- Email: [email protected]
Duration of Indomethacin Treatment of the Preterm Patent Ductus Arteriosus as Directed by Echocardiography
Duration of Indomethacin Treatment of the Preterm Patent Ductus Arteriosus as Directed by Echocardiography Kathryn Browning Carmo, BMED, FRACP, Nick Evans, MRCPCH, DM, and Mary Paradisis, MBBS, FRACP Objective To determine whether the duration of indomethacin administration could be shortened in infants with good early constrictive response of patent ductus arteriosus (PDA). Study design Infants born at < 30 weeks’ gestational age were assessed with echocardiography in the first 12 hours of life and treated with indomethacin (0.1 mg/kg) if the PDA was > 2 mm in diameter. Randomization occurred before the second dose to either standard treatment (2 more doses of indomethacin at 0.1 mg/kg irrespective of echocardiographic findings) or to echocardiographically directed duration of indomethacin treatment (ECHO; further doses only if the PDA was >1.6 mm). Serial echocardiography was performed to day 28 of age. The primary outcome was failure of PDA closure. Results The infants were randomized to either the ECHO arm (n = 34) or the standard treatment arm (n = 40). No differences between the arms were seen in terms of failure of PDA closure, PDA reopening, need for further doses of indomethacin, or need for surgical ligation. More doses of indomethacin were given in the standard treatment arm (median, 3 doses [range, 1 to 12] vs 1 dose [range, 1 to 15]; P < .0001). Conclusion Echocardiographically directed duration of indomethacin treatment is effective in achieving PDA closure and offers the potential for dose minimization. (J Pediatr 2009;155:819-22). See editorial, p 774
P
atent ductus arteriosus (PDA), resulting in a left-to-right shunt, is associated with various complications of prematurity.1,2 There is considerable controversy surrounding when and how best to treat PDA. This controversy reflects a balance between the uncertainties based on evidence regarding the benefits of PDA treatment versus the risks from the known side effects of indomethacin (ie, decreased renal, splanchnic, and cerebral blood flow). Whenever a drug treatment has significant side effects, the goal should be to design a regimen to give the minimum effective dose. Indomethacin is usually given in 3 to 6 doses, usually at 0.1 mg/kg, at 24-hour intervals. We have observed widely varying early constrictive responses of PDA to the first dose of indomethacin, ranging from minimal constriction with ducts that remain widely patent to complete duct closure within 24 hours. The aim of the present study was to explore whether the duration of indomethacin therapy could be shortened in infants exhibiting the best early constrictive response, as determined by echocardiography.
Methods This study was conducted at a tertiary referral neonatal intensive care unit at Royal Prince Alfred Hospital, Sydney, Australia between 2003 and 2007. The study design was approved by the Human Research Ethics Committee of the Sydney South Area Health Service. Written informed parental consent was obtained before study commencement. Infants born before 30 weeks of gestational age (GA) and requiring respiratory support were eligible. In each infant, an echocardiogram was performed between 3 and 12 hours of age. Exclusion criteria were the presence of intraventricular hemorrhage (IVH) grade 3-4, infant not expected to survive, infant more than 12 hours old, or lack of parental consent. This was a nonblinded, randomized controlled pilot study. The usual treatment for PDA in our institution at the time of this study involved an early targeted approach with three 0.1-mg/kg doses of indomethacin given at 24-hour intervals. PDA diameter was determined within the first 6 hours of life as described previously.3 If the duct diameter was > 2 mm at this time and there were no contraindications, the first dose of indomethacin was administered. Previous studies have shown that 60% of ducts exceeding this median diameter
ECHO GA IVH PDA
Echocardiographically directed indomethacin treatment arm Gestational age Intraventricular hemorrhage Patent ductus arteriosus
From the Department of Newborn Care, Royal Prince Alfred Hospital, Sydney, Australia (K.C., N.E.); Grace Centre for Newborn Care, Children’s Hospital at Westmead, Sydney, Australia (K.C.); Department of Newborn Care, Royal North Shore Hospital, Sydney, Australia (N.E., M.P.); and Faculty of Medicine, University of Sydney, Sydney, Australia (K.C., M.P.) The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.06.013
819
THE JOURNAL OF PEDIATRICS
www.jpeds.com
