- Email: [email protected]
The therapeutic actions of theophylline in preterm ventilated infants
Early Human Development, Elsevier
15
12 (1985) 15-22
EHD 00681
The therapeutic actions of theophylline in preterm ventilated infants Anne Greenough,
A. Elias-Jones,
Department
J. Pool, C.J. Morley and J.A. Davis
of Paediatrics, University of Cambridge, Cambudge, U.K. Accepted
for publication
17 May 1985
Summary
40 preterm, ventilated infants (gestational ages 24-33 weeks) were entered into a double-blind randomised trial to assess the effect of oral theophylline on lung function and ventilator dependence. Theophylline administration was associated with a significant improvement in compliance (P < 0.05) and hastened weaning from ventilation (P < 0.01).
theophylline;
artificial
ventilation;
premature
babies
Introduction Methylxanthines are useful in the prophylaxis of apnoea in preterm infants [22] and are effective given orally [23]. Preliminary evidence suggests that they may also have a role in weaning infants from artificial ventilation [2]. In a pilot, nonrandomised study we had previously found that theophylline given orally to preterm ventilated neonates increased compliance compared to matched controls [lo] and in some reduced the duration of ventilator support. We now report the results of a double-blind randomised trial which assessed the effects of oral theophylline on lung function and dependence on artificial ventilation.
Address for correspondence: Dr. Anne Greenough. Denmark Hill, London. U.K.
0378-3782/85/$03.30
Department
0 1985 Elsevier Science Publishers
of Child Health.
B.V. (Biomedical
King’ College
Division)
Hospital.
16
Methods and patients Infants were entered into the trial if they fulfilled the following criteria: (1) gestational age less than 34 weeks; (2) postnatal age less than 10 days; (3) ventilated for RDS and no longer receiving paralysing agents; (4) no known cardiac abnormality; (5) respiratory distress improving, enabling ventilator settings to be reduced to a peak pressure of 20 cm H,O and a rate of 20/min. The policy of the NICU to wean infants from ventilation once their RDS has started to improve, is first to reduce the peak pressures to 20 cm H,O and then to reduce the rates. (6) AG present to make the respiratory measurements. On entry to the study the infant was assigned his or her own bottle of ‘theophylline trial solution’. These had been made up by the hospital pharmacy and contained either theophylline in a concentration of 5 mg/ml and vehicle or simply vehicle alone. Both formed a clear solution and were indistinguishable. 50 bottles were randomised by the pharmacy who kept the code which was not released until the end of the trial. The prescriber (A.G.) and the clinical team were unaware of which treatment the infant received. The infant was prescribed a loading dose of 1 ml/kg of the trial solution, this meant infants receiving the active solution would receive a loading dose of theophylline of 5 mg/kg. Subsequently infants were prescribed 1 ml/kg per day in 4 divided doses; the second dose was not given until 6 h after the loading dose. The trial solution was given orally via a nasogastric tube without milk. The trial solution was discontinued: (1) if side-effects occurred; (2) 48 h after artificial ventilation was stopped; (3) if, after 48 h of treatment with the trial solution, there was no improvement in the infant’s clinical condition, that is no reduction in ventilator settings. Blood samples were taken via an indwelling arterial catheter inserted for clinical purposes, for theophylline assay by A. E.