Early Human Development, 29 (1992) 281-292 Elsevier Scientific Publishers Ireland Ltd.
287
EHD 01290
Patent ductus arteriosus: how important to which babies? D.B. Knight Department
of Paediatrics,
National
Women
S Hospital,
Auckland,
(New
Zealand)
Sununary An overview is presented of 21 randomised controlled trials of either surgical closure of the ductus arteriosus or indomethacin therapy in preterm infants. All trials included backup treatment if the ductus arteriosus persisted. Overall, there is no significant effect on mortality or chronic lung disease. In trials treating at a presymptomatic stage, there is a trend to reduce. the incidence of chronic lung disease. Early treatment with indomethacin reduces the incidence of periventricular haemorrhage. An ultrasound study of 110 very low birth weight infants showed ductus arteriosus size at 3 days to be related to factors reflecting the infants’ condition (ventilation indices, blood product administration), but not to birth weight or gestational age. Infants with a moderate to large ductus arteriosus at 3 days had a significantly lower blood pressure from 12 h of age onwards than those with a closed or small ductuses. Key words: patent ductus arteriosus; chronic lung disease; premature infant; blood pressure; overview
Introduction It is accepted that patent ductus arteriosus (PDA) adversely affects outcome in preterm infants, with worse respiratory sequelae and other undesirable effects. Prompt closure is thought to improve outcome. The evidence for this needs to be reviewed. An overview [l] of 21 randomised controlled trials on the use of indomethacin or surgical closure of PDA is presented, as well as data on the incidence, antecedents and effects of PDA in very low birth weight (VLBW) infants. Correspondence
to:
D.B. Knight, Department of Paediatrics, National Women’s Hospital, Auckland, New
Zealand. 0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
288
I
PW I I 0
I
I
1.0
Fig. 1. Odds ratios studies only. PDA,
Random&d
Cl& Confid.. Trials Babies Ratio Intervals 0.93
0.71-1.21
19
1558
0.79
0.50-1.24
12
1233
0.89
0.55-1.43
7
869
0.22
0.17-0.27
17
1410
I
1 2.0
and 95% confidence subsequent symtomatic
intervals PDA
for different in indomethacin
outcomes. studies
PVH only.
in early
indomethacin
controlled trials
The trials can be grouped into those treating either late, when ‘congestive heart failure’ was present [2-71, presymptomatic, at the first signs of or ultrasound evidence of PDA, between 2 and 5 days of age [8-121, or early, prophylactically in the first 24 h [ 13-221. The early trials had periventricular haemorrhage (PVH), PDA or chronic lung disease as their primary outcomes. 18 trials used indomethacin, two M Ratio
I
Confii.. TrialsBabies intervals
1.20
0.91-1.58
12
1109
Early SL
1.27
0.81-1.87
6
534
Pr
0.35
0.11-1.12
3
74
Late
1.44
0.96-2.16
3
501
*
0
1.0
2.0
Fig. 2. Chronic lung disease. Odds ratios and 95% confidence intervals in all trials overall, in early [ l5- 18,21,22], presymptomatic [8, IO, I l] and late [2,4,6] studies.