will eventually require therapeutic closure, and the other 40% will close spontaneously.4 Before the second indomethacin dose was given and after informed written consent was obtained from the parents, each infant was randomized into either the standard treatment arm or the ECHO arm. PDA diameter was remeasured just before the second dose was given. Infants in the standard treatment arm received three 0.1-mg/kg doses of indomethacin at 24-hour intervals irrespective of PDA diameter. Infants in the ECHO arm were given further doses of indomethacin only when the duct diameter remained >1.6 mm. Once the diameter had constricted to < 1.6 mm, no further doses were given. Randomization was by opaque, sealed, randomly assigned envelopes with block randomization in 2 GA groups, < 27 weeks GA and 27 to 29 weeks GA. All infants underwent echocardiography daily for the first 4 days and then on days 7, 14, and 28, to assess duct size and patency. Indomethacin was not given to any infant with a serum creatinine level >120 mmol/L. This level was chosen pragmatically as the level at which the clinicians in our unit would discontinue indomethacin. Further doses and repeat courses were administered at the discretion of the treating physician based on the clinical situation and the echocardiographic findings. Further courses of indomethacin 0.1 mg/kg for 3 days were given only if the PDA was >1.6 mm and the infant required respiratory support. Clinically nonapparent and nonsymptomatic reopening ducts seen on echocardiography were not retreated. All infants underwent routine head ultrasound examination at 7 and 28 days of age. The primary outcome was failure of PDA closure, defined as a duct remaining patent 24 hours after the final dose of the 3-day course of indomethacin would have been given (usually at about 72 hours of age). Secondary outcomes were those relating to the duct, including surgical ligation of the duct, reopening of the duct after documented closure, and total doses of indomethacin. Outcomes relating to side effects of indomethacin were serum creatinine >120 mmol/L, gastrointestinal bleeding (ie, blood in the gastric aspirate), necrotizing enterocolitis, and oliguria (urine output < 0.5 mL/kg/hour). Other clinical outcomes were pulmonary hemorrhage; IVH, Papile5 grade 2-4; chronic lung disease, defined as oxygen dependency at 36 weeks postmenstrual age; and mortality before hospital discharge. Our initial power calculation indicated that we needed a total of 180 infants (90 in each arm) to detect an increase in the incidence of late symptomatic PDA from 20% to 40% in the ECHO arm (power, 80%; P = .05), allowing for 80% recruitment. After 4 years of slower-than-expected recruitment, an interim analysis of the first 74 recruits found no difference in the incidence of the primary outcome between the 2 arms. In light of the slow recruitment and this lack of difference in the primary outcome, recruitment was ceased. Data were analyzed using SPSS version 15.0 (SPSS Inc., Chicago, Illinois). A P value < .05 was considered significant. The data analysis was done on an intention-to-treat basis. Categorical variables were analyzed using the Student 820
Vol. 155, No. 6 t-test, c2 test, or Fisher’s exact test for differences in proportions of independent populations. The Mann-Whitney Utest was used to assess nonparametric data.
Results We recruited 74 infants into the study between January 1, 2003 and June 30, 2007 (Figure 1; available at www.jpeds. com). Of 318 infants born before 30 weeks GA admitted to the nursery during this time period, 148 were eligible for the study, 138 either did not have a significant duct (< 2 mm) or had a closed duct, 72 were not approached, and 2 refused consent. During 2005, the study was suspended because there was no primary researcher on site. One infant was randomized to the standard treatment arm but was treated as in the ECHO arm, because the analysis was by intention to treat; this infant was maintained in the standard treatment arm. Thirty-four infants were randomized to the ECHO arm, and 40 were randomized to the standard treatment arm. The 2 arms were well matched at enrollment (Table I). All infants required respiratory support; 72 were initially ventilated, and 2 were supported with continuous positive airway pressure alone. The PDA diameter was >2.0 mm in all infants enrolled, and the direction of shunting was predominantly left to right. The incidence of failure of duct closure at 72 hours of age did not differ between the 2 arms (8 of 34 [25%] in the ECHO arm vs 10 of 40 [25%] in the standard treatment arm). The ECHO arm received significantly fewer doses of indomethacin than the standard treatment arm (median, 1 dose [range, 1 to 15 doses] vs 3 doses [range, 1 to 9 doses]; P < .001). Most infants in the ECHO arm received only 1 dose (22 [65%]), whereas only 1 (2.5%) infant in the standard treatment arm received only 1 dose (Figure 2). There was no significant difference in the incidence of reopening of PDA after closure between the 2 arms (8% in the ECHO arm vs 3% in the standard treatment arm; P = .5). There also were no significant differences between the arms in terms of the administration of a second course of indomethacin (18% vs 23%; P = .6) and the need for surgical ligation (3% vs 5%; P = .65). The second course of indomethacin was initiated on days 6, 8, 13, 18, and 20 (2 patients) in the ECHO arm and on days 4 (4 patients), 7, 12, 14, 21, and 23 in the standard treatment arm. One patient in the ECHO arm received a third course, initiated on day 55. The 3 surgical Table I. Baseline characteristics at study entry
Male sex, n (%) Mean GA, weeks Mean birth weight, g (SD) Mean cord pH GA < 27 weeks, n (%) GA 27 to 30 weeks, n (%) Complete antenatal steroids, n (%)
ECHO (n = 34)
Standard (n = 40)
P value
19 (56) 26.6 966 (294) 7.26 17 (50) 17 (50) 15 (44)
23 (57.5) 26.7 1008 (185) 7.27 19 (47.5) 21 (53) 24 (60)
1.0 .7 .4 .4 .8 .8 .2
Carmo, Evans, and Paradisis
ORIGINAL ARTICLES
December 2009
Figure 2. Recruitment and randomization of babies.