-J. [5], who altered subsequent doses of the trial solution to keep the theophylline concentration within the therapeutic range, 5-13 mg/l. Doses of the placebo solution were also altered so that it was not apparent which infants were receiving the active solution. Both the clinicians and A.G. were kept ‘blind’. Respiratory function was measured in all infants at trial entry, immediately prior to the first dose and then at 30 min and 1, 2, 3 and 6 h later, using equipment described previously [ll]. To assess lung function, static compliance was used while the infants remained ventilated except where an accurate measurement was impossible due to active expiration [12], in such circumstances dynamic compliance was used. Static compliance was measured using the peak pressure inflation maintained at a plateau for 0.5 s and the resultant volume change. Once ventilation had been discontinued dynamic compliance was measured using a pneumotachograph inserted into a tightly fitting face mask and an oesophageal balloon, the accuracy of the oesophageal pressure measurements was assessed by an occlusion test [3]. Arterial blood gases were assessed approximately 30-40 min after trial entry and similiarly after each change in ventilator rate, as was the NICU’s policy. Reductions in ventilator rate were made if there was evidence of a respiratory alkalosis (PaCO, < 40 mm Hg). Otherwise, in infants who were clinically stable, arterial blood
17
gases were checked 4-hourly, as our usual practice, in the presence of continuous oxygen monitoring (either transcutaneously or via an indwelling arterial electrode). The usual NICU’s policy of weaning was followed [20], that is, reduction of rate in 5 breaths/min stages to endotracheal CPAP, the infant finally being extubated once satisfactory blood gases had been confirmed. The larger infants, establishing vigorous respiration sooner, were extubated from IMV, once showing regular respiration and satisfactory blood gases. This policy was adopted for both of the trial groups. as the clinicians supervising the weaning process were of course unaware of to which trial group a particular infant belonged. The effect of theophylline was assessed by comparing the compliance of the two groups both at trial entry and six hours later and the length of time on ventilation from administration of the trial solution each required. Side-effects possibly caused by the theophylline were noted, but are reported elsewhere in detail (5).
Trial design The study was designed to detect a difference in compliance of 0.3 ml/cm Hz0 with a standard difference of 0.3 ml/cm H,O at the 5% level. Results from the pilot study had suggested that such a worthwhile improvement in compliance could occur following treatment with theophylline [lo]. 40 patients would be required to detect a difference of this order with an 85% power at the 5% level. Consequently the randomisation code was not broken until 40 infants had been entered into the trial.
Patients 40 infants were included in the study. Two infants were withdrawn from the trial within 4 h of entry (see Results), consequently their results were not included in the analysis. The clinical characteristics of the remaining 38 infants are shown in Table I. The two trial groups were well matched for gestational age, birthweight, sex and lung function at trial entry. Although those infants receiving the theophylline were on average one day younger than the ‘controls’ (see Table I), this did not reach statistical significance. Neither was there a significant difference between the two groups in the incidence of complications likely to affect the length of ventilator
TABLE
1
Clinical
characteristics Theophylline
Gestational age (wk) Birthweight (kg) Postnatal age at trial entry(h) Males Compliance at trial entry (ml/cm
H,O)
Values are mean & S.D.
29.8 1448 91.6 13 0.67+
(18)
+ 2.4 +503 k 12.9
0.35
Control
(20)
29.5 1423 111.0 15
k 2.3 k492 + 75.6
0.63+
0.26
18 TABLE
II
Complications Theophylline Pneumothorax IVH Had received pancuronium prior to trial entry (18) Given artificial surfactant at birth (14)
dependence Committee.
(18)
Control
5 3
7 4
12
8
3
4
(see Table II). This study was approved
(20)
by the Cambridge
Ethical
Statistical methods Student’s t-test, the Wilcoxon rank sum test and the x2-test with Yate’s correction as necessary were used.