reporting
incidence;
289
surgical ligation [1,22] and one both [6]. In all, further treatment to close the PDA was undertaken if a significant PDA persisted after the initial randomised treatment. There was no significant difference in the incidence of death, chronic lung disease (CLD), necrotising enterocolitis or retinopathy of prematurity between the treated and control groups (Figs 1 and 2). This is true when the early, presymptomatic or late trials are considered separately. Only in the presymptomatic group for CLD, does the confidence interval approach significance. This group is heterogeneous in the selection of infants. CLD is reported for only 74 babies (3 of 5 trials), so an important beneficial effect may not reach significance (type 2 error). Overall, the trend for CLD is for an increase in the treatment groups (Fig. 2). The indomethacin studies show that subsequent symptomatic PDA is significantly less common in the treated groups, as are all severities of PVH (early trials only). The trials reporting PVH in babies under 1000 g separately do not show a lower incidence in the indomethacin groups. The mechanism of the effect of indomethacin on PVH is thought to be independent of its action on PDA. Of the 16 trials reporting data, only four [2-4,101 had significantly less time and one [16] more time on ventilation or intubated. Two had less time in oxygen [3,10] (in one the treated babies were significantly larger and more mature than controls [3]). In the six trials reporting results in < 1000 g infants treated in the first five days, with 277 babies [6,9,11,18,19,22], none had a significant difference in ventilation or intubation time and only one, with 22 babies, had less time in oxygen [9]. Incidence, antecedents
and effects
of PDA
One-hundred ten VLBW infants were followed with ultrasound imaging, Doppler and echo-contrast. All babies in the nursery and alive at 3 days were included. The studies at 72 h of age are presented. Treatment to close PDA did not influence these data. The mean birth weight of the group was 1120 g and gestational age 27.9 weeks. Sixty-two percent had a diagnosis of idiopathic respiratory distress syndrome and 81% required assisted ventilation at some stage during their hospital course. Fortyfive were under 28 weeks gestation and 50 under 1000 g. TABLE I Clinical antecedents of PDA. Significant
Not significant
Apgar scores at 1 and 5 mm Ventilation index days 1, 2 and 3 AaDO day 1 Blood product volume day 1 and 2a
Gestational age Birth weight Sexa Crystalloid fluid volume days 1-3 Fluid balance (excluding colloid)
Significant and nonsignificant association with ductus arteriosus size at 3 days. x2 and linear regression analysis. %tdicates significance by stepwise regression analysis, including these and other factors.
290
Ductus small/closed
1
11
Ductus moderate/large
I 2o
1
6
12
18 24
30
36
48
60
72
84
J 96
AGE (hrs) Fig. 3. Mean blood pressure over the first 4 days according to ductus size at 3 days of age. Mean and 95% confidence intervals.
Thirty-nine percent of babies had spontaneously closed their ducts by 3 days. In 26% the PDA was small (- 1 mm) and in 34% it was moderate to large (2-4 mm internal dimension at narrowest point). Ductus size was independent of gestational age (38% of 45 babies < 28 weeks closed versus 40% of 65 babies 1 28 weeks) and of birth weight (38% of 50 babies < 1000 g closed versus 40% of 60 babies 1 1000 g). Univariate analysis showed it to be related to factors reflecting the clinical condition of the babies (Table I). Stepwise regression analysis produced a significant correlation with colloid intake over the first 2 days and sex, with males being more likely to have closed ducts. The blood pressure from 12 h of age onwards was significantly lower in babies with a moderate to large PDA at 3 days than in those with a closed or small ductus (Fig. 3). This remained so when correcting for birthweight, gestational age and ventilation indices. It was true of systolic, diastolic and mean blood pressures. Only blood pressures recorded by indwelling arterial catheters were included. There are several possible explanations for this hypotension. It is possible that there was a significant left to right shunt developing at this early age. This is supported by observations of the early development of retrograde diastolic flow in the descending aorta, indicating a significant ‘run off’ into the pulmonary circulation, in other VLBW infants followed in this hospital. It may be that some of these infants who went on to have a moderate to large PDA at 3 days had a low cardiac output early on. Others have reported a high left ventricular output preceding the signs of a symptomatic PDA, so this is less likely. The babies could have a low systemic vascular resistance from circulating vasodilator prostaglandins, but high prostaglandin levels have not been correlated with PDA in preterm infants. Therefore, one of the contributors to hypotension in the first few days of life in VLBW infants may be a significant left to right shunt through the PDA. Treatment with volume expansion would not help this.
