882
Workshop on B P D
tended, "bubble lung" (Fig. 7). These spaces may become permanent, increasing in size with time. Some involve only one lobe, appearing as lobar emphysema (Figs. 8 and 9). Perhaps in an attempt by the lung to create a functional gas diffusing space from a useless dilated lymphatic space, there appears to be an invasion of large cells, sometimes appearing as multinuceated giant cells, sometimes covered with cilia, often containing lamellar inclusions similar to Type II alveolar cells (Fig. 10). As the
The Journal of Pediatrics November 1979
false channels expand, lung tissue is compressed, leading to less and less functional gas diffusing surface area. Chronic hypoxemia, hypercapnia, and respiratory acidosis lead to persistent pulmonary hypertension and cor pulmonale, ventilator dependence, and oxygen dependence. Low-grade infection frequently is superimposed, and all of the ingredients for chronic respirator lung now exist.
Theophylline therapy in bronchopulmonary dysplasia Anthony R. Rookiin, M.D., Ara S. Moomjian, M.D., John G. Shutack, D.O., Jacob G. Schwartz, M.S., and William W. Fox, M.D.,* Philadelphia, Pa.
BRONCHOPULMONARY DYSPLASIA is the most common neonatal pulmonarY disease requiring long-term mechanical ventilation. After establishing this diagnos!s, current therapy includes fluid restriction, diuretics, digitalization, and chest physiotherapy. During weaning and long-term management, several complications may occur, such as increased secretions, recurrent atelectasis, intermittent bronchospasm, and difficulty weaning from mechanical ventilation to continuous positive airway pressure. These complications may be related either to increased airway resistance or to unstable maintenance of lung volume; Although the pathologic changes in bronchopulmonary dysplasia result in increased airway resistance/there have been few clinical reports on the efficacy of bronchodilators for treating bronchopulmonary dysplasia? To establish the effect of theophylline therapy, a group 0fneonates with bronchopulmonary dysplasia .were treated with aminophylline intravenously, followed by measurements of serial pulmonary function tests and serum theophylline levels. PATIENTS
AND METHODS
Eleven infants with birth weights between 800 and 1,690 gm were studied in either the Infant Intensive Care Unit or the Intermediate Intensive Care Unit at The Children's Hospital of Philadelphia. Informed parental consent was obtained for all studies. All infants had moderate-to-severe bronchopulmonary dy~;p~asia as determined by clinical course and serial ro~iatgenographic *Reprint address: Division of Neonatology, The Children's Hospital of Philadelphia, 34th St. & Civic Center Blvd, Philadelphia, PA 19104.
examination, when intravenous aminophylline therapy was started, mechanical ventilation at a mean of 6.6 intermittent mandatory ventilation breaths per minute was required for ten of the 11 infants studied. The babies were between 24 and 145 days of age and weighed between 930 and 4,500 gm when studied. Respiratory rate, tidal volume, dynamic lung compliance, and inspiratory and expiratory resistance were measured. Intraesophageal pressure was determined by placing a soft latex balloon attached to a polyvinylchloride catheter in the lower third of the esophagus. Air flow was measured with a pneumotachograph and electronically integrated to tidal volume and recorded on a four-channel polygraph. Abbreviations used CPAP: continuous positive airway pressure Pco2: partial pressure of carbon dioxide AMP: adenos~femonophosphate Dynamic compliance was calculated from volume and pressure tracings, and airway resistance was computed from flow and pressure tracings. Each value was based on the average of at least ten regular breaths. In nine patients, control pulmonary function tests were measured ~rior to starting aminophylline therapy. The patients were then given an infusion of 7 mg/kg of aminophylline over 20 minutes followed by 2 mg/kg of intravenous aminophylline every eight hours. At two and 24 hours after starting aminophylline, serum theophylline (the pharmacologically active fraction) was measured and pulmonary function tests were again measured. After three days of intravenous aminophylline therapy, theo-
0022-34i6/79/110882+04500.40/0 9 1979 The C. V. Mosby Co.