Results
Withdrawls Two infants were withdrawn from the study within the first 4 h. One infant of 24 weeks gestation developed a tachycardia of greater than 200 beats/min and the other (gestational age 31 weeks, postnatal age 5 h), became agitated and to improve ventilation had to be paralysed. Both these infants had received the active solution. During the course of the study there were no other serious side-effects. Compliance measurements The compliance results from the remaining 38 infants were analysed. In all cases it was possible to make accurate static compliance measurements during ventilation and these were used in the analysis. Dynamic compliance measurements were used in the only two infants extubated within 6 h of trial entry. There was no significant difference in the compliance measurements of the two groups at trial entry (see Table I). However, 6 h after trial entry, the infants receiving theophylline had significantly better lung function (0.95 k 0.42 ml/cm H,O, mean & S.D.) than those infants who had received the placebo solution (0.67 k 0.28 ml/cm H,O, mean f S.D:, P -= 0.05). Length of time remaining on ventilation following trial entry Infants receiving the theophylline solution required significantly less ventilation after entering the trial than those infants receiving the placebo (P < 0.01; see Fig. 1). During the study only one infant died, he had suffered from a large IVH following an unplanned home delivery at 29 weeks gestation; this infant had received the control trial solution. Re-analysing the data, including only the surviving infants,
19
E
8-
Y 5
6-
8 f5
a-
P =
20 do
lo-24
25-48
TIMETO DlSCONTlNtIATlONOFVENTllATlON
m
THEOPHYLLINE
0
CONTROLS
Fig. l.Treatment
with theophylline
significantly
>48 HOURS
reduced
the length of ventilator
dependence
(P c 0.01).
still demonstrates that those infants receiving theophylline required significantly less ventilation (P < 0.01). The effect of theophylline on hastening weaning from ventilation was seen in infants of maturity greater than 26 weeks gestation (P < 0.01). Although only 4 infants of maturity less than this were included in the study, all 4 required prolonged ventilation (> 10 days after trial entry). In those surviving infants of maturity greater than 26 weeks, theophylline resulted in ventilation being discontinued approximately one day earlier than in the controls (13.1 h mean as compared to 46.3 h mean in the controls).
Discussion These results confirm preliminary evidence [10,15] that theophylline given orally can hasten weaning from the ventilator. The present study eliminated any bias possibly associated with those non-randomised studies [10,15], as the clinicians caring for the infant were kept blind to the nature of the trial treatment. The two trial groups were well matched for factors which could have affected the severity of their RDS and hence the need for ventilation. Although more theophylline infants had received pancuronium this had been stopped for some time prior to trial entry and as the infants were all entered into the study at identical ventilator settings this indicated similar severity of RDS, as supported by the compliance measurements at trial entry. In fact the controls were at a theoretical advantage in that they were on average one day older than the ‘theophylline’ infants. Theophylline given orally, despite the immaturity of the infants studied was effectively absorbed. In only 2 infants did complications necessitate discontinuation of therapy. One of these infants was extremely immature, i.e. 24 weeks gestation. In infants of gestational age less than 27 weeks gestation, theophylline was much less effective in hastening weaning from ventilation, side-effects could thus be reduced by placing a
20