291 Conclusioa
The overview of 21 randomised controlled trials fails to show significant benefit from treating PDA at any particular age or stage of presentation. There are no significant differences in the incidence of death, chronic lung disease, necrotising enterocolitis or retinopathy of prematurity between treatment and control groups. All studies included treatment to close a PDA if it persisted after the initial randomised treatment. Therefore the effect of closure verses non-closure cannot be assessed. The numbers in the trials treating at a presymptomatic stage are small and therefore firm conclusions cannot be made for this group. The incidence and size of PDA in VLBW at three days of age is related not to birth weight or gestational age, but to indices of the clinical condition of the infant. These same factors are antecedents of CLD. It is possible that PDA is as much a marker of as it is a contributor to CLD. Babies who went on to have a moderate to large PDA at 3 days of age had a significantly lower blood pressure from 12 h of age onwards, suggesting the possibility of the early development of a significant left to right shunt in some babies. References I 2 3 4 5 6 7 8
12
Antiplatelet Trialists’ Collaboration. (1988): Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br. Med. J., 296, 320-331. Cotton, R.B., Stahhnan, M.T., Bender, H.W., Graham, T.P., Catterton, W.Z. and Kovar, I. (1978): Randomised trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. J. Pediatr., 93, 647-651. Yanagi, R.M., Wilson, A., Newfeld, E.A., Aziz, K.U. and Hunt, C.E. (1981): Indomethacin treatment for symptomatic patent ductus arteriosus: a double-blind control study. Pediatrics, 67, 647-652. Yeh, T.F., Luken, J.A., Thalji, A., Raval, D., Carr, I. and Phildes, R.S. (1981): Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus - a double-blind controlled study. J. Pediatr., 98, 137-145. Mullett, M.D., Croghan, T.W., Myerberg, D.Z., Krall, J.M. and Neal, W.A. (1982): Indomethacin for closure of patent ductus arteriosus in prematures. Clin. Pediatr., 21, 217-220. Gersony, W.M., Peckham, G.J., Ellison, R.C., Miettinen, OS. and Nadas, A.S. (1983): Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J. Pediatr., 102, 895-906. Rudd, P., Montanez, P., Hallidie-Smith, K. and Silverman, M. (1983): Indomethacin treatment for patent ductus arteriosus in very low birthweight infants: a double blind trial. Arch. Dis. Child., 58, 267-270. Merritt, T.A., Harris, J.P., Roghmann, K., Wood, B., Campanella, V., Alexson, C., Manning, J. and Shapiro, D.L. (1981): Early closure of the patent ductus arteriosus in very low-birth-weight infants: a controlled trial. J. Pediatr., 99, 281-286. Mahony, L., Canero, V., Brett, C., Heymann, M.A. and Clyman, RI. (1982): Prophylactic indomethacin therapy for patent ductus arteriosus in very-low-birth-weight infants. N. Engl. J. Med., 306, 506-5 10. Kalpii, P., Lanning, P. and Koivisto, M. (1983): Early closure of patent ductus arteriosus with indomethacin in pretenn infants with idiopathic respiratory distress syndrome. Acta. Paediatr. Stand., 72, 179-184. Hammerman, C., Strates, E., Komar, K. and Bui, K.-c. (1987): Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Dev. Pharm. Ther., 10, 393-404. Vogtmann, C., Grubbe, G., Ruckhaberle, K.-E., Biittcher, H. and Ockert, C. (1988): Auswirkungen
292
13 14 15 16 17 18 19 20 21 22