Volume 95 Number 5, part 2
BPD: Causes, prevention, and therapy
883
Table L Clinical summary of patients*
Age (days) Younger < 30 (N = 5) Older > 3O (N = 6)
Birth weight (gin) 1,167 840-1,690 1,176 800-1,580
Age studied (days)
Time > 60% 02 (days)
Peak inspiratory pressure (cm H20)
1,216 gm 930-1,900
25 20-29
1.2
22
22 9-29
2,510 1,150-4,500
84 41-145
4 patients, 0 1 patient, 5 1 patient, 7
28
59 41-100
Study weight (gin)
Days ventilated
*Allvaluesexpressed as meanand/or range. phylline was given orally at a dosage of 2 mg/kg every 12 hours. Theophylline levels were measured and the serum concentration was maintained at 5 to 12 mg/1. Respiratory rate and arterial Pco~ were measured prior to the study and after theophylline therapy. In the remaining two patients, pulmonary function tests were not performed, but the clinical response following theophylline therapy was documented. RESULTS Evaluation of dynamic lung compliance and pulmonary resistance after 24 hours of theophylline therapy revealed that all neonates less than 30 days of age who had pulmonary function tests had improvement in these values. For this reason, all patients were divided into two groups for analysis: those less than 30 days of age (younger) and those greater than 30 days of age (older). There were five infants in the younger group and six infants in the older group. Table I summarizes the clinical data for the two groups. Birth weights were similar and, as expected, the older group weighed twice as much when studied. The younger infants were mechanically ventilated for 22 days (mean) and the older infants for 59 days (mean). Table II shows serum theophylline levels for the two groups at two and 24 hours after intravenous administration of aminophylline. The mean serum theophylline values obtained in this study were within the range recommended as therapeutic for neonatal apnea. ~ These values are lower than levels recommended for the treatment of asthma in adults because there is decreased serum protein binding of theophylline in the neonate. 4 Fig. 1 demonstrates mean values for dynamic lung compliance at control, two hours and 24 hours for the two groups of patients. The younger patients had a trend toward increase in compliance after infusion of aminophylline. At two and 24 hours, respectively, the compliance increased by 153% and 294% compared to
Table II. Serum theophylline levels
Age Younger < 30 days Older > 30 days
Mean serum theophylline (rag~l) at 2 hr
Mean serum theophylline (rag~l) at 24 hr
6.08 (N = 4)
7.30 (N = 3)
5.50 (N = 3)
8.30 (N = 6)
control. The older infants showed a trend toward decrease in compliance of 25% at 24 hours. Fig. 2 shows a trend toward decrease in both inspiratory and expiratory resistance for the younger infants. The younger infants had a 68% decrease in inspiratory and a 67% decrease in expiratory resistance at 24 hours. There was either no resistance change or a trend toward increase in older patients after aminophylline therapy. The older infants showed a 38% increase in inspiratory resistance and a 4% decrease in expiratory resistance at 24 hours. There were no significant changes in either arterial Pco~ or respiratory rate in any of the patients after administration of theophylline. Clinically, four of the five younger patients were weaned from the respirator to continuous positive airway pressure within 72 hours of theophylline therapy. Two of these four were weaned from the respirator within 24 hours of theophylline therapy. The fifth patient developed sepsis and subsequently died. The older patients showed a variable clinical response. One patient was weaned to continuous positive airway pressure after 48 hours of theophylline therapy. Two were weaned to continuous positive airway pressure seven days after theophylline therapy. The remaining three infants continued to require the same level of respiratory support as before the study. Theophylline therapy was continued
884
Workshop on B P D
The Journal of Pediatrics November 1979
6i
200 n
"I" 4 E
n~
100
Y
E
~
0
Y
I
!
I
0
2
24
O I
I
I
0
2
24
T I M E , hrs
Fig. 1. Changes in dynamic lung compliance (C~) in younger (Y = 30 days) infants with bronchopulmonary dysplasia treated with intravenous aminophylline. for 39 days (mean) for the younger group and 64 days (mean) for the older group.