lower gestational age limit on infants to be included in such a study. The other infant was treated in the first 24 h of life and had not been observed for long enough for the full severity of his RDS to be declared. Methylxanthines have many actions which could contribute to their effectiveness in reducing ventilator dependence: (1) Increased sensitivity to CO,; (2) increased strength of the Hering-Breuer reflex; (3) improvement in diaphragmatic efficiency; (4) stimulation of the surfactant pathway. In infants treated for apnoea, aminophylline administration was associated with a 33% increase in oesophageal pressure change per breath and a 20% increase in oxygen consumption above the basal value [7]. The mechanism for this could be due to an increased respiratory centre output, as a result of a lowered threshold of the central chemoreceptor to COz, such treatment has indeed been associated with an increased sensitivity to CO, and a pronounced shift of the CO, response curve to the left [4]. Gerhardt et al. [8] demonstrated this change in respiratory effort by an increase in both the maximum pressure and the pressure 100 ms after occlusion [8]. Associated with this was an increase in the strength of the Hering-Breuer reflex, indicating an alteration in the phasic vagal afferent impulses from pulmonary stretch receptors. We too have noted increased reflex activity following the administration of theophylline [13]. Such an increase could enhance and regularise respiratory effort. On the other hand, evidence from an animal model suggests that the effect may be caused by an improvement in diaphragmatic efficiency rather than an increase in CNS output [l]. In that study, transdiaphragmatic pressure generated at FRC against closed airways was proportional to varying plasma concentrations of aminophylline whereas the electrical activity remained constant. In the present study theophylline therapy was associated with a significant improvement in compliance (P < 0.05). This effect has also been noted in infants suffering from bronchopulmonary dysplasia less than 30 days old [21] and was thought to be due to an action on the increased bronchiolar smooth muscle of these patients. Caffeine administration in animal studies also improves compliance [19], whereas aminophylline therapy in humans has been associated with either a non-significant increase [9], or no change [4,6]. The discrepancy in these results may be explained by the different maturity of the patients included in the studies. In the previous reports preterm infants in their second [4] and third [9] week of life were included. All the patients included in the present investigation were less than 10 days old and the majority were still in their first postnatal week. In such infants the stimulatory effect of theophylline on the surfactant pathway [16] could have resulted in improved compliance. Another ‘early’ effect of theophylline is its enhancement of the frequency of provoked augmented inspirations, which were only seen in the first 5 days of life [8]. In the present study theophylline could therefore have exerted its effect on lung function by increasing that reflex, which is known to be important in maintaining and preserving compliance [17]. This study has demonstrated that oral theophylline, even in very preterm infants, is a safe and effective means of hastening weaning from ventilation. The longer the preterm infant has to be ventilated, the greater the risk of such complications as
21
infection and local trauma. Surely then the effective reduction of even one day’s dependence on ventilation must be of benefit to the preterm baby, as well as providing a saving in neonatal intensive care resources.
Acknowledgements
We acknowledge the invaluable help of Mr. McHutchinson (Pharmacy Department) who prepared and randomised the trial solutions and Dr. S. Gore (MRC Biostatistics Unit) who gave helpful advice regarding the design of the trial. Sister J. Pool was supported by a grant from the Medical Research Council.
References
10 11 12 13 14 15 16 17 18
Aubier. M., Murciano. D., Vines, N. et al. (1983): Increased ventilation caused by Improved diaphragmatic efficiency during aminophylline infusion. Am. Rev. Respir. Dis., 127. 1488151. Barr, P.A. (1978): Weaning very low birthweight infants from mechanical ventilation using intermittent mandatory ventilation and theophylline. Arch. Dis. Child. 53, 5988600. Beardsmore, C.. Helms, P., Stocks. J., Hatch, D.J. and Silverman. M. (1980): Improved oesophageal balloon technique for use in infants, J. Appl. Physiol., 49. 735-742. Davi, M.J.. Sankaran, K., Simons. K.J. et al. (1978): Physiologic changes induced by theophylline rn the treatment of apnoea in preterm infants. J. Pediatr.. 92, 91-94. Elias-Jones, A., Dhillon, S. and Greenough. A. (1985): The efficacy of oral theophylline in ventilated premature infants. Early Hum. Dev., 12, 9-14. Estenne, M., Yernault, J.