einer Friihtherapie mit Indomethazin auf die Manifestation eines persistlerenden Ductus arteriosus bei extrem ,untergewichtigen Frtihgeborenen. Monatsschr. Kinderheilkd., 136, 636-9. Mahony, L., Caldwell, R.L., Girod, D.A., Hurwitz, R.A., Jansen, R.D., Lemons, J.A. and Schreiner, R.L. (1985): Indomethacin therapy on the first day of life in infants with very low birth weight. J. Pediatr., 106, 801-805. Ment, L.R., Duncan, C.C., Ehrenkranz, R.A., Kleinman, C.S., Pitt, B.R., Taylor, K.J.W., Scott, D.T., Stewart, W.B. and Gettner, P. (1985): Randomised indomethacin trial for prevention of intraventricuiar hemorrhage in very low birth weight infants. J. Pediatr., 107, 937-943. Bennie, J.M., Doyle, J. and Cooke, R.W.I. (1986): Early administration of indomethacin to preterm infants. Arch. Dis. Child., 61, 233-238. Vincer, M., Evans, A.J., Nwaesei, C., Stinson, D., Rees, E. and Fraser, A. (1987): Early intravenous indomethacin prolongs respiratory support in very low birth weight infants. Acta. Paediatr. Stand., 76, 894-897. Krueger, E., Mellander, M., Bratton, D. and Cotton, R. (1987): Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. J. Pediatr., 111, 749-754. Setzer Bandstra, E., Montalvo, B.M., Goldberg, R.N., Pacheco, I., Ferrer, P.L., Flynn, J., Gregorios, J.B. and Bancalari, E. (1988): Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics, 82, 533-542. Hanigan, W.C., Kennedy, G., Roemisch, F., Anderson, R., Cusack, T. and Powers, W. (1988): Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in high-risk neonates. J. Pediatr., 112, 941-947. Ment, L.R., Duncan, C.C., Ehrenkranz, R.A., Kleinman, C.S., Taylor, K.J.W., Scott, D.T., Gettner, P., Sherwonit, E. and Williams, J. (1988): Randomised low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J. Pediatr., 112, 948-955. Bada, H.S., Green, R.S., Pourcyrous, M., Leffier, C.W., Korones, S.B., Magill, H.L., Arheart, K., Fitch, C.W., Anderson, G.D., Somes, G., Tullis, K. and Campbell, J. (1989): Indomethacin reduces the risk of severe intraventricular hemorrhage. J. Pediatr., 115, 631-637. Cassady, G., Crouse, D.T., Kirklin, J.W., Strange, M.J., Joiner, C.H., Godoy, G., Odrezin, G.T., Cutter, G.R., Kirklin, J.K., Pacifico, A.D., Collins, M.V., Lell, W.A., Satterwhite, C. and Phillips, J.B. (1989): A randomised controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N. Engl. J. Med., 320, 1511-1516.
287
EHD 01290
Patent ductus arteriosus: how important to which babies? D.B. Knight Department
of Paediatrics,
National
Women
S Hospital,
Auckland,
(New
Zealand)
Sununary An overview is presented of 21 randomised controlled trials of either surgical closure of the ductus arteriosus or indomethacin therapy in preterm infants. All trials included backup treatment if the ductus arteriosus persisted. Overall, there is no significant effect on mortality or chronic lung disease. In trials treating at a presymptomatic stage, there is a trend to reduce. the incidence of chronic lung disease. Early treatment with indomethacin reduces the incidence of periventricular haemorrhage. An ultrasound study of 110 very low birth weight infants showed ductus arteriosus size at 3 days to be related to factors reflecting the infants’ condition (ventilation indices, blood product administration), but not to birth weight or gestational age. Infants with a moderate to large ductus arteriosus at 3 days had a significantly lower blood pressure from 12 h of age onwards than those with a closed or small ductuses. Key words: patent ductus arteriosus; chronic lung disease; premature infant; blood pressure; overview
Introduction It is accepted that patent ductus arteriosus (PDA) adversely affects outcome in preterm infants, with worse respiratory sequelae and other undesirable effects. Prompt closure is thought to improve outcome. The evidence for this needs to be reviewed. An overview [l] of 21 randomised controlled trials on the use of indomethacin or surgical closure of PDA is presented, as well as data on the incidence, antecedents and effects of PDA in very low birth weight (VLBW) infants. Correspondence
to:
D.B. Knight, Department of Paediatrics, National Women’s Hospital, Auckland, New
Zealand. 0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
288
I
PW I I 0
I
I
1.0
Fig. 1. Odds ratios studies only. PDA,
Random&d
Cl& Confid.. Trials Babies Ratio Intervals 0.93
0.71-1.21
19
1558
0.79
0.50-1.24
12
1233
0.89
0.55-1.43
7
869
0.22
0.17-0.27
17
1410
I
1 2.0
and 95% confidence subsequent symtomatic
intervals PDA
for different in indomethacin
outcomes. studies
PVH only.