ligations were performed on days 26, 27, and 28. At 28 days of age, no ducts were still patent in the ECHO arm, but 1 duct (3%) remained patent in the standard treatment arm (Table II). Thirty-six infants (17 in the ECHO arm and 19 in the standard treatment arm) were born before 27 weeks GA. Mean birth weight was 848 g (range, 517 to 1220 g) in the < 27 weeks GA group and 1122 g (range, 590 to 1536 g) in the 27 to 29 weeks GA group. Failure of duct closure occurred in 20 (55%) infants in the < 27 weeks GA group, compared with only 3 (8%) infants in the 27 to 29 weeks GA group (P < .001). Reopening of the PDA occurred only in the < 27 weeks GA group (17 of 36 infants); in this group, 9 infants in the ECHO arm received only a single dose of indomethacin, whereas 8 infants in the standard treatment arm received 3 or more doses (P = .012). There were no significant differences in clinical outcomes between the 2 arms (Table III). Seven infants in the ECHO arm and 3 infants in the standard treatment arm had significant IVH. Seven of these cases (4 in the ECHO arm and 3 in the standard treatment arm) were grade 3-4 IVH. Three of the 4 infants in the ECHO arm with grade 3-4 IVH received more than 1 dose of indomethacin; in other words, they had a poor initial constrictive response to the first dose of indomethacin (Table IV; available at www.jpeds.com).
Discussion This study has shown that by tailoring the duration of indomethacin treatment to the ductal constrictive response Table II. PDA outcomes ECHO (n = 34)
Standard (n = 40) P value
Patent at 72 hours, n (%) 9 (26) 10 (25) Reopening after documented closure, n (%) 2/25 (8) 1/30 (3) Second course of indomethacin, n (%) 6 (18) 9 (23) Third course of indomethacin, n (%) 1 (3) 0 Patent at day 28, n (%) 0 1 (3) Surgical ligation, n (%) 1 (3) 2 (5)
.9 .5 .6 .3 .4 .6
24hours after the first dose, it is possible to significantly reduce the exposure to the drug without affecting eventual successful closure rates. Empirically, this strategy for dose minimization would allow therapy for ductal closure to at a reduced risk of side effects. Our data are consistent with those reported by Su et al,6 who used the Doppler pattern of flow through the ductus to limit the duration of indomethacin treatment. They used the high-velocity turbulent left-to-right pattern of flow that is seen when the ductus constricts, which they called the ‘‘closing pattern,’’ to determine when to cease further doses of indomethacin. By doing so, they achieved similar closure rates with significantly lower doses of indomethacin. There is a close relationship between the diameter of the ductus and the Doppler pattern of flow, so these 2 methods probably give the same information. In general terms, with ultrasound it often is preferable to measure variables by more than one method as a cross-check, so it may be logical to use both Doppler pattern, as described by Su et al,6 and diameter measurement, as used in the present study, when implementing this strategy. That PDAs respond to conservative management is demonstrated by the fact that only 1 duct (in the standard treatment arm) was still patent at 28 days of age. Immaturity of the infant and the duct-closing mechanisms is always the dominant risk factor for failure of duct closure, and our data are consistent with this. Lower GA was the main risk factor for both failure to close and reopening of the duct; thus, suggesting caution in applying this strategy to the least mature infants would seem reasonable. The infant who received 15 doses of indomethacin was in the ECHO arm, a 694 g, 25-week GA infant who received an initial 6-day course of indomethacin, a 3-day course on day 18, and then a third 6-day course on day 55 with documented closure. Consideration is given for PDA ligation when infants remain ventilator-dependent with increased pulmonary blood flow from a PDA. Clinically asymptomatic infants with PDA are managed conservatively, with the duct allowed