o9
soo r
hE
400
300
200 LU n-
DISCUSSION This study suggests that theophylline may be beneficial for decreasing airway resistance, increasing dynamic compliance, and shortening duration of ventilator weaning of infants less than 30 days of age with bronchopulmonary dysplasia. The five younger infants were weaned from mechanical ventilation within 72 hours of therapy. Three of six older patients were weaned from mechanical ventilation within seven days of theophylline therapy. One previous study demonstrated decreased lung compliance, decreased functional residual capacity, and CO2 retention in infants with bronchopulmonary dysplasia? These findings suggest that increased airway resistance is an important feature of this disease. However, theophylline has not been widely used in infants with bronchopulmonary dysplasia because of the belief that the quantity of smooth muscle in the Mrways of infants is minimal. One investigator suggested that the bronchiolar smooth muscle is "feebly developed" in younger infants. 6 Other studies have reported that nebulized salbutamol, a specific beta-2 bronchodilator, did not lower airway resistance in infants less than 6 months of age with an acute viral infection. 7' ~ An additionai study by Matsubo and Thurlbeck" revealed a relative decrease in the percent of smooth muscle in the small airways of children. However, none of the patients in the above studies had bronchopulmonary dysplasia. In contras3~to the small amount of smooth muscle in the airways of healthy infants, Rosan 1~reported that bronchiolat smooth muscle swelling and hypertrophy are two major histologic features of infants lungs with hyaline membrane disease
100
O
I
I
I
0
2 TIME, hrs
24
Fig. 2. Changes in inspiratory (RE) and expiratory (RE) pulmonary resistance in younger (Y = 30 days) infants with bronchopulmonary dysplasia following intravenous administration of aminophylline. treated with mechanical ventilation and high inspired oxygen concentrations. These findings can be seen as early as three to five days after the onset of ventilatory support with high inspired oxygen concentration. The increased airway resistance in infants with bronchopulmonary d y s p l a ~ is partly due to smooth muscle hypertrophy in the:gmali airways. If variable airway obstruction exists throughout the lungs, different lung units have different ventilatory time constants with maldistribution of ventilation. Dynamic lung compliance is affected by lowered functional residual capacity and maldistribution of ventilation. The low dynamic lung compliance seen in the infants presented in this study ~f most like!y occurred because of airway occlusion from either smooth muscle spasm or hypertrophy. In the younger infants with bronchopulmonary dysplasia, theophylline may have alleviated airway obstruction by relaxing smooth muscle, thus improving distribution of ventilation and dynamic lung compliance. The diminished effectiveness of theophylline in the older group of infants
Volume 95 Number 5, part 2
may have been due to extensive pulmonary fibrosis which caused less reversibility of airway obstruction. The effect of theophylline as a smooth muscle relaxant is usually attributed to its ability to enhance intracellular levels of cyclic 3',5' adenosine monophosphate. Theophylline inhibits phosphodiesterase, the enzyme responsible for converting active cyclic A M P to inactive 5'AMP. There appears to be a relationship between levels of cyclic A M P and the degree of smooth muscle relaxation. T M 12 Although there is some evidence that theophylline accelerates lung maturation by increasing cyclic A M P levels, '3 it is doubtful that significant lung maturation occurred during the 24 hours of pulmonary function measurements. In contrast to a previous study, TM there were no significant changes seen in either arterial Pco2 or respiratory rate in any of the patients after administration of theophylline. This study suggests that a trial of theophylline may be indicated in all infants who are ventilator dependent with bronchopulmonary dysplasia. There is a wide spectrum of pulmonary fibrosis in patients with b r o n c h o p u l m o n a r y dysplasia, and theophylline appears to be most effective in those infants with the least fibrosis. The decision to use theophylline should be individualized for each patient and should depend on several factors, including the clinical course, radiographic changes, and the type and degree of ventilatory support required by each patient. REFERENCES
1. Coates AL, Bergsteinsson H, Desmond K, Outerbridge EW, and Beaudry PH: Long-term pulmonary sequelae of premature birth with and without idiopathic respiratory distress syndrome, J PEDIATR90"611, 1977. 2. Fox WW: Bronchopulmonary dysplasia (respirator lung syndrome): Clinical course and outpatient therapy, Pediatr Ann 7:40, 1978.
