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Successful extubation of infants with respiratory distress syndrome using aminophylline
Clinical and laboratory observations
Successful extubation of infants with respiratory distress syndrome using aminophylline Mary Catherine Harris, M.D., Stephen Baumgart, M.D., Anthony R. Rooklin, M.D., and William W. Fox, M.D. Philadelphia, Pa.
METHYLXANTHINES (aminophylline, theophylline, and caffeine) have been demonstrated to be effective in the therapy of respiratory insufficiency resulting from apnea of prematurity). 2 Theophylline has been shown to improve lung compliance and to reduce expiratory resistance in infants during the early phase of evolving bronchopulmonary dysplasia.3 In these infants with bronchopulmonary dysplasia, four of five patients younger than 1 month were successfully weaned to endotracheal continuous end expiratory pressure within 72 hours of theophylline administration? To date, there have been no controlled studies to evaluate the use of aminophylline for extubating infants with respiratory distress syndrome from mechanical ventilation. The purpose of our study was to evaluate the effectiveness of aminophylline for successfully extubating infants recovering from respiratory distress syndrome. METHODS
AND PATIENTS
Ten premature neonates and 10 Control infants were entered in the study. Criteria for entry were (1) less than 36 weeks gestation, (2) clinical diagnosis of respiratory distress syndrome, (3) dependence on intermittent mandatory ventilation with a rate requirement of less than 15 breaths per minute or continuous positive airway pressure within 24 hours of trial, (4) failure to wean from the ventilator for 24 hours or more prior to study. Informed parental consent was obtained prior to entry into the study protocol. Ten control infants with similar diagnosis and clinical
From the Division of Neonatology, The Children's Hospital of Philadelphia; and the Department of Pediatrics, University of Pennsylvania School of Medicine. Reprint requests: Mary Catherine Harris, M.D., Division of Neonatology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
course were selected retrospectively from chart reviews and matched for birth weight, gestational age, age at the time of study, and extent of ventilatory support. At the time of entrance into the study, there were no significant differences between the two groups when compared for birth weight (1340 _+ 90 gm vs 1370 _+ 100 gm, study vs control, mean _+ SEM), gestational age (31 _+ 2 weeks vs 31 _+ 1 weeks), study age (10 + 2 days vs 11 _+ 2 days), percent on intermittent mandatory ventilation within 24 hours prior to enrollment (80% vs 90%), fraction of inspired oxygen (0.30 _+ 0.02 vs 0.30 _+ 0.03), end expiratory pressure (3.5 ___ 0.2 cm HzO vs 3.4 + 0.3 cm H~O), peak inspiratory pressure (16 ___ 1 cm H20 vs 15 _+ 1 cm H20), IMV (6 _+ 2 bpm vs 10 _ 11 bpm), initial arterial oxygen tension (67 _+ 6 mm Hg vs 63 + 4 mm Hg), initial arterial carbon dioxide tension (49 _+ 3 mm Hg vs 45 _+ 2 mm Hg), and alveolar-arterial oxygen gradient (196 ___ 65 mm Hg vs 187 + 20 mm Hg). Vital signs and the following pulmonary function tests were evaluated in the study infants prior to the initiation of aminophylline therapy: heart rate, respiratory rate, arterial blood gas sampling for pH, carbon dioxide tension and oxygen tension, dynamic lung compliance, inspiratory and expiratory pulmonary resistances, tidal volume, and minute ventilation (methods previously reported3). Control infants did not receive pulmonary function testing. After pulmonary function tests, study infants received a 7 mg/kg loading dose of aminophylline intravenously over 20 to 30 minutes, followed by maintenance therapy, aminophylline intravenously or theophylline orally, 1 to 2 mg/kg every eight hours. Doses were adjusted to maintain blood concentrations between 8 and 12 t~g/ml) At 2 and 24 hours following the initial loading dose of aminophylline, pulmonary function tests were repeated. In addition, blood for theophylline concentration was drawn at 2 and 24 hours. Results of all clinical and laboratory measurements TheJournalofPEDIATRlCS Vol. 103, No. 2, August 1983
303
304
Clinical and laboratory observations
The Journal of Pediatrics August 1983
ii = =
Study
I nfonts (n:lO) ooq
0
i
i
I
2
t
Aminophylline
BPD
i
14 Days
Cant rol Infants (n=lO) ooe ooo
o
i
Ib
BPD BPD
l'l
Days
Figure. Time to successful extubation in study infants (aminophylline treated) and in control infants with respiratory distress syndrome. BPD, Bronchopulmonary dysplasia.
