used grouped data to determine a response. Furthermore, none of these s t ~ d i e have s ~ ~included ~ a control group. A wide variation exists in lung function of individual infants, and we recently demonstrated that the coefficients of variation of the commonly used measures of infant lung function approximately doubled if the infant was moved between sets of measurements.6 We, therefore, hypothesized that the variable results reported in the literature may be due to an inappropriate measure of response. To test this hypothesis we studied infants recovering from acute viral bronchiolitis, using a doubleblind, placebo-controlled protocol in which a significant change was defined as being greater than twice the coefficient of variation of the baseline measurements.
MATERIALS AND METHODS
Twenty-two infants, less than 6 months of age (mean, 3.0 1 1.2 [SD] months), in the recovery phase from
0 1991 Wiley-Liss, Inc.
acute viral bronchiolitis, caused by the respiratory syncytial virus were studied. The studies were performed prior to discharge from hospital when the infants were clinically stable and no longer required supplemental oxygen. The infants were under sedation with chloral hydrate (70-100 mg/kg) and lying supine with their heads supported in the midline, so that their necks were slightly extended. A face mask (30331; Respironics Inc., Kawloon, Hong Kong) covered the nose and mouth, and silicone putty was used to form an airtight seal. A pneumotachograph (Fleisch No. 1) attached to the face mask measured flow (V). Pressure in the face mask was measured using a HP270 pressure transducer (Hewlett-Packard). The pressure and flow signals were amplified, lowpassed filtered using eight-pole bessel filters (902LPF; Frequency Devices, Haverhill, MA), with the corner frequency set at 20 Hz, sampled at 100 Hz using a 12-bit analogue-to-digital converter (DT280 1-A; Data Translation, Marlborough, MA) and stored on computer. Flow was numerically integrated to give volume (V). Maximum flow at functional residual capacity (Vmax,,,) was measured from forced expirations produced with an inflatable bag placed over the chest and
From the Department of Thoracic Medicine, Royal Children’s Hospital, Melbourne, Victoria Australia. Received June 20, 1990; (revision) accepted for publication August 23, 1990. This study was supported in part by a grant from the Royal Children’s Hospital Research Foundation. Address correspondence and reprint requests to P.D. Sly, Department of Thoracic Medicine, Royal Children’s Hospital, Flemington Rd., Parkville, Victoria 3052, Australia.
Salbutamol in Wheezy Infants
upper abdomen anteriorly and surrounded by a nonexpandable jacket. Infants were studied with the jacket loosely applied and with their arms out. A compressive force of 20 cmH,O was applied to the bag at end-inspiration by rapidly opening the bag to a pressure reservoir, and the flow at FRC was measured. FRC was defined as the end-expiratory position of the breaths preceding the forced expiration. Bag pressure was increased progressively in 5 cmH,O steps to a maximum of 60 cmH,O until the forced expiratory flow at FRC reached a maximum (Vmax,,). After the bag pressure that gave the maximum flow was determined, at least five technically satisfactory forced expirations were performed at that pressure. The mean and standard deviation of the baseline Vmax,,, was determined. The coefficient of variation of the baseline measurements was calculated by dividing the standard deviation by the mean. Following the baseline measurements, the infants were randomly allocated in a double-blind fashion to receive either salbutamol (5 mg in saline) or saline. Four milliliters of either solution was nebulized using a Hudson Updraft nebulizer driven at 8 L/min by a clinical air pump. This nebulizer system produces an aerosol with a mass-median diameter of approximately 3.5 km. Aerosol was delivered to the face mask for 10 min and the measurements of Vmax,, repeated 5 , 10, and 15 min following completion of the nebulization. Repeated measures analysis of variance was performed on grouped data to determine whether there was a different response to salbutamol compared to placebo and to examine the time course of any changes in Vmax,,,. For each individual infant's data, a significant change from baseline was defined as a mean value of Vmax,, that differed from the baseline measurements by more than twice the coefficient of variation. Informed consent was obtained from at least one parent, and the study protocol was approved by the institution's ethics committee.
RESULTS No differences were found between the active and placebo groups with respect to age, height, weight, and baseline VmaxFRC(Table 1). The two groups were not different in their response to the aerosol received. On grouped data, the change in VmaxFRCwas not different between the infants receiving salbutamol and those receiving placebo (Table 2). There was no tendency for Vmax,,, to increase or decrease in the 15 min following either salbutamol or placebo inhalations (Table 2). Examination of individual infants' data did not reveal any differences between the infants treated with salbutamol and those who received placebo (Table 2). Six had no significant change in VmaxFR, following inhaling
TABLE 1-Anthropometric Placebo Groups
37
Data of the Medicated and
Age (months)
Height (cm)
Weight (kg)
(% pred.)"