-C. and De Troyer. A. (1980): Effects of parenteral aminophylline on lung mechanics in normal human. Am. Rev. Resp. Dis., 121, 9677971. Gerhardt. T., McCarthy, J. and Bancalari. E. (1979): Effect of aminophylline on respiratory centre activity and metabolic rate in premature infants with idiopathic apnoea. Pediatrics. 63, 537-542. Gerhardt. T.. McCarthy, J. and Bancalari, E. (1983): Effects of aminophylline on respiratory centre and reflex activity in premature infants with apnoea. Pediatr. Res.. 17, 188-191. Gerhardt. T., McCarthy J. and Bancalari, E. (1978): Aminophylline therapy for idiopathic apnoea In premature infants: Effects on lung function. Pediatrics, 62, 801-805. Greenough, A. and Morley, C.J. (1985): Provoked augmented inspirations in preterm ventilated infants In: The Physiological Development of the Foetus and Newborn, Academic Press. London. Greenough. A.. Morley, C.J. and Davis, J.A. (1983): The interaction of the infant’s spontaneous respiration with artificial ventilation. J. Pediatr.. 103. 769-773. Greenough, A., Morley, C.J. and Wood, S. (1983): Dynamic compliance in ventilated low brithwsetght babies. Biol. Neonate, 44. 322. Greenough. A., Morley, C.J. and Davis. J.A. (1984): Provoked augmented inspirations. Early Hum. Dev.. 9. 111-115. Greenough, A., Wood, S., Morley, C.J. and Davis, J.A. (1984): Pancuronium prevents pneumothoraces in ventilated premature babies who actively expire against positive pressure ventilation. Lancet, i, l-4. Harris, M.C.. Baumgart, S., Rooklin, A.R. and Fox, W.W. (1983): Successful extubation of infants with respiratory distress syndrome using aminophylline. J. Pediatrics, 103, 3033306. Korotkin, E.H. (1976): Acceleration of foetal lung maturation. Pediatr. Res.. 10. 722-726. Mead, J. and Collier, C. (1959); Relation of volume histories of lungs to respiratory mechanics in anaesthetised dogs. J. Appl. Physiol., 14, 669-678. Morley, C.J., Miller, N.. Bangham. A.D. and Davis, J.A. (1980): Dry artificial lung surfactant and its effect on very premature babies. Lancet, i, 64-68.
22 19 Oskoui, M., Aviado, D.M. and Bellet, S. (1970): Bronchopulmonary effects of caffeine in the anaesthetised dog. Respiration, 27, 63-68. 20 Roberton, N.R.C. (1981): Respiratory distress syndrome and hyaline membrane disease. In Arnold, (Ed.), A Manual of Neonatal Intensive Care, London, p. 89. 21 Rooklin, A.R., Moomjian, A.S., Shutack, J.G., Schwartz, J.G. and Fox, W.W. (1979): Theophylline therapy in bronchopulmonary dysplasia. J. Pediatr., 95, 882-885. 22 Shannon, D.C., Gotay, F., Stein, I.M. et al. (1975): Prevention of apnoea and bradycardia in low birthweight infants. Pediatrics 55, 589-595. 23 Uauy, R., Shapiro, D.L., Smith, B. and Warshaw, J.B. (1975): Treatment of severe apnoea in prematures with orally administered theophylline. Pediatrics, 55, 595-599.
15
12 (1985) 15-22
EHD 00681
The therapeutic actions of theophylline in preterm ventilated infants Anne Greenough,
A. Elias-Jones,
Department
J. Pool, C.J. Morley and J.A. Davis
of Paediatrics, University of Cambridge, Cambudge, U.K. Accepted
for publication
17 May 1985
Summary
40 preterm, ventilated infants (gestational ages 24-33 weeks) were entered into a double-blind randomised trial to assess the effect of oral theophylline on lung function and ventilator dependence. Theophylline administration was associated with a significant improvement in compliance (P < 0.05) and hastened weaning from ventilation (P < 0.01).
theophylline;
artificial
ventilation;
premature
babies
Introduction Methylxanthines are useful in the prophylaxis of apnoea in preterm infants [22] and are effective given orally [23]. Preliminary evidence suggests that they may also have a role in weaning infants from artificial ventilation [2]. In a pilot, nonrandomised study we had previously found that theophylline given orally to preterm ventilated neonates increased compliance compared to matched controls [lo] and in some reduced the duration of ventilator support. We now report the results of a double-blind randomised trial which assessed the effects of oral theophylline on lung function and dependence on artificial ventilation.
Address for correspondence: Dr. Anne Greenough. Denmark Hill, London. U.K.
0378-3782/85/$03.30
Department
0 1985 Elsevier Science Publishers
of Child Health.
B.V. (Biomedical
King’ College
Division)
Hospital.