BPD: Causes, prevention, and therapy
885
3. Shannon DC, Gotay F, Stein IM, Rogers MC, Todres ID, and Moylan FMB: Prevention of apnea and bradycardia in low birthweight infants, Pediatrics 55:589, 1975. 4. Aranda JV, Sitar DS, Parsons WD, Loughnan PM, and Neims AH: Pharmacokinetic aspects of theophylline in premature newborns, N Engl J Med 295:413, 1976. 5. Bryan MH, Hardie MI, Reilly B J, and Swyer PR: Pulmonary function studies during the first year of life in infants recovering from respiratory distress syndrome, Pediatrics 52:169, 1973. 6. Engel S: Lung structure, Springfield, Ill., 1962, Charles C Thomas, Publisher, p 27. 7. Rutter N, Milner AD, and Hiller EJ: Effect of bronchodilators on respiratory resistance in infants and younger children with bronchiolitis and wheezy bronchitis, Arch Dis Child 50:719, 1975. 8. Radford M: Effect of nebulized salbutamol in infants with wheezy bronchitis, Arch Dis Child 49"243, 1974. 9. Matsubo K, and Thurlbeck WM: A morphometric study of bronchial and bronchiolar walls in children, Am Rev Resp Dis 105:908, 1972. 10. Rosan RC: Hyaline membrane disease and a related spectrum of neonatal pneumopathies: The relationship of normal to diseased neonatal lung, in Rosenberg HS, and Bolande RP, editors, Perspectives in pediatric pathology, Vol 2, Chicago, 1975, Yearbook Medical Publishers Inc., p 35. 11. Anderson RGG: Cyclic AMP and calcium ions in mechanical and metabolic responses of smooth muscles; influence of some hormones and drugs, Acta Physiol Scand 382(Suppl): 1, 1972. 12. Sutherland EW, Robison GA, and Butcher RW: Some aspects of the biological role of adenosine 3',5'-monophosphate (cyclic AMP), Circulation 37:279, 1968. 13. Barret CT, Sevanian A, Phelps DL, Gilden C, and Kaplan SA: Effects of cortisol and aminophylline upon survival, pulmonary mechanics, and secreted phosphatidyl choline of prematurely delivered rabbits, Pediatr Res 12:38, 1978. 14. Barr PA: Weaning very low birthweight infants from mechanical ventilation using intermittent mandatory ventilation and theophylline, Arch Dis Child 53:598, 1978.
BPD--causes, prevention, and therapy: Discussion Dr. Philip Farrell, Moderator
DR. NELSON: IS it really possible to ventilate an infant of less than 1,000 gm in a negative pressure respirator without excessive trauma, cooling, and so on? DR. STERN: The negative pressure respirator was not used for this group of very low-birth-weight infants at my previous insti.tution (McGill University); however, it is
0022-3476/79/110885 +04500.40/0 9 1979 The C. V. Mosby Co.
feasible to use this approach~ which is presently being utilized at Brown University. DR. JAMES: What pressures were being used in your evaluation of negative pressure respirators? DR. STERN: The readings on the pressure gauge generally ranged from 40 to 50 cm, but there were leaks in the
Workshop on B P D
tended, "bubble lung" (Fig. 7). These spaces may become permanent, increasing in size with time. Some involve only one lobe, appearing as lobar emphysema (Figs. 8 and 9). Perhaps in an attempt by the lung to create a functional gas diffusing space from a useless dilated lymphatic space, there appears to be an invasion of large cells, sometimes appearing as multinuceated giant cells, sometimes covered with cilia, often containing lamellar inclusions similar to Type II alveolar cells (Fig. 10). As the
The Journal of Pediatrics November 1979
false channels expand, lung tissue is compressed, leading to less and less functional gas diffusing surface area. Chronic hypoxemia, hypercapnia, and respiratory acidosis lead to persistent pulmonary hypertension and cor pulmonale, ventilator dependence, and oxygen dependence. Low-grade infection frequently is superimposed, and all of the ingredients for chronic respirator lung now exist.
Theophylline therapy in bronchopulmonary dysplasia Anthony R. Rookiin, M.D., Ara S. Moomjian, M.D., John G. Shutack, D.O., Jacob G. Schwartz, M.S., and William W. Fox, M.D.,* Philadelphia, Pa.
BRONCHOPULMONARY DYSPLASIA is the most common neonatal pulmonarY disease requiring long-term mechanical ventilation. After establishing this diagnos!s, current therapy includes fluid restriction, diuretics, digitalization, and chest physiotherapy. During weaning and long-term management, several complications may occur, such as increased secretions, recurrent atelectasis, intermittent bronchospasm, and difficulty weaning from mechanical ventilation to continuous positive airway pressure. These complications may be related either to increased airway resistance or to unstable maintenance of lung volume; Although the pathologic changes in bronchopulmonary dysplasia result in increased airway resistance/there have been few clinical reports on the efficacy of bronchodilators for treating bronchopulmonary dysplasia? To establish the effect of theophylline therapy, a group 0fneonates with bronchopulmonary dysplasia .were treated with aminophylline intravenously, followed by measurements of serial pulmonary function tests and serum theophylline levels. PATIENTS
AND METHODS
Eleven infants with birth weights between 800 and 1,690 gm were studied in either the Infant Intensive Care Unit or the Intermediate Intensive Care Unit at The Children's Hospital of Philadelphia. Informed parental consent was obtained for all studies. All infants had moderate-to-severe bronchopulmonary dy~;p~asia as determined by clinical course and serial ro~iatgenographic *Reprint address: Division of Neonatology, The Children's Hospital of Philadelphia, 34th St. & Civic Center Blvd, Philadelphia, PA 19104.