in early
indomethacin
controlled trials
The trials can be grouped into those treating either late, when ‘congestive heart failure’ was present [2-71, presymptomatic, at the first signs of or ultrasound evidence of PDA, between 2 and 5 days of age [8-121, or early, prophylactically in the first 24 h [ 13-221. The early trials had periventricular haemorrhage (PVH), PDA or chronic lung disease as their primary outcomes. 18 trials used indomethacin, two M Ratio
I
Confii.. TrialsBabies intervals
1.20
0.91-1.58
12
1109
Early SL
1.27
0.81-1.87
6
534
Pr
0.35
0.11-1.12
3
74
Late
1.44
0.96-2.16
3
501
*
0
1.0
2.0
Fig. 2. Chronic lung disease. Odds ratios and 95% confidence intervals in all trials overall, in early [ l5- 18,21,22], presymptomatic [8, IO, I l] and late [2,4,6] studies.
reporting
incidence;
289
surgical ligation [1,22] and one both [6]. In all, further treatment to close the PDA was undertaken if a significant PDA persisted after the initial randomised treatment. There was no significant difference in the incidence of death, chronic lung disease (CLD), necrotising enterocolitis or retinopathy of prematurity between the treated and control groups (Figs 1 and 2). This is true when the early, presymptomatic or late trials are considered separately. Only in the presymptomatic group for CLD, does the confidence interval approach significance. This group is heterogeneous in the selection of infants. CLD is reported for only 74 babies (3 of 5 trials), so an important beneficial effect may not reach significance (type 2 error). Overall, the trend for CLD is for an increase in the treatment groups (Fig. 2). The indomethacin studies show that subsequent symptomatic PDA is significantly less common in the treated groups, as are all severities of PVH (early trials only). The trials reporting PVH in babies under 1000 g separately do not show a lower incidence in the indomethacin groups. The mechanism of the effect of indomethacin on PVH is thought to be independent of its action on PDA. Of the 16 trials reporting data, only four [2-4,101 had significantly less time and one [16] more time on ventilation or intubated. Two had less time in oxygen [3,10] (in one the treated babies were significantly larger and more mature than controls [3]). In the six trials reporting results in < 1000 g infants treated in the first five days, with 277 babies [6,9,11,18,19,22], none had a significant difference in ventilation or intubation time and only one, with 22 babies, had less time in oxygen [9]. Incidence, antecedents
and effects
of PDA
One-hundred ten VLBW infants were followed with ultrasound imaging, Doppler and echo-contrast. All babies in the nursery and alive at 3 days were included. The studies at 72 h of age are presented. Treatment to close PDA did not influence these data. The mean birth weight of the group was 1120 g and gestational age 27.9 weeks. Sixty-two percent had a diagnosis of idiopathic respiratory distress syndrome and 81% required assisted ventilation at some stage during their hospital course. Fortyfive were under 28 weeks gestation and 50 under 1000 g. TABLE I Clinical antecedents of PDA. Significant
Not significant
Apgar scores at 1 and 5 mm Ventilation index days 1, 2 and 3 AaDO day 1 Blood product volume day 1 and 2a
Gestational age Birth weight Sexa Crystalloid fluid volume days 1-3 Fluid balance (excluding colloid)
Significant and nonsignificant association with ductus arteriosus size at 3 days. x2 and linear regression analysis. %tdicates significance by stepwise regression analysis, including these and other factors.
290
Ductus small/closed
1
11
Ductus moderate/large
I 2o
1
6
12
18 24
30
36
48
60
72
84
J 96
AGE (hrs) Fig. 3. Mean blood pressure over the first 4 days according to ductus size at 3 days of age. Mean and 95% confidence intervals.