to close spontaneously. The lack of blinding was a limitation of the present study. But because many clinicians were involved in the care of these infants, this had no significant impact on the subsequent management of PDA. The study was not powered or designed to explore effects on clinical outcomes, and thus we cannot be confident that this strategy has no negative effects. Insignificant trends in both directions were seen. There was a trend of infants with IVH being randomized to the ECHO arm; however, those with major IVH received a similar number of indomethacin doses as those in the standard treatment arm (Table IV). In other words, they tended to have indomethacin-unresponsive ducts. Empirically, reducing drug exposure should reduce the risk of side effects. Insignificant trends toward less elevated serum creatinine levels and less gastrointestinal bleeding in the ECHO arm were consistent with this. Another limitation of this study is that it was tested using an early targeted strategy for PDA closure, when
Duration of Indomethacin Treatment of the Preterm Patent Ductus Arteriosus as Directed by Echocardiography
821
THE JOURNAL OF PEDIATRICS
www.jpeds.com
preterm newborns achieves similar closure rates while limiting exposure to a drug with known risks. n
Table III. Clinical outcomes
IVH grade 2-4, n (%) Pulmonary hemorrhage, n (%) Chronic lung disease, n (%) Creatinine > 120 mmol/L, n (%) Oliguria < 0.5 mL/kg/hour, n (%) Gastrointestinal bleeding, n (%) Necrotizing enterocolitis, n (%) Death, n (%)
Vol. 155, No. 6
ECHO (n = 34)
Standard (n = 40)
P value
7 (21) 2 (6) 2 (6) 2 (6) 4 (10) 3 (8) 3 (8) 7 (20)
3 (7) 5 (12) 6 (15) 5 (13) 2 (5) 6 (15) 2 (5) 5 (13)
.1 .3 .3 .3 .5 .5 .5 .4
We thank Dr Philip Beeby for statistical advice and the parents of the infants who consented to participate in this trial. Submitted for publication Nov 21, 2008; last revision received Apr 1, 2009; accepted Jun 8, 2009. Reprint requests: Dr Kathryn Browning Carmo, Grace Centre for Newborn Care, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia. E-mail: [email protected].
References indomethacin’s serum half-life is 60 to 70 hours and infants are exposed to serum concentrations for a prolonged period even after a single dose. It may be that our results cannot be extrapolated to a setting of late symptomatic treatment when drug levels decline much more rapidly. The study of Su et al6 did indicate that echocardiographically directed duration of late symptomatic treatment was as effective in closing the ductus arteriosus. This strategy also requires timely access to echocardiography in the neonatal intensive care unit, which may be difficult in a setting in which consultative echocardiography must be requested and reports are not immediately available. This may add another item to the growing list of reasons why neonatologists need to acquire point-of-care ultrasound skills.7 In summary, directing the duration of indomethacin therapy according to the early constrictive response of the PDA in
822
1. Bancalari E. Changes in the pathogenesis and prevention of chronic lung disease of prematurity. Am J Perinatol 2001;18:1-9. 2. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183-6. 3. Evans N, Iyer P. Assessment of ductus arteriosus shunt in preterm infants supported by mechanical ventilation: effect of interatrial shunting. J Pediatr 1994;125:t-85. 4. Evans N. Patent ductus arteriosus in the newborn. Curr Paediatr 2005;15: 381-9. 5. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 g. J Pediatr 1978;92:529-34. 6. Su BH, Peng CT, Tsai CH. Echocardiographic flow pattern of patent ductus arteriosus: a guide to indomethacin treatment in premature infants. Arch Dis Child Fetal Neonatal Ed 1999;81:F197-200. 7. Kluckow M, Seri I, Evans N. Functional echocardiography: an emerging clinical tool for the neonatologist. J Pediatr 2007;150:125-30.
Carmo, Evans, and Paradisis
ORIGINAL ARTICLES
December 2009
Figure 1. Total doses of Indomethacin.