were averaged and compared using a dependent Student t test. Successful tracheal extubation by 72 hours following entry into the study was compared in study and control groups using a one-tailed Fisher exact test. RESULTS 9 Eight of 10 study infants were successfully extubated within 72 hours after the initiation of aminophylline therapy, whereas only two control infants were extubated during the study period (P < 0.02). Four of the study infants were extubated by 24 hours, three by 48 hours, and one by 72 hours (Figure). Two control infants were extubated by 48 hours after entry into the study. One was extubated on day 4, and five more control infants were extubated between 7 and 12 days. The remaining two infants required endotracheal intubation and respiratory support for more than two weeks following entry into the control group. Results of pulmonary function testing in the study group prior to the aminophylline loading dose and at 2 and 24 hours after the initial dose demonstrated a significant decrease in the arterial tension (r~ean + SEM) of carbon dioxide for both the two hour (43 +_ 3 mm Hg) and the 24 hour (41 ___ 2 mm Hg) samples as compared with the CO2 tension prior to the initiation of aminophylline therapy (49 • 3 mm Hg, P < 0.01). In the study group, pH (mean _+ SEM) was significantly higher at both 2 and 24
hours following the aminophylline loading dose, compared with the preaminophylline value (7.32 _+ 0.02 vs 7.36 • 0.01 and 7.37 • 0.01, respectively; P < 0.01). This change in pH was secondary to the observed Paco2 decreases at 2 and 24 hours. There was no significant increase in minute ventilation (mean + SEM) at 2 hours following the loading dose of aminophylline; however, by 24 hours, minute ventilation was significantly increased from the preaminophylline value of 333 + 70 ml/min to 467 + 80 ml/min ( P < 0 . 0 5 ) . The increase in minute ventilation was observed concurrently with an increase in respiratory rate from 61 + 6 ~!bm to 74 + 5 bpm at 24 hours (P < 0.05), but tidal volume did not change significantly (5.3 • 0.7 ml prior to loading, 5.7 ___ 0.6 ml at 2 hours, and 6.7 ___ 0.9 ml 24 hours after therapy was begun). Dynamic lung compliance, inspiratory resistance, and expiratory resistance were not significantly altered by aminophylline therapy. Arterial oxygen tension was also unchanged. Mean theophylline ooncentration at two hours was 5.7 ___ 0.8 #g/ml and at 24 hours was 7.2 _+ 0.6/~g/ml. DISCUSSION This preliminary study suggests that aminophylline therapy in LBW infants facilitates weaning from mechanical ventilation and endotracheal extubation during the recovery phase of respiratory distress syndrome. Pulmonary functiontests in the group of infants receiving
Volume 103 Number 2
aminophylline demonstrated decreased Paco2, increased minute ventilation, and increased respiratory rate, as compared with Pretreatment values. One explanation for the successful extubation of infants after aminophylline therapy is suggested by the increase in minute ventilation coinciding with a decrease in arterial carbon dioxide tension in treated infants. Theophylline increases metabolic rate in animals,4 decreases apnea, 1"5'6 increases respiratory muscle efficiency, 7 and increases central COz responsivenessY~ Improved ventilatory response to lower carbon dioxide levels suggests that aminophylline stimulates the central nervous system chemoreceptors for CO2 response? This hypothesis is consistent with the observation that many very LBW infants appear apneic when ventilated at rates less than 6 bpm, but when given aminophylline, may improve sufficiently to be extubated. A previous study of infants with bronchopulmonary dysplasia3 suggested that theophylline relaxed smooth muscle in hypertrophied small bronehioles. The infants in our study did not demonstrate clinical, radiographic, or pulmonary function evidence of bronchopulmonary dysplasia, and therefore smooth muscle relaxation is an unlikely explanation for the improvement observed. Aminophylline therapy allowed weaning of LBW infants with respiratory distress syndrome from low levels of mechanical ventilatory support and successful endotracheal extubation of most treated patients. Methylxanthine therapy should be considered to promote weaning of infants with respiratory distress syndrome from low rates of ventilatory support and to facilitate extubation.