Thirty-nine percent of babies had spontaneously closed their ducts by 3 days. In 26% the PDA was small (- 1 mm) and in 34% it was moderate to large (2-4 mm internal dimension at narrowest point). Ductus size was independent of gestational age (38% of 45 babies < 28 weeks closed versus 40% of 65 babies 1 28 weeks) and of birth weight (38% of 50 babies < 1000 g closed versus 40% of 60 babies 1 1000 g). Univariate analysis showed it to be related to factors reflecting the clinical condition of the babies (Table I). Stepwise regression analysis produced a significant correlation with colloid intake over the first 2 days and sex, with males being more likely to have closed ducts. The blood pressure from 12 h of age onwards was significantly lower in babies with a moderate to large PDA at 3 days than in those with a closed or small ductus (Fig. 3). This remained so when correcting for birthweight, gestational age and ventilation indices. It was true of systolic, diastolic and mean blood pressures. Only blood pressures recorded by indwelling arterial catheters were included. There are several possible explanations for this hypotension. It is possible that there was a significant left to right shunt developing at this early age. This is supported by observations of the early development of retrograde diastolic flow in the descending aorta, indicating a significant ‘run off’ into the pulmonary circulation, in other VLBW infants followed in this hospital. It may be that some of these infants who went on to have a moderate to large PDA at 3 days had a low cardiac output early on. Others have reported a high left ventricular output preceding the signs of a symptomatic PDA, so this is less likely. The babies could have a low systemic vascular resistance from circulating vasodilator prostaglandins, but high prostaglandin levels have not been correlated with PDA in preterm infants. Therefore, one of the contributors to hypotension in the first few days of life in VLBW infants may be a significant left to right shunt through the PDA. Treatment with volume expansion would not help this.
291 Conclusioa
The overview of 21 randomised controlled trials fails to show significant benefit from treating PDA at any particular age or stage of presentation. There are no significant differences in the incidence of death, chronic lung disease, necrotising enterocolitis or retinopathy of prematurity between treatment and control groups. All studies included treatment to close a PDA if it persisted after the initial randomised treatment. Therefore the effect of closure verses non-closure cannot be assessed. The numbers in the trials treating at a presymptomatic stage are small and therefore firm conclusions cannot be made for this group. The incidence and size of PDA in VLBW at three days of age is related not to birth weight or gestational age, but to indices of the clinical condition of the infant. These same factors are antecedents of CLD. It is possible that PDA is as much a marker of as it is a contributor to CLD. Babies who went on to have a moderate to large PDA at 3 days of age had a significantly lower blood pressure from 12 h of age onwards, suggesting the possibility of the early development of a significant left to right shunt in some babies. References I 2 3 4 5 6 7 8
12
Antiplatelet Trialists’ Collaboration. (1988): Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br. Med. J., 296, 320-331. Cotton, R.B., Stahhnan, M.T., Bender, H.W., Graham, T.P., Catterton, W.Z. and Kovar, I. (1978): Randomised trial of early closure of symptomatic patent ductus arteriosus in small preterm infants. J. Pediatr., 93, 647-651. Yanagi, R.M., Wilson, A., Newfeld, E.A., Aziz, K.U. and Hunt, C.E. (1981): Indomethacin treatment for symptomatic patent ductus arteriosus: a double-blind control study. Pediatrics, 67, 647-652. Yeh, T.F., Luken, J.A., Thalji, A., Raval, D., Carr, I. and Phildes, R.S. (1981): Intravenous indomethacin therapy in premature infants with persistent ductus arteriosus - a