6.0 3.5 2.3 3.0 3.0 4.3 5.0 2.0 1.3 2.0 2.8 3.2 (1.4)
67.0 64.5 60.0 61.5 62.5 61.5 51.0 59.5 51.0 57.0 57.5 59.9 (4.3)
8.4 6.7 5.8 5.6 6.4 4.8 4.6 5.4 2.9 4.6 4.5 5.4 (1.4)
19 65 63 36 34 62 25 81 30 45 29 44.5 (20.2)
11
4.5 2.8 3.5 4.0 1.o 2.5 2.5 2.0 2.3 4.0 2.0
61.8 57.0 60.0 61 .O 50.5 61.5 56.0 61.5 56.5 65.0 56.5
4.1 5.6 4.8 5.2 3.9 6.1 4.3 5.0 4.8 7 .O 4.5
29 54 49 73 50 21 34 26 61 48 68
Mean (SD)
2.8 (1.1)
58.8 (4.0)
5.1 (1.0)
47.2 (16.5)
Subject No. Salbutamol 1 2 3 4 5 6 7 8 9 10 11 Mean (SD) Placebo I 2 3 4 5 6 7 8 9 10
Vmax,,,
"Calculated using the formula of Tepper et al.: VmaxFRC(mUsec) = (4.5 X height) - 123.'
salbutamol, whereas three had an increased \jmaxFRC and 2 had a decreased VmaxFKC.Four infants had no change following saline inhalation, 5 had an increased and 2 a decreased VmaxFR,. DISCUSSION There is no agreement in the literature regarding the response of young wheezy infants to inhaled bronchodilators. Clinical studies have suggested that these infants do benefit from treatment with inhaled bronchodilators. However, studies using objective measures of pulmonary function have failed to demonstrate such benefit3 or have found a detrimental r e ~ p o n s e ~to- ~inhaled sympathomimetics. A significant change in pulmonary function has traditionally been determined from repeated measures, made at a single testing. A coefficient of variation is determined for each individual and then the group mean coefficient of variation calculated. We have recently published data demonstrating that the coefficient of variation for the commonly used tests of infant pulmonary function approximately doubles if the infant is moved between sets of measurements.6 In this respect, replacing
Sly et al.
38
TABLE 2-VmaxF,, or Placeboa Subject No.
(mL/s) Following Inhaled Salbutamol
‘
Baseline
5 Min
10 Min
15 Min
34.3 107.8 92.5 54.7 53.6 96.2 33.5 117.5 32.0 59.7 40.1
40.7 100.5 81.8 50.2 34.0 98.3
41.5 94.0 73.5 44.4 33.1 105.5 64.0 168.7 8.7 105.6 37.2
40.5 90.0 51.8 48.2 36.3 127.8 63.0 243.5 10.2 77.6 33.0
44.3 71.9 72.2 110.9 51.8 41.9 43.4 40.6 79.3 80.6 89.4
52.8 86.8 67.6 104.3 52.8 36.3 60.2 31.9 93.6 107.7 85.1
53.9 68.5 97.5 100.7 75.6 32.0 60.0
58.4 81.1 Y0.6 105.4 76.8 44.3 57.5 33.1 77.2 115.2 92.6
Salbutamol 1 2 3 4
5 6 7 8 9 10 11
Placebo I 2 3 4 5 6 7 8 9 10
I1
the clinical studies demonstrating benefit from treatment with salbutamol’ and the ‘‘physiological’’ studies that do not”-5 is that the clinical response is generally assessed
-
134.2 22.1 84.5 38.8
92.3 116.3 63 .0
“Missing values represents technical difficulty in obtaining data.