examination, when intravenous aminophylline therapy was started, mechanical ventilation at a mean of 6.6 intermittent mandatory ventilation breaths per minute was required for ten of the 11 infants studied. The babies were between 24 and 145 days of age and weighed between 930 and 4,500 gm when studied. Respiratory rate, tidal volume, dynamic lung compliance, and inspiratory and expiratory resistance were measured. Intraesophageal pressure was determined by placing a soft latex balloon attached to a polyvinylchloride catheter in the lower third of the esophagus. Air flow was measured with a pneumotachograph and electronically integrated to tidal volume and recorded on a four-channel polygraph. Abbreviations used CPAP: continuous positive airway pressure Pco2: partial pressure of carbon dioxide AMP: adenos~femonophosphate Dynamic compliance was calculated from volume and pressure tracings, and airway resistance was computed from flow and pressure tracings. Each value was based on the average of at least ten regular breaths. In nine patients, control pulmonary function tests were measured ~rior to starting aminophylline therapy. The patients were then given an infusion of 7 mg/kg of aminophylline over 20 minutes followed by 2 mg/kg of intravenous aminophylline every eight hours. At two and 24 hours after starting aminophylline, serum theophylline (the pharmacologically active fraction) was measured and pulmonary function tests were again measured. After three days of intravenous aminophylline therapy, theo-
0022-34i6/79/110882+04500.40/0 9 1979 The C. V. Mosby Co.
Volume 95 Number 5, part 2
BPD: Causes, prevention, and therapy
883
Table L Clinical summary of patients*
Age (days) Younger < 30 (N = 5) Older > 3O (N = 6)
Birth weight (gin) 1,167 840-1,690 1,176 800-1,580
Age studied (days)
Time > 60% 02 (days)
Peak inspiratory pressure (cm H20)
1,216 gm 930-1,900
25 20-29
1.2
22
22 9-29
2,510 1,150-4,500
84 41-145
4 patients, 0 1 patient, 5 1 patient, 7
28
59 41-100
Study weight (gin)
Days ventilated
*Allvaluesexpressed as meanand/or range. phylline was given orally at a dosage of 2 mg/kg every 12 hours. Theophylline levels were measured and the serum concentration was maintained at 5 to 12 mg/1. Respiratory rate and arterial Pco~ were measured prior to the study and after theophylline therapy. In the remaining two patients, pulmonary function tests were not performed, but the clinical response following theophylline therapy was documented. RESULTS Evaluation of dynamic lung compliance and pulmonary resistance after 24 hours of theophylline therapy revealed that all neonates less than 30 days of age who had pulmonary function tests had improvement in these values. For this reason, all patients were divided into two groups for analysis: those less than 30 days of age (younger) and those greater than 30 days of age (older). There were five infants in the younger group and six infants in the older group. Table I summarizes the clinical data for the two groups. Birth weights were similar and, as expected, the older group weighed twice as much when studied. The younger infants were mechanically ventilated for 22 days (mean) and the older infants for 59 days (mean). Table II shows serum theophylline levels for the two groups at two and 24 hours after intravenous administration of aminophylline. The mean serum theophylline values obtained in this study were within the range recommended as therapeutic for neonatal apnea. ~ These values are lower than levels recommended for the treatment of asthma in adults because there is decreased serum protein binding of theophylline in the neonate. 4 Fig. 1 demonstrates mean values for dynamic lung compliance at control, two hours and 24 hours for the two groups of patients. The younger patients had a trend toward increase in compliance after infusion of aminophylline. At two and 24 hours, respectively, the compliance increased by 153% and 294% compared to
Table II. Serum theophylline levels
Age Younger < 30 days Older > 30 days
Mean serum theophylline (rag~l) at 2 hr
Mean serum theophylline (rag~l) at 24 hr
6.08 (N = 4)
7.30 (N = 3)
5.50 (N = 3)
8.30 (N = 6)
control. The older infants showed a trend toward decrease in compliance of 25% at 24 hours. Fig. 2 shows a trend toward decrease in both inspiratory and expiratory resistance for the younger infants. The younger infants had a 68% decrease in inspiratory and a 67% decrease in expiratory resistance at 24 hours. There was either no resistance change or a trend toward increase in older patients after aminophylline therapy. The older infants showed a 38% increase in inspiratory resistance and a 4% decrease in expiratory resistance at 24 hours. There were no significant changes in either arterial Pco~ or respiratory rate in any of the patients after administration of theophylline. Clinically, four of the five younger patients were weaned from the respirator to continuous positive airway pressure within 72 hours of theophylline therapy. Two of these four were weaned from the respirator within 24 hours of theophylline therapy. The fifth patient developed sepsis and subsequently died. The older patients showed a variable clinical response. One patient was weaned to continuous positive airway pressure after 48 hours of theophylline therapy. Two were weaned to continuous positive airway pressure seven days after theophylline therapy. The remaining three infants continued to require the same level of respiratory support as before the study. Theophylline therapy was continued
884
Workshop on B P D
The Journal of Pediatrics November 1979
6i
200 n
"I" 4 E
n~
100
Y
E
~
0
Y
I
!