Table IV. Infants with grade 3-4 IVH Patient number
GA, weeks Randomization Inborn or outborn Antenatal steroid coverage Failure of closure at 72 hours Time of grade 3 or 4 IVH Doses of indomethacin
1
2
3
4
5
6
7
24 Standard Inborn < 24 hours Died 6 hours 3
25 ECHO Inborn < 24 hours Yes 4 days 3
24 Standard Inborn None Died 36 hours 2
27 Standard Inborn < 24 hours No 48 hours 2
25 ECHO Inborn Complete No 48 hours 2
25 ECHO Outborn < 24 hours Died 30 hours 1
25 ECHO Outborn None Yes 72 hours 3
Duration of Indomethacin Treatment of the Preterm Patent Ductus Arteriosus as Directed by Echocardiography
822.e1
P
atent ductus arteriosus (PDA), resulting in a left-to-right shunt, is associated with various complications of prematurity.1,2 There is considerable controversy surrounding when and how best to treat PDA. This controversy reflects a balance between the uncertainties based on evidence regarding the benefits of PDA treatment versus the risks from the known side effects of indomethacin (ie, decreased renal, splanchnic, and cerebral blood flow). Whenever a drug treatment has significant side effects, the goal should be to design a regimen to give the minimum effective dose. Indomethacin is usually given in 3 to 6 doses, usually at 0.1 mg/kg, at 24-hour intervals. We have observed widely varying early constrictive responses of PDA to the first dose of indomethacin, ranging from minimal constriction with ducts that remain widely patent to complete duct closure within 24 hours. The aim of the present study was to explore whether the duration of indomethacin therapy could be shortened in infants exhibiting the best early constrictive response, as determined by echocardiography.
Methods This study was conducted at a tertiary referral neonatal intensive care unit at Royal Prince Alfred Hospital, Sydney, Australia between 2003 and 2007. The study design was approved by the Human Research Ethics Committee of the Sydney South Area Health Service. Written informed parental consent was obtained before study commencement. Infants born before 30 weeks of gestational age (GA) and requiring respiratory support were eligible. In each infant, an echocardiogram was performed between 3 and 12 hours of age. Exclusion criteria were the presence of intraventricular hemorrhage (IVH) grade 3-4, infant not expected to survive, infant more than 12 hours old, or lack of parental consent. This was a nonblinded, randomized controlled pilot study. The usual treatment for PDA in our institution at the time of this study involved an early targeted approach with three 0.1-mg/kg doses of indomethacin given at 24-hour intervals. PDA diameter was determined within the first 6 hours of life as described previously.3 If the duct diameter was > 2 mm at this time and there were no contraindications, the first dose of indomethacin was administered. Previous studies have shown that 60% of ducts exceeding this median diameter
ECHO GA IVH PDA
Echocardiographically directed indomethacin treatment arm Gestational age Intraventricular hemorrhage Patent ductus arteriosus
From the Department of Newborn Care, Royal Prince Alfred Hospital, Sydney, Australia (K.C., N.E.); Grace Centre for Newborn Care, Children’s Hospital at Westmead, Sydney, Australia (K.C.); Department of Newborn Care, Royal North Shore Hospital, Sydney, Australia (N.E., M.P.); and Faculty of Medicine, University of Sydney, Sydney, Australia (K.C., M.P.) The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.06.013
819
THE JOURNAL OF PEDIATRICS
www.jpeds.com
will eventually require therapeutic closure, and the other 40% will close spontaneously.4 Before the second indomethacin dose was given and after informed written consent was obtained from the parents, each infant was randomized into either the standard treatment arm or the ECHO arm. PDA diameter was remeasured just before the second dose was given. Infants in the standard treatment arm received three 0.1-mg/kg doses of indomethacin at 24-hour intervals irrespective of PDA diameter. Infants in the ECHO arm were given further doses of indomethacin only when the duct diameter remained >1.6 mm. Once the diameter had constricted to < 1.6 mm, no further doses were given. Randomization was by opaque, sealed, randomly assigned envelopes with block randomization in 2 GA groups, < 27 weeks GA and 27 to 29 weeks GA. All infants underwent echocardiography daily for the first 4 days and then on days 7, 14, and 28, to assess duct size and patency. Indomethacin was not given to any infant with a serum creatinine level >120 mmol/L. This level was chosen pragmatically as the level at which the clinicians in our unit would discontinue indomethacin. Further doses and repeat courses were administered at the discretion of the treating physician based on the clinical situation