Clinical and laboratory observations
30 5
REFERENCES 1. Aranda .IV, Turmen T: Methylxanthines in apnea of prematurity. Clin Perinatol 6:87, 1979. 2. Daily WJR, Klaus M, Meyer HBP: Apnea in premature infants: Monitoring, incidence, heart rate changes and an effect of environmental temperature. Pediatrics 43:510, 1969. 3. Rooklin AR, Moomjian AS, Shutack JG, Schwartz JG, Fox WW: Theophyllinetherapy in bronchopulmonarydysplasia. J P~DIATR95:882, 1979. 4. Thurston JH, Hauhart RE, Dirgo JA: Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice. Science 201:649, 1978. 5. Aranda .IV, Grondin D, Sasyniuk BI: Pharmacologic considerations in the therapy of neonatal apnea. Pediatr Clin North Am 28:113, 1981. 6. Bednarek F.I, Roloff DW: Treatment ofapnea of prematurity with aminophylline. Pediatrics 58:335, 1976. 7. Aubier M, Detroyer A, Sampson M, Maklim PT, Ronssoc C: Amonophyllineimprovesdiaphragmatic contractility. N Engl .I Med 305:249, 1981. 8. Aranda .IV, Zinman R, Collinge J, Outerbridge EW: Effect of caffeine on control of ventilation in premature infants with apnea. Clin Pharmacol Ther 25:212, 1979. 9. Gerhardt T, McCarthy J, Bancalari E: Effect of aminophylline on respiratory center activity and metabolic rate in premature infants with idiopathic apnea. Pediatrics 63:537, 1979. 10. Davi MJ, Sankaran K, Simons KJ, Simons ER, Seshia MM, Rigatto H: Physiologicchanges induced by theophyllinein the treatment of apnea in preterm infants. J PEDIATR 92:91, 1978.
Effects of vitamin D and phosphorus supplementation on calcium retention in preterm infants fed banked human milk J. Senterre, M.D., Ph.D., G. Putet, M.D., B. Salle, M.D., and J. Rigo, M.D. Libge, B e l g i u m , and Lyon, France
THE ADEQUACY of mineral and vitamin D content of human milk for feeding preterm infants is still a matter for discussion. 1-5 The aim of our study was to investigate, by
metabolic balance studies, the effects of vitamin D and phosphorus supplementation on calcium absorption and retention in preterm infants fed banked human milk. SUBJECTS AND METHODS
From the Department of Pediatrics, State University of Libge, and the Department of Neonatology, Hbpital Herriot, University of Lyon. Reprint requests: J. Senterre, M.D., Department of Pediatrics, Division of Neonatology, State University of Libge, Hbpital de Bavibre, B 4020 Libge, Belgium.
Thirty 3-day metabolic balance studies were carried out in three groups of 10 preterm infant boys with birth weights <1500 gm (mean 1275 + 150 gm). All infants were appropriate for gestational age (30.0 _+ 1 week). They were free from congenital abnormalities and did not
Successful extubation of infants with respiratory distress syndrome using aminophylline Mary Catherine Harris, M.D., Stephen Baumgart, M.D., Anthony R. Rooklin, M.D., and William W. Fox, M.D. Philadelphia, Pa.
METHYLXANTHINES (aminophylline, theophylline, and caffeine) have been demonstrated to be effective in the therapy of respiratory insufficiency resulting from apnea of prematurity). 2 Theophylline has been shown to improve lung compliance and to reduce expiratory resistance in infants during the early phase of evolving bronchopulmonary dysplasia.3 In these infants with bronchopulmonary dysplasia, four of five patients younger than 1 month were successfully weaned to endotracheal continuous end expiratory pressure within 72 hours of theophylline administration? To date, there have been no controlled studies to evaluate the use of aminophylline for extubating infants with respiratory distress syndrome from mechanical ventilation. The purpose of our study was to evaluate the effectiveness of aminophylline for successfully extubating infants recovering from respiratory distress syndrome. METHODS
AND PATIENTS
Ten premature neonates and 10 Control infants were entered in the study. Criteria for entry were (1) less than 36 weeks gestation, (2) clinical diagnosis of respiratory distress syndrome, (3) dependence on intermittent mandatory ventilation with a rate requirement of less than 15 breaths per minute or continuous positive airway pressure within 24 hours of trial, (4) failure to wean from the ventilator for 24 hours or more prior to study. Informed parental consent was obtained prior to entry into the study protocol. Ten control infants with similar diagnosis and clinical
From the Division of Neonatology, The Children's Hospital of Philadelphia; and the Department of Pediatrics, University of Pennsylvania School of Medicine. Reprint requests: Mary Catherine Harris, M.D., Division of Neonatology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