16
Methods and patients Infants were entered into the trial if they fulfilled the following criteria: (1) gestational age less than 34 weeks; (2) postnatal age less than 10 days; (3) ventilated for RDS and no longer receiving paralysing agents; (4) no known cardiac abnormality; (5) respiratory distress improving, enabling ventilator settings to be reduced to a peak pressure of 20 cm H,O and a rate of 20/min. The policy of the NICU to wean infants from ventilation once their RDS has started to improve, is first to reduce the peak pressures to 20 cm H,O and then to reduce the rates. (6) AG present to make the respiratory measurements. On entry to the study the infant was assigned his or her own bottle of ‘theophylline trial solution’. These had been made up by the hospital pharmacy and contained either theophylline in a concentration of 5 mg/ml and vehicle or simply vehicle alone. Both formed a clear solution and were indistinguishable. 50 bottles were randomised by the pharmacy who kept the code which was not released until the end of the trial. The prescriber (A.G.) and the clinical team were unaware of which treatment the infant received. The infant was prescribed a loading dose of 1 ml/kg of the trial solution, this meant infants receiving the active solution would receive a loading dose of theophylline of 5 mg/kg. Subsequently infants were prescribed 1 ml/kg per day in 4 divided doses; the second dose was not given until 6 h after the loading dose. The trial solution was given orally via a nasogastric tube without milk. The trial solution was discontinued: (1) if side-effects occurred; (2) 48 h after artificial ventilation was stopped; (3) if, after 48 h of treatment with the trial solution, there was no improvement in the infant’s clinical condition, that is no reduction in ventilator settings. Blood samples were taken via an indwelling arterial catheter inserted for clinical purposes, for theophylline assay by A. E.-J. [5], who altered subsequent doses of the trial solution to keep the theophylline concentration within the therapeutic range, 5-13 mg/l. Doses of the placebo solution were also altered so that it was not apparent which infants were receiving the active solution. Both the clinicians and A.G. were kept ‘blind’. Respiratory function was measured in all infants at trial entry, immediately prior to the first dose and then at 30 min and 1, 2, 3 and 6 h later, using equipment described previously [ll]. To assess lung function, static compliance was used while the infants remained ventilated except where an accurate measurement was impossible due to active expiration [12], in such circumstances dynamic compliance was used. Static compliance was measured using the peak pressure inflation maintained at a plateau for 0.5 s and the resultant volume change. Once ventilation had been discontinued dynamic compliance was measured using a pneumotachograph inserted into a tightly fitting face mask and an oesophageal balloon, the accuracy of the oesophageal pressure measurements was assessed by an occlusion test [3]. Arterial blood gases were assessed approximately 30-40 min after trial entry and similiarly after each change in ventilator rate, as was the NICU’s policy. Reductions in ventilator rate were made if there was evidence of a respiratory alkalosis (PaCO, < 40 mm Hg). Otherwise, in infants who were clinically stable, arterial blood
17
gases were checked 4-hourly, as our usual practice, in the presence of continuous oxygen monitoring (either transcutaneously or via an indwelling arterial electrode). The usual NICU’s policy of weaning was followed [20], that is, reduction of rate in 5 breaths/min stages to endotracheal CPAP, the infant finally being extubated once satisfactory blood gases had been confirmed. The larger infants, establishing vigorous respiration sooner, were extubated from IMV, once showing regular respiration and satisfactory blood gases. This policy was adopted for both of the trial groups. as the clinicians supervising the weaning process were of course unaware of to which trial group a particular infant belonged. The effect of theophylline was assessed by comparing the compliance of the two groups both at trial entry and six hours later and the length of time on ventilation from administration of the trial solution each required. Side-effects possibly caused by the theophylline were noted, but are reported elsewhere in detail (5).
Trial design The study was designed to detect a difference in compliance of 0.3 ml/cm Hz0 with a standard difference of 0.3 ml/cm H,O at the 5% level. Results from the pilot study had suggested that such a worthwhile improvement in compliance could occur following treatment with theophylline [lo]. 40 patients would be required to detect a difference of this order with an 85% power at the 5% level. Consequently the randomisation code was not broken until 40 infants had been entered into the trial.