and the echocardiographic findings. Further courses of indomethacin 0.1 mg/kg for 3 days were given only if the PDA was >1.6 mm and the infant required respiratory support. Clinically nonapparent and nonsymptomatic reopening ducts seen on echocardiography were not retreated. All infants underwent routine head ultrasound examination at 7 and 28 days of age. The primary outcome was failure of PDA closure, defined as a duct remaining patent 24 hours after the final dose of the 3-day course of indomethacin would have been given (usually at about 72 hours of age). Secondary outcomes were those relating to the duct, including surgical ligation of the duct, reopening of the duct after documented closure, and total doses of indomethacin. Outcomes relating to side effects of indomethacin were serum creatinine >120 mmol/L, gastrointestinal bleeding (ie, blood in the gastric aspirate), necrotizing enterocolitis, and oliguria (urine output < 0.5 mL/kg/hour). Other clinical outcomes were pulmonary hemorrhage; IVH, Papile5 grade 2-4; chronic lung disease, defined as oxygen dependency at 36 weeks postmenstrual age; and mortality before hospital discharge. Our initial power calculation indicated that we needed a total of 180 infants (90 in each arm) to detect an increase in the incidence of late symptomatic PDA from 20% to 40% in the ECHO arm (power, 80%; P = .05), allowing for 80% recruitment. After 4 years of slower-than-expected recruitment, an interim analysis of the first 74 recruits found no difference in the incidence of the primary outcome between the 2 arms. In light of the slow recruitment and this lack of difference in the primary outcome, recruitment was ceased. Data were analyzed using SPSS version 15.0 (SPSS Inc., Chicago, Illinois). A P value < .05 was considered significant. The data analysis was done on an intention-to-treat basis. Categorical variables were analyzed using the Student 820
Vol. 155, No. 6 t-test, c2 test, or Fisher’s exact test for differences in proportions of independent populations. The Mann-Whitney Utest was used to assess nonparametric data.
Results We recruited 74 infants into the study between January 1, 2003 and June 30, 2007 (Figure 1; available at www.jpeds. com). Of 318 infants born before 30 weeks GA admitted to the nursery during this time period, 148 were eligible for the study, 138 either did not have a significant duct (< 2 mm) or had a closed duct, 72 were not approached, and 2 refused consent. During 2005, the study was suspended because there was no primary researcher on site. One infant was randomized to the standard treatment arm but was treated as in the ECHO arm, because the analysis was by intention to treat; this infant was maintained in the standard treatment arm. Thirty-four infants were randomized to the ECHO arm, and 40 were randomized to the standard treatment arm. The 2 arms were well matched at enrollment (Table I). All infants required respiratory support; 72 were initially ventilated, and 2 were supported with continuous positive airway pressure alone. The PDA diameter was >2.0 mm in all infants enrolled, and the direction of shunting was predominantly left to right. The incidence of failure of duct closure at 72 hours of age did not differ between the 2 arms (8 of 34 [25%] in the ECHO arm vs 10 of 40 [25%] in the standard treatment arm). The ECHO arm received significantly fewer doses of indomethacin than the standard treatment arm (median, 1 dose [range, 1 to 15 doses] vs 3 doses [range, 1 to 9 doses]; P < .001). Most infants in the ECHO arm received only 1 dose (22 [65%]), whereas only 1 (2.5%) infant in the standard treatment arm received only 1 dose (Figure 2). There was no significant difference in the incidence of reopening of PDA after closure between the 2 arms (8% in the ECHO arm vs 3% in the standard treatment arm; P = .5). There also were no significant differences between the arms in terms of the administration of a second course of indomethacin (18% vs 23%; P = .6) and the need for surgical ligation (3% vs 5%; P = .65). The second course of indomethacin was initiated on days 6, 8, 13, 18, and 20 (2 patients) in the ECHO arm and on days 4 (4 patients), 7, 12, 14, 21, and 23 in the standard treatment arm. One patient in the ECHO arm received a third course, initiated on day 55. The 3 surgical Table I. Baseline characteristics at study entry
Male sex, n (%) Mean GA, weeks Mean birth weight, g (SD) Mean cord pH GA < 27 weeks, n (%) GA 27 to 30 weeks, n (%) Complete antenatal steroids, n (%)
ECHO (n = 34)
Standard (n = 40)
P value
19 (56) 26.6 966 (294) 7.26 17 (50) 17 (50) 15 (44)
23 (57.5) 26.7 1008 (185) 7.27 19 (47.5) 21 (53) 24 (60)
1.0 .7 .4 .4 .8 .8 .2
Carmo, Evans, and Paradisis
ORIGINAL ARTICLES
December 2009
Figure 2. Recruitment and randomization of babies.