I
0
2
24
O I
I
I
0
2
24
T I M E , hrs
Fig. 1. Changes in dynamic lung compliance (C~) in younger (Y = 30 days) infants with bronchopulmonary dysplasia treated with intravenous aminophylline. for 39 days (mean) for the younger group and 64 days (mean) for the older group.
o9
soo r
hE
400
300
200 LU n-
DISCUSSION This study suggests that theophylline may be beneficial for decreasing airway resistance, increasing dynamic compliance, and shortening duration of ventilator weaning of infants less than 30 days of age with bronchopulmonary dysplasia. The five younger infants were weaned from mechanical ventilation within 72 hours of therapy. Three of six older patients were weaned from mechanical ventilation within seven days of theophylline therapy. One previous study demonstrated decreased lung compliance, decreased functional residual capacity, and CO2 retention in infants with bronchopulmonary dysplasia? These findings suggest that increased airway resistance is an important feature of this disease. However, theophylline has not been widely used in infants with bronchopulmonary dysplasia because of the belief that the quantity of smooth muscle in the Mrways of infants is minimal. One investigator suggested that the bronchiolar smooth muscle is "feebly developed" in younger infants. 6 Other studies have reported that nebulized salbutamol, a specific beta-2 bronchodilator, did not lower airway resistance in infants less than 6 months of age with an acute viral infection. 7' ~ An additionai study by Matsubo and Thurlbeck" revealed a relative decrease in the percent of smooth muscle in the small airways of children. However, none of the patients in the above studies had bronchopulmonary dysplasia. In contras3~to the small amount of smooth muscle in the airways of healthy infants, Rosan 1~reported that bronchiolat smooth muscle swelling and hypertrophy are two major histologic features of infants lungs with hyaline membrane disease
100
O
I
I
I
0
2 TIME, hrs
24
Fig. 2. Changes in inspiratory (RE) and expiratory (RE) pulmonary resistance in younger (Y = 30 days) infants with bronchopulmonary dysplasia following intravenous administration of aminophylline. treated with mechanical ventilation and high inspired oxygen concentrations. These findings can be seen as early as three to five days after the onset of ventilatory support with high inspired oxygen concentration. The increased airway resistance in infants with bronchopulmonary d y s p l a ~ is partly due to smooth muscle hypertrophy in the:gmali airways. If variable airway obstruction exists throughout the lungs, different lung units have different ventilatory time constants with maldistribution of ventilation. Dynamic lung compliance is affected by lowered functional residual capacity and maldistribution of ventilation. The low dynamic lung compliance seen in the infants presented in this study ~f most like!y occurred because of airway occlusion from either smooth muscle spasm or hypertrophy. In the younger infants with bronchopulmonary dysplasia, theophylline may have alleviated airway obstruction by relaxing smooth muscle, thus improving distribution of ventilation and dynamic lung compliance. The diminished effectiveness of theophylline in the older group of infants
Volume 95 Number 5, part 2
may have been due to extensive pulmonary fibrosis which caused less reversibility of airway obstruction. The effect of theophylline as a smooth muscle relaxant is usually attributed to its ability to enhance intracellular levels of cyclic 3',5' adenosine monophosphate. Theophylline inhibits phosphodiesterase, the enzyme responsible for converting active cyclic A M P to inactive 5'AMP. There appears to be a relationship between levels of cyclic A M P and the degree of smooth muscle relaxation. T M 12 Although there is some evidence that theophylline accelerates lung maturation by increasing cyclic A M P levels, '3 it is doubtful that significant lung maturation occurred during the 24 hours of pulmonary function measurements. In contrast to a previous study, TM there were no significant changes seen in either arterial Pco2 or respiratory rate in any of the patients after administration of theophylline. This study suggests that a trial of theophylline may be indicated in all infants who are ventilator dependent with bronchopulmonary dysplasia. There is a wide spectrum of pulmonary fibrosis in patients with b r o n c h o p u l m o n a r y dysplasia, and theophylline appears to be most effective in those infants with the least fibrosis. The decision to use theophylline should be individualized for each patient and should depend on several factors, including the clinical course, radiographic changes, and the type and degree of ventilatory support required by each patient. REFERENCES
1. Coates AL, Bergsteinsson H, Desmond K, Outerbridge EW, and Beaudry PH: Long-term pulmonary sequelae of premature birth with and without idiopathic respiratory distress syndrome, J PEDIATR90"611, 1977. 2. Fox WW: Bronchopulmonary dysplasia (respirator lung syndrome): Clinical course and outpatient therapy, Pediatr Ann 7:40, 1978.