course were selected retrospectively from chart reviews and matched for birth weight, gestational age, age at the time of study, and extent of ventilatory support. At the time of entrance into the study, there were no significant differences between the two groups when compared for birth weight (1340 _+ 90 gm vs 1370 _+ 100 gm, study vs control, mean _+ SEM), gestational age (31 _+ 2 weeks vs 31 _+ 1 weeks), study age (10 + 2 days vs 11 _+ 2 days), percent on intermittent mandatory ventilation within 24 hours prior to enrollment (80% vs 90%), fraction of inspired oxygen (0.30 _+ 0.02 vs 0.30 _+ 0.03), end expiratory pressure (3.5 ___ 0.2 cm HzO vs 3.4 + 0.3 cm H~O), peak inspiratory pressure (16 ___ 1 cm H20 vs 15 _+ 1 cm H20), IMV (6 _+ 2 bpm vs 10 _ 11 bpm), initial arterial oxygen tension (67 _+ 6 mm Hg vs 63 + 4 mm Hg), initial arterial carbon dioxide tension (49 _+ 3 mm Hg vs 45 _+ 2 mm Hg), and alveolar-arterial oxygen gradient (196 ___ 65 mm Hg vs 187 + 20 mm Hg). Vital signs and the following pulmonary function tests were evaluated in the study infants prior to the initiation of aminophylline therapy: heart rate, respiratory rate, arterial blood gas sampling for pH, carbon dioxide tension and oxygen tension, dynamic lung compliance, inspiratory and expiratory pulmonary resistances, tidal volume, and minute ventilation (methods previously reported3). Control infants did not receive pulmonary function testing. After pulmonary function tests, study infants received a 7 mg/kg loading dose of aminophylline intravenously over 20 to 30 minutes, followed by maintenance therapy, aminophylline intravenously or theophylline orally, 1 to 2 mg/kg every eight hours. Doses were adjusted to maintain blood concentrations between 8 and 12 t~g/ml) At 2 and 24 hours following the initial loading dose of aminophylline, pulmonary function tests were repeated. In addition, blood for theophylline concentration was drawn at 2 and 24 hours. Results of all clinical and laboratory measurements TheJournalofPEDIATRlCS Vol. 103, No. 2, August 1983
303
304
Clinical and laboratory observations
The Journal of Pediatrics August 1983
ii = =
Study
I nfonts (n:lO) ooq
0
i
i
I
2
t
Aminophylline
BPD
i
14 Days
Cant rol Infants (n=lO) ooe ooo
o
i
Ib
BPD BPD
l'l
Days
Figure. Time to successful extubation in study infants (aminophylline treated) and in control infants with respiratory distress syndrome. BPD, Bronchopulmonary dysplasia.
were averaged and compared using a dependent Student t test. Successful tracheal extubation by 72 hours following entry into the study was compared in study and control groups using a one-tailed Fisher exact test. RESULTS 9 Eight of 10 study infants were successfully extubated within 72 hours after the initiation of aminophylline therapy, whereas only two control infants were extubated during the study period (P < 0.02). Four of the study infants were extubated by 24 hours, three by 48 hours, and one by 72 hours (Figure). Two control infants were extubated by 48 hours after entry into the study. One was extubated on day 4, and five more control infants were extubated between 7 and 12 days. The remaining two infants required endotracheal intubation and respiratory support for more than two weeks following entry into the control group. Results of pulmonary function testing in the study group prior to the aminophylline loading dose and at 2 and 24 hours after the initial dose demonstrated a significant decrease in the arterial tension (r~ean + SEM) of carbon dioxide for both the two hour (43 +_ 3 mm Hg) and the 24 hour (41 ___ 2 mm Hg) samples as compared with the CO2 tension prior to the initiation of aminophylline therapy (49 • 3 mm Hg, P < 0.01). In the study group, pH (mean _+ SEM) was significantly higher at both 2 and 24
hours following the aminophylline loading dose, compared with the preaminophylline value (7.32 _+ 0.02 vs 7.36 • 0.01 and 7.37 • 0.01, respectively; P < 0.01). This change in pH was secondary to the observed Paco2 decreases at 2 and 24 hours. There was no significant increase in minute ventilation (mean + SEM) at 2 hours following the loading dose of aminophylline; however, by 24 hours, minute ventilation was significantly increased from the preaminophylline value of 333 + 70 ml/min to 467 + 80 ml/min ( P < 0 . 0 5 ) . The increase in minute ventilation was observed concurrently with an increase in respiratory rate from 61 + 6 ~!bm to 74 + 5 bpm at 24 hours (P < 0.05), but tidal volume did not change significantly (5.3 • 0.7 ml prior to loading, 5.7 ___ 0.6 ml at 2 hours, and 6.7 ___ 0.9 ml 24 hours after therapy was begun). Dynamic lung compliance, inspiratory resistance, and expiratory resistance were not significantly altered by aminophylline therapy. Arterial oxygen tension was also unchanged. Mean theophylline ooncentration at two hours was 5.7 ___ 0.8 #g/ml and at 24 hours was 7.2 _+ 0.6/~g/ml. DISCUSSION This preliminary study suggests that aminophylline therapy in LBW infants facilitates weaning from mechanical ventilation and endotracheal extubation during the recovery phase of respiratory distress syndrome. Pulmonary functiontests in the group of infants receiving