ligations were performed on days 26, 27, and 28. At 28 days of age, no ducts were still patent in the ECHO arm, but 1 duct (3%) remained patent in the standard treatment arm (Table II). Thirty-six infants (17 in the ECHO arm and 19 in the standard treatment arm) were born before 27 weeks GA. Mean birth weight was 848 g (range, 517 to 1220 g) in the < 27 weeks GA group and 1122 g (range, 590 to 1536 g) in the 27 to 29 weeks GA group. Failure of duct closure occurred in 20 (55%) infants in the < 27 weeks GA group, compared with only 3 (8%) infants in the 27 to 29 weeks GA group (P < .001). Reopening of the PDA occurred only in the < 27 weeks GA group (17 of 36 infants); in this group, 9 infants in the ECHO arm received only a single dose of indomethacin, whereas 8 infants in the standard treatment arm received 3 or more doses (P = .012). There were no significant differences in clinical outcomes between the 2 arms (Table III). Seven infants in the ECHO arm and 3 infants in the standard treatment arm had significant IVH. Seven of these cases (4 in the ECHO arm and 3 in the standard treatment arm) were grade 3-4 IVH. Three of the 4 infants in the ECHO arm with grade 3-4 IVH received more than 1 dose of indomethacin; in other words, they had a poor initial constrictive response to the first dose of indomethacin (Table IV; available at www.jpeds.com).
Discussion This study has shown that by tailoring the duration of indomethacin treatment to the ductal constrictive response Table II. PDA outcomes ECHO (n = 34)
Standard (n = 40) P value
Patent at 72 hours, n (%) 9 (26) 10 (25) Reopening after documented closure, n (%) 2/25 (8) 1/30 (3) Second course of indomethacin, n (%) 6 (18) 9 (23) Third course of indomethacin, n (%) 1 (3) 0 Patent at day 28, n (%) 0 1 (3) Surgical ligation, n (%) 1 (3) 2 (5)
.9 .5 .6 .3 .4 .6
24hours after the first dose, it is possible to significantly reduce the exposure to the drug without affecting eventual successful closure rates. Empirically, this strategy for dose minimization would allow therapy for ductal closure to at a reduced risk of side effects. Our data are consistent with those reported by Su et al,6 who used the Doppler pattern of flow through the ductus to limit the duration of indomethacin treatment. They used the high-velocity turbulent left-to-right pattern of flow that is seen when the ductus constricts, which they called the ‘‘closing pattern,’’ to determine when to cease further doses of indomethacin. By doing so, they achieved similar closure rates with significantly lower doses of indomethacin. There is a close relationship between the diameter of the ductus and the Doppler pattern of flow, so these 2 methods probably give the same information. In general terms, with ultrasound it often is preferable to measure variables by more than one method as a cross-check, so it may be logical to use both Doppler pattern, as described by Su et al,6 and diameter measurement, as used in the present study, when implementing this strategy. That PDAs respond to conservative management is demonstrated by the fact that only 1 duct (in the standard treatment arm) was still patent at 28 days of age. Immaturity of the infant and the duct-closing mechanisms is always the dominant risk factor for failure of duct closure, and our data are consistent with this. Lower GA was the main risk factor for both failure to close and reopening of the duct; thus, suggesting caution in applying this strategy to the least mature infants would seem reasonable. The infant who received 15 doses of indomethacin was in the ECHO arm, a 694 g, 25-week GA infant who received an initial 6-day course of indomethacin, a 3-day course on day 18, and then a third 6-day course on day 55 with documented closure. Consideration is given for PDA ligation when infants remain ventilator-dependent with increased pulmonary blood flow from a PDA. Clinically asymptomatic infants with PDA are managed conservatively, with the duct allowed to close spontaneously. The lack of blinding was a limitation of the present study. But because many clinicians were involved in the care of these infants, this had no significant impact on the subsequent management of PDA. The study was not powered or designed to explore effects on clinical outcomes, and thus we