the infant’s face mask caused as much variability in the measurement as removing and repositioning the infant on the test site, taking care to position the head and neck in the same way. From these observations we reasoned that a significant change in lung function determined from group data may not be appropriate for judging an individual’s response to a therapeutic intervention. In the present study we defined a significant change of Vmax,,, as one that differed from the mean of the baseline measurements by more than twice the coefficient of variation of the baseline measurements. By this definition of a significant change, the responses to saline or salbutamol were not different. Most infants did not show any change, and as many infants responded with a significant change to inhaled saline as to inhaled salbutamol. Traditionally, a change in VmaxFRC greater than 35% of the baseline measurement has been taken as a significant change. If this definition of significant change was used in the present study, 6 infants had no change in Vmax,,, following inhaled salbutamol, 3 had an increase in flows, and 2 had a decrease in VmaxFRC.In the placebo group, seven had no change in VmaxFRC,5 had an increase, and 2 had a decrease. It is worth noting that in variance with other reports4.’ no tendency for a paradoxical response in VmaxFRc following inhaled salbutamol was observed. One possible explanation for the discrepency between
after a period of treatment, whereas the functional studies are performed before and after a single treatment. If mucosal edema and mucous secretion contribute significantly to the airway obstruction in these infants, more than one dose of salbutamol may be required to enlarge airway caliber. Another possible explanation for the differences seen between the clinical and “physiological” studies is that the latter are almost invariably performed under sedation with chloral hydrate. Although it has been established that chloral hydrate does not alter respiratory mechanics in healthy infants,879no data exist on the effect of chloral hydrate on respiratory mechanics in infants with respiratory disease. Also, it remains possible, although unlikely, that chloral hydrate may interfere with the pharmacologic action of salbutamol. Some “physiological” studies have reported a fall in VmaxFRC following inhaled salb~tamol.’-~Hughes et al. speculated that salbutamol decreases bronchomotor tone thus making the airways more prone to collapse on forced expiration. Le Souef et aL7 have demonstrated the so-called negative-effort dependence phenomenon: if the pressure in the “squeeze” bag is higher than that required to produce maximal flow at FRC the shape of the expiratory limb of the flow-volume curve may be altered and result in a lower Vmax,,,. The reports of a fall in VmaxFRCfollowing inhaled s a l b ~ t a m o l ”do ~ not specify whether the same pressures were used to produce forced expiration before and after salbutamol. If the mechanism proposed by Hughes et al.3 is correct, negative-effort dependence may explain the lower values of VmaxFRC reported following salbutamol. This phenomenon may contribute to the apparent discrepancy between the clinical and “physiological” studies. We have seen no evidence of negative effort dependence following inhaled salbutamol. Zn conclusion, the present study has failed to demonstrate any benefit from a single dose of inhaled salbutamol in infants during the first 6 months of life, even when using each infant’s individual variability to determine a significant response. Thus the apparent discrepency between the clinical and physiological studies cannot be explained by an inappropriate methodology of assessing the functional response. REFERENCES 1. Mall01 J , Barmeto L, Girardi G, et al. Use of nebulized broncho-
dilators in infants under 1 year of age: Analysis of four forms of therapy. Pediatr Pulrnonol. 1987; 3:298-303. 2. Soto ME. Sly PD, Uren E, Taussig LM, Landau LI. Bronchodilator response during acute viral bronchiolities in infancy. Pediatr Pulmonol. 1985; 2 3 - 9 0 ,
Salbutamol in Wheezy infants 3. Hughes DM, LeSouef PN, Landau LI. Effect of salbutamol on respiratory mechanics in bronchiolitis. Pediatr Res. 1987; 22:8386. 4. Prendiville A, Green S, Silverman M. Paradoxical response to nebulized salbutamol in wheezy infants, assessed by partial expiratory flow-volume curves. Thorax. 1987; 42:86-9 I . 5 . O’Callaghan C, Milner AD, Swarbrick A. Paradoxical deterioration in lung function after nebulized salbutamol in wheezy infants. Lancet. 1986; 2:1424-1425. 6. Mallol J, Hibbert ME, Robertson CF, Olinsky A, Phelan PD, Sly PD. Inherent variability of pulmonary function tests in infants with bronchiolitis. Pediatr Pulmonol. 1988; 5:152-157.
39
7. Le Souef PN, Hughes DM, Landau LI. Effect of compression pressure on forced expiratory flow in infants. J Appl Physiol. 1986; 61:1639-1646. 8. Tepper RS, Morgan WJ, Cota C , Wright A , Taussig LM, GHMA Pediatricians. Physiologic growth and development of the lung during the first year of life. Am Rev Respir Dis. 1988; 138590591. 9. Turner DJ, Morgan SEG, Landau LI, LeSouef PN. Methodological aspects of flow-volume studies in infants. Pediatr Pulmonol. 1990; 8:289-293.