Volume 103 Number 2
aminophylline demonstrated decreased Paco2, increased minute ventilation, and increased respiratory rate, as compared with Pretreatment values. One explanation for the successful extubation of infants after aminophylline therapy is suggested by the increase in minute ventilation coinciding with a decrease in arterial carbon dioxide tension in treated infants. Theophylline increases metabolic rate in animals,4 decreases apnea, 1"5'6 increases respiratory muscle efficiency, 7 and increases central COz responsivenessY~ Improved ventilatory response to lower carbon dioxide levels suggests that aminophylline stimulates the central nervous system chemoreceptors for CO2 response? This hypothesis is consistent with the observation that many very LBW infants appear apneic when ventilated at rates less than 6 bpm, but when given aminophylline, may improve sufficiently to be extubated. A previous study of infants with bronchopulmonary dysplasia3 suggested that theophylline relaxed smooth muscle in hypertrophied small bronehioles. The infants in our study did not demonstrate clinical, radiographic, or pulmonary function evidence of bronchopulmonary dysplasia, and therefore smooth muscle relaxation is an unlikely explanation for the improvement observed. Aminophylline therapy allowed weaning of LBW infants with respiratory distress syndrome from low levels of mechanical ventilatory support and successful endotracheal extubation of most treated patients. Methylxanthine therapy should be considered to promote weaning of infants with respiratory distress syndrome from low rates of ventilatory support and to facilitate extubation.
Clinical and laboratory observations
30 5
REFERENCES 1. Aranda .IV, Turmen T: Methylxanthines in apnea of prematurity. Clin Perinatol 6:87, 1979. 2. Daily WJR, Klaus M, Meyer HBP: Apnea in premature infants: Monitoring, incidence, heart rate changes and an effect of environmental temperature. Pediatrics 43:510, 1969. 3. Rooklin AR, Moomjian AS, Shutack JG, Schwartz JG, Fox WW: Theophyllinetherapy in bronchopulmonarydysplasia. J P~DIATR95:882, 1979. 4. Thurston JH, Hauhart RE, Dirgo JA: Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice. Science 201:649, 1978. 5. Aranda .IV, Grondin D, Sasyniuk BI: Pharmacologic considerations in the therapy of neonatal apnea. Pediatr Clin North Am 28:113, 1981. 6. Bednarek F.I, Roloff DW: Treatment ofapnea of prematurity with aminophylline. Pediatrics 58:335, 1976. 7. Aubier M, Detroyer A, Sampson M, Maklim PT, Ronssoc C: Amonophyllineimprovesdiaphragmatic contractility. N Engl .I Med 305:249, 1981. 8. Aranda .IV, Zinman R, Collinge J, Outerbridge EW: Effect of caffeine on control of ventilation in premature infants with apnea. Clin Pharmacol Ther 25:212, 1979. 9. Gerhardt T, McCarthy J, Bancalari E: Effect of aminophylline on respiratory center activity and metabolic rate in premature infants with idiopathic apnea. Pediatrics 63:537, 1979. 10. Davi MJ, Sankaran K, Simons KJ, Simons ER, Seshia MM, Rigatto H: Physiologicchanges induced by theophyllinein the treatment of apnea in preterm infants. J PEDIATR 92:91, 1978.
Effects of vitamin D and phosphorus supplementation on calcium retention in preterm infants fed banked human milk J. Senterre, M.D., Ph.D., G. Putet, M.D., B. Salle, M.D., and J. Rigo, M.D. Libge, B e l g i u m , and Lyon, France
THE ADEQUACY of mineral and vitamin D content of human milk for feeding preterm infants is still a matter for discussion. 1-5 The aim of our study was to investigate, by
metabolic balance studies, the effects of vitamin D and phosphorus supplementation on calcium absorption and retention in preterm infants fed banked human milk. SUBJECTS AND METHODS
From the Department of Pediatrics, State University of Libge, and the Department of Neonatology, Hbpital Herriot, University of Lyon. Reprint requests: J. Senterre, M.D., Department of Pediatrics, Division of Neonatology, State University of Libge, Hbpital de Bavibre, B 4020 Libge, Belgium.
Thirty 3-day metabolic balance studies were carried out in three groups of 10 preterm infant boys with birth weights <1500 gm (mean 1275 + 150 gm). All infants were appropriate for gestational age (30.0 _+ 1 week). They were free from congenital abnormalities and did not