cannot be confident that this strategy has no negative effects. Insignificant trends in both directions were seen. There was a trend of infants with IVH being randomized to the ECHO arm; however, those with major IVH received a similar number of indomethacin doses as those in the standard treatment arm (Table IV). In other words, they tended to have indomethacin-unresponsive ducts. Empirically, reducing drug exposure should reduce the risk of side effects. Insignificant trends toward less elevated serum creatinine levels and less gastrointestinal bleeding in the ECHO arm were consistent with this. Another limitation of this study is that it was tested using an early targeted strategy for PDA closure, when
Duration of Indomethacin Treatment of the Preterm Patent Ductus Arteriosus as Directed by Echocardiography
821
THE JOURNAL OF PEDIATRICS
www.jpeds.com
preterm newborns achieves similar closure rates while limiting exposure to a drug with known risks. n
Table III. Clinical outcomes
IVH grade 2-4, n (%) Pulmonary hemorrhage, n (%) Chronic lung disease, n (%) Creatinine > 120 mmol/L, n (%) Oliguria < 0.5 mL/kg/hour, n (%) Gastrointestinal bleeding, n (%) Necrotizing enterocolitis, n (%) Death, n (%)
Vol. 155, No. 6
ECHO (n = 34)
Standard (n = 40)
P value
7 (21) 2 (6) 2 (6) 2 (6) 4 (10) 3 (8) 3 (8) 7 (20)
3 (7) 5 (12) 6 (15) 5 (13) 2 (5) 6 (15) 2 (5) 5 (13)
.1 .3 .3 .3 .5 .5 .5 .4
We thank Dr Philip Beeby for statistical advice and the parents of the infants who consented to participate in this trial. Submitted for publication Nov 21, 2008; last revision received Apr 1, 2009; accepted Jun 8, 2009. Reprint requests: Dr Kathryn Browning Carmo, Grace Centre for Newborn Care, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW 2145, Australia. E-mail: [email protected].
References indomethacin’s serum half-life is 60 to 70 hours and infants are exposed to serum concentrations for a prolonged period even after a single dose. It may be that our results cannot be extrapolated to a setting of late symptomatic treatment when drug levels decline much more rapidly. The study of Su et al6 did indicate that echocardiographically directed duration of late symptomatic treatment was as effective in closing the ductus arteriosus. This strategy also requires timely access to echocardiography in the neonatal intensive care unit, which may be difficult in a setting in which consultative echocardiography must be requested and reports are not immediately available. This may add another item to the growing list of reasons why neonatologists need to acquire point-of-care ultrasound skills.7 In summary, directing the duration of indomethacin therapy according to the early constrictive response of the PDA in
822
1. Bancalari E. Changes in the pathogenesis and prevention of chronic lung disease of prematurity. Am J Perinatol 2001;18:1-9. 2. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;75:F183-6. 3. Evans N, Iyer P. Assessment of ductus arteriosus shunt in preterm infants supported by mechanical ventilation: effect of interatrial shunting. J Pediatr 1994;125:t-85. 4. Evans N. Patent ductus arteriosus in the newborn. Curr Paediatr 2005;15: 381-9. 5. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 g. J Pediatr 1978;92:529-34. 6. Su BH, Peng CT, Tsai CH. Echocardiographic flow pattern of patent ductus arteriosus: a guide to indomethacin treatment in premature infants. Arch Dis Child Fetal Neonatal Ed 1999;81:F197-200. 7. Kluckow M, Seri I, Evans N. Functional echocardiography: an emerging clinical tool for the neonatologist. J Pediatr 2007;150:125-30.
Carmo, Evans, and Paradisis
ORIGINAL ARTICLES
December 2009
Figure 1. Total doses of Indomethacin.
Table IV. Infants with grade 3-4 IVH Patient number
GA, weeks Randomization Inborn or outborn Antenatal steroid coverage Failure of closure at 72 hours Time of grade 3 or 4 IVH Doses of indomethacin
1
2
3
4
5
6
7
24 Standard Inborn < 24 hours Died 6 hours 3
25 ECHO Inborn < 24 hours Yes 4 days 3
24 Standard Inborn None Died 36 hours 2
27 Standard Inborn < 24 hours No 48 hours 2
25 ECHO Inborn Complete No 48 hours 2
25 ECHO Outborn < 24 hours Died 30 hours 1
25 ECHO Outborn None Yes 72 hours 3
Duration of Indomethacin Treatment of the Preterm Patent Ductus Arteriosus as Directed by Echocardiography
822.e1