Patients 40 infants were included in the study. Two infants were withdrawn from the trial within 4 h of entry (see Results), consequently their results were not included in the analysis. The clinical characteristics of the remaining 38 infants are shown in Table I. The two trial groups were well matched for gestational age, birthweight, sex and lung function at trial entry. Although those infants receiving the theophylline were on average one day younger than the ‘controls’ (see Table I), this did not reach statistical significance. Neither was there a significant difference between the two groups in the incidence of complications likely to affect the length of ventilator
TABLE
1
Clinical
characteristics Theophylline
Gestational age (wk) Birthweight (kg) Postnatal age at trial entry(h) Males Compliance at trial entry (ml/cm
H,O)
Values are mean & S.D.
29.8 1448 91.6 13 0.67+
(18)
+ 2.4 +503 k 12.9
0.35
Control
(20)
29.5 1423 111.0 15
k 2.3 k492 + 75.6
0.63+
0.26
18 TABLE
II
Complications Theophylline Pneumothorax IVH Had received pancuronium prior to trial entry (18) Given artificial surfactant at birth (14)
dependence Committee.
(18)
Control
5 3
7 4
12
8
3
4
(see Table II). This study was approved
(20)
by the Cambridge
Ethical
Statistical methods Student’s t-test, the Wilcoxon rank sum test and the x2-test with Yate’s correction as necessary were used.
Results
Withdrawls Two infants were withdrawn from the study within the first 4 h. One infant of 24 weeks gestation developed a tachycardia of greater than 200 beats/min and the other (gestational age 31 weeks, postnatal age 5 h), became agitated and to improve ventilation had to be paralysed. Both these infants had received the active solution. During the course of the study there were no other serious side-effects. Compliance measurements The compliance results from the remaining 38 infants were analysed. In all cases it was possible to make accurate static compliance measurements during ventilation and these were used in the analysis. Dynamic compliance measurements were used in the only two infants extubated within 6 h of trial entry. There was no significant difference in the compliance measurements of the two groups at trial entry (see Table I). However, 6 h after trial entry, the infants receiving theophylline had significantly better lung function (0.95 k 0.42 ml/cm H,O, mean & S.D.) than those infants who had received the placebo solution (0.67 k 0.28 ml/cm H,O, mean f S.D:, P -= 0.05). Length of time remaining on ventilation following trial entry Infants receiving the theophylline solution required significantly less ventilation after entering the trial than those infants receiving the placebo (P < 0.01; see Fig. 1). During the study only one infant died, he had suffered from a large IVH following an unplanned home delivery at 29 weeks gestation; this infant had received the control trial solution. Re-analysing the data, including only the surviving infants,
19
E
8-
Y 5
6-
8 f5
a-
P =
20 do
lo-24
25-48
TIMETO DlSCONTlNtIATlONOFVENTllATlON
m
THEOPHYLLINE
0
CONTROLS
Fig. l.Treatment
with theophylline
significantly
>48 HOURS
reduced
the length of ventilator
dependence
(P c 0.01).
still demonstrates that those infants receiving theophylline required significantly less ventilation (P < 0.01). The effect of theophylline on hastening weaning from ventilation was seen in infants of maturity greater than 26 weeks gestation (P < 0.01). Although only 4 infants of maturity less than this were included in the study, all 4 required prolonged ventilation (> 10 days after trial entry). In those surviving infants of maturity greater than 26 weeks, theophylline resulted in ventilation being discontinued approximately one day earlier than in the controls (13.1 h mean as compared to 46.3 h mean in the controls).