double-blind controlled study. J. Pediatr., 98, 137-145. Mullett, M.D., Croghan, T.W., Myerberg, D.Z., Krall, J.M. and Neal, W.A. (1982): Indomethacin for closure of patent ductus arteriosus in prematures. Clin. Pediatr., 21, 217-220. Gersony, W.M., Peckham, G.J., Ellison, R.C., Miettinen, OS. and Nadas, A.S. (1983): Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J. Pediatr., 102, 895-906. Rudd, P., Montanez, P., Hallidie-Smith, K. and Silverman, M. (1983): Indomethacin treatment for patent ductus arteriosus in very low birthweight infants: a double blind trial. Arch. Dis. Child., 58, 267-270. Merritt, T.A., Harris, J.P., Roghmann, K., Wood, B., Campanella, V., Alexson, C., Manning, J. and Shapiro, D.L. (1981): Early closure of the patent ductus arteriosus in very low-birth-weight infants: a controlled trial. J. Pediatr., 99, 281-286. Mahony, L., Canero, V., Brett, C., Heymann, M.A. and Clyman, RI. (1982): Prophylactic indomethacin therapy for patent ductus arteriosus in very-low-birth-weight infants. N. Engl. J. Med., 306, 506-5 10. Kalpii, P., Lanning, P. and Koivisto, M. (1983): Early closure of patent ductus arteriosus with indomethacin in pretenn infants with idiopathic respiratory distress syndrome. Acta. Paediatr. Stand., 72, 179-184. Hammerman, C., Strates, E., Komar, K. and Bui, K.-c. (1987): Failure of prophylactic indomethacin to improve the outcome of the very low birth weight infant. Dev. Pharm. Ther., 10, 393-404. Vogtmann, C., Grubbe, G., Ruckhaberle, K.-E., Biittcher, H. and Ockert, C. (1988): Auswirkungen
292
13 14 15 16 17 18 19 20 21 22
einer Friihtherapie mit Indomethazin auf die Manifestation eines persistlerenden Ductus arteriosus bei extrem ,untergewichtigen Frtihgeborenen. Monatsschr. Kinderheilkd., 136, 636-9. Mahony, L., Caldwell, R.L., Girod, D.A., Hurwitz, R.A., Jansen, R.D., Lemons, J.A. and Schreiner, R.L. (1985): Indomethacin therapy on the first day of life in infants with very low birth weight. J. Pediatr., 106, 801-805. Ment, L.R., Duncan, C.C., Ehrenkranz, R.A., Kleinman, C.S., Pitt, B.R., Taylor, K.J.W., Scott, D.T., Stewart, W.B. and Gettner, P. (1985): Randomised indomethacin trial for prevention of intraventricuiar hemorrhage in very low birth weight infants. J. Pediatr., 107, 937-943. Bennie, J.M., Doyle, J. and Cooke, R.W.I. (1986): Early administration of indomethacin to preterm infants. Arch. Dis. Child., 61, 233-238. Vincer, M., Evans, A.J., Nwaesei, C., Stinson, D., Rees, E. and Fraser, A. (1987): Early intravenous indomethacin prolongs respiratory support in very low birth weight infants. Acta. Paediatr. Stand., 76, 894-897. Krueger, E., Mellander, M., Bratton, D. and Cotton, R. (1987): Prevention of symptomatic patent ductus arteriosus with a single dose of indomethacin. J. Pediatr., 111, 749-754. Setzer Bandstra, E., Montalvo, B.M., Goldberg, R.N., Pacheco, I., Ferrer, P.L., Flynn, J., Gregorios, J.B. and Bancalari, E. (1988): Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. Pediatrics, 82, 533-542. Hanigan, W.C., Kennedy, G., Roemisch, F., Anderson, R., Cusack, T. and Powers, W. (1988): Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in high-risk neonates. J. Pediatr., 112, 941-947. Ment, L.R., Duncan, C.C., Ehrenkranz, R.A., Kleinman, C.S., Taylor, K.J.W., Scott, D.T., Gettner, P., Sherwonit, E. and Williams, J. (1988): Randomised low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates. J. Pediatr., 112, 948-955. Bada, H.S., Green, R.S., Pourcyrous, M., Leffier, C.W., Korones, S.B., Magill, H.L., Arheart, K., Fitch, C.W., Anderson, G.D., Somes, G., Tullis, K. and Campbell, J. (1989): Indomethacin reduces the risk of severe intraventricular hemorrhage. J. Pediatr., 115, 631-637. Cassady, G., Crouse, D.T., Kirklin, J.W., Strange, M.J., Joiner, C.H., Godoy, G., Odrezin, G.T., Cutter, G.R., Kirklin, J.K., Pacifico, A.D., Collins, M.V., Lell, W.A., Satterwhite, C. and Phillips, J.B. (1989): A randomised controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N. Engl. J. Med., 320, 1511-1516.