BPD: Causes, prevention, and therapy
885
3. Shannon DC, Gotay F, Stein IM, Rogers MC, Todres ID, and Moylan FMB: Prevention of apnea and bradycardia in low birthweight infants, Pediatrics 55:589, 1975. 4. Aranda JV, Sitar DS, Parsons WD, Loughnan PM, and Neims AH: Pharmacokinetic aspects of theophylline in premature newborns, N Engl J Med 295:413, 1976. 5. Bryan MH, Hardie MI, Reilly B J, and Swyer PR: Pulmonary function studies during the first year of life in infants recovering from respiratory distress syndrome, Pediatrics 52:169, 1973. 6. Engel S: Lung structure, Springfield, Ill., 1962, Charles C Thomas, Publisher, p 27. 7. Rutter N, Milner AD, and Hiller EJ: Effect of bronchodilators on respiratory resistance in infants and younger children with bronchiolitis and wheezy bronchitis, Arch Dis Child 50:719, 1975. 8. Radford M: Effect of nebulized salbutamol in infants with wheezy bronchitis, Arch Dis Child 49"243, 1974. 9. Matsubo K, and Thurlbeck WM: A morphometric study of bronchial and bronchiolar walls in children, Am Rev Resp Dis 105:908, 1972. 10. Rosan RC: Hyaline membrane disease and a related spectrum of neonatal pneumopathies: The relationship of normal to diseased neonatal lung, in Rosenberg HS, and Bolande RP, editors, Perspectives in pediatric pathology, Vol 2, Chicago, 1975, Yearbook Medical Publishers Inc., p 35. 11. Anderson RGG: Cyclic AMP and calcium ions in mechanical and metabolic responses of smooth muscles; influence of some hormones and drugs, Acta Physiol Scand 382(Suppl): 1, 1972. 12. Sutherland EW, Robison GA, and Butcher RW: Some aspects of the biological role of adenosine 3',5'-monophosphate (cyclic AMP), Circulation 37:279, 1968. 13. Barret CT, Sevanian A, Phelps DL, Gilden C, and Kaplan SA: Effects of cortisol and aminophylline upon survival, pulmonary mechanics, and secreted phosphatidyl choline of prematurely delivered rabbits, Pediatr Res 12:38, 1978. 14. Barr PA: Weaning very low birthweight infants from mechanical ventilation using intermittent mandatory ventilation and theophylline, Arch Dis Child 53:598, 1978.
BPD--causes, prevention, and therapy: Discussion Dr. Philip Farrell, Moderator
DR. NELSON: IS it really possible to ventilate an infant of less than 1,000 gm in a negative pressure respirator without excessive trauma, cooling, and so on? DR. STERN: The negative pressure respirator was not used for this group of very low-birth-weight infants at my previous insti.tution (McGill University); however, it is
0022-3476/79/110885 +04500.40/0 9 1979 The C. V. Mosby Co.
feasible to use this approach~ which is presently being utilized at Brown University. DR. JAMES: What pressures were being used in your evaluation of negative pressure respirators? DR. STERN: The readings on the pressure gauge generally ranged from 40 to 50 cm, but there were leaks in the