Discussion These results confirm preliminary evidence [10,15] that theophylline given orally can hasten weaning from the ventilator. The present study eliminated any bias possibly associated with those non-randomised studies [10,15], as the clinicians caring for the infant were kept blind to the nature of the trial treatment. The two trial groups were well matched for factors which could have affected the severity of their RDS and hence the need for ventilation. Although more theophylline infants had received pancuronium this had been stopped for some time prior to trial entry and as the infants were all entered into the study at identical ventilator settings this indicated similar severity of RDS, as supported by the compliance measurements at trial entry. In fact the controls were at a theoretical advantage in that they were on average one day older than the ‘theophylline’ infants. Theophylline given orally, despite the immaturity of the infants studied was effectively absorbed. In only 2 infants did complications necessitate discontinuation of therapy. One of these infants was extremely immature, i.e. 24 weeks gestation. In infants of gestational age less than 27 weeks gestation, theophylline was much less effective in hastening weaning from ventilation, side-effects could thus be reduced by placing a
20
lower gestational age limit on infants to be included in such a study. The other infant was treated in the first 24 h of life and had not been observed for long enough for the full severity of his RDS to be declared. Methylxanthines have many actions which could contribute to their effectiveness in reducing ventilator dependence: (1) Increased sensitivity to CO,; (2) increased strength of the Hering-Breuer reflex; (3) improvement in diaphragmatic efficiency; (4) stimulation of the surfactant pathway. In infants treated for apnoea, aminophylline administration was associated with a 33% increase in oesophageal pressure change per breath and a 20% increase in oxygen consumption above the basal value [7]. The mechanism for this could be due to an increased respiratory centre output, as a result of a lowered threshold of the central chemoreceptor to COz, such treatment has indeed been associated with an increased sensitivity to CO, and a pronounced shift of the CO, response curve to the left [4]. Gerhardt et al. [8] demonstrated this change in respiratory effort by an increase in both the maximum pressure and the pressure 100 ms after occlusion [8]. Associated with this was an increase in the strength of the Hering-Breuer reflex, indicating an alteration in the phasic vagal afferent impulses from pulmonary stretch receptors. We too have noted increased reflex activity following the administration of theophylline [13]. Such an increase could enhance and regularise respiratory effort. On the other hand, evidence from an animal model suggests that the effect may be caused by an improvement in diaphragmatic efficiency rather than an increase in CNS output [l]. In that study, transdiaphragmatic pressure generated at FRC against closed airways was proportional to varying plasma concentrations of aminophylline whereas the electrical activity remained constant. In the present study theophylline therapy was associated with a significant improvement in compliance (P < 0.05). This effect has also been noted in infants suffering from bronchopulmonary dysplasia less than 30 days old [21] and was thought to be due to an action on the increased bronchiolar smooth muscle of these patients. Caffeine administration in animal studies also improves compliance [19], whereas aminophylline therapy in humans has been associated with either a non-significant increase [9], or no change [4,6]. The discrepancy in these results may be explained by the different maturity of the patients included in the studies. In the previous reports preterm infants in their second [4] and third [9] week of life were included. All the patients included in the present investigation were less than 10 days old and the majority were still in their first postnatal week. In such infants the stimulatory effect of theophylline on the surfactant pathway [16] could have resulted in improved compliance. Another ‘early’ effect of theophylline is its enhancement of the frequency of provoked augmented inspirations, which were only seen in the first 5 days of life [8]. In the present study theophylline could therefore have exerted its effect on lung function by increasing that reflex, which is known to be important in maintaining and preserving compliance [17]. This study has demonstrated that oral theophylline, even in very preterm infants, is a safe and effective means of hastening weaning from ventilation. The longer the preterm infant has to be ventilated, the greater the risk of such complications as
21
infection and local trauma. Surely then the effective reduction of even one day’s dependence on ventilation must be of benefit to the preterm baby, as well as providing a saving in neonatal intensive care resources.
Acknowledgements
We acknowledge the invaluable help of Mr. McHutchinson (Pharmacy Department) who prepared and randomised the trial solutions and Dr. S. Gore (MRC Biostatistics Unit) who gave helpful advice regarding the design of the trial. Sister J. Pool was supported by a grant from the Medical Research Council.
References
10 11 12 13 14 15 16 17 18
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