Published online December 1, 2005
PEDIATRICS Vol. 116 No. 6 December 2005, pp. 1361-1366 (doi:10.1542/peds.2005-0293)
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Effectiveness and Side Effects of an Escalating, Stepwise Approach to Indomethacin Treatment for Symptomatic Patent Ductus Arteriosus in Premature Infants Below 33 Weeks of Gestation

Markus Sperandio, MD*, Bernd Beedgen, MD*, Reinhard Feneberg, MD*,{ddagger}, Christina Huppertz, MD*, Jürgen Brüssau, MD*, Johannes Pöschl, MD* and Otwin Linderkamp, MD*

* Division of Neonatology, Department of Pediatrics
{ddagger} Coordination Center for Clinical Trials, University of Heidelberg, Heidelberg, Germany


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. Symptomatic patent ductus arteriosus (sPDA) is a common problem in premature infants and can be treated effectively with intravenous indomethacin, leading to permanent ductal closure in 70% to 80% of infants. Infants who do not respond to pharmacologic closure of the duct ultimately have to undergo surgical or interventional closure of the PDA. Optimizing the pharmacologic treatment could offer an interesting approach to reduce the number of infants who need surgical closure of the duct.

Methods. We conducted a retrospective analysis in infants who were <33 weeks’ gestation, had sPDA, and were treated with high-dose intravenous indomethacin. From 1993 to 2002, 129 infants with sPDA received indomethacin after diagnosis of sPDA was confirmed by echocardiography. Treatment was started in all infants with intravenous indomethacin (0.2 mg/kg given 5 times at 0 hours, 12 hours, 24 hours, 48 hours, and 72 hours). When the ductus was still open at 36 hours, indomethacin every 12 hours was continued and single doses increased up to 1 mg/kg until ductal closure was achieved.

Results. In 68 (53%) of 129 infants who were treated with indomethacin, ductal closure occurred during intermediate-dose indomethacin therapy (up to 1.5 mg/kg total dose). In the 61 initial nonresponders, the continuation of indomethacin led to ductal closure in 59 infants. When infants who were treated with an intermediate dose were compared with the initial nonresponders, no differences in the incidences of renal or electrolyte abnormalities, gastrointestinal bleeding, intraventricular hemorrhage, or periventricular leukomalacia were found.

Conclusions. High-dose indomethacin after intermediate-dose therapy resulted in an overall closure rate of 98.5% (127 of 129). Although single indomethacin doses of up to 1 mg/kg were given, high-dose indomethacin was safe.

Key Words: patent ductus • indomethacin • premature infants

Abbreviations: sPDA, symptomatic patent ductus arteriosus • GI, gastrointestinal • NEC, necrotizing enterocolitis

Indomethacin, an indol derivative that inhibits prostaglandin synthesis, has been used since the early 1970s to treat symptomatic patent ductus arteriosus (sPDA) in premature infants.1,2 Intermediate indomethacin treatment is reported to be effective in 70% to 80% of cases.3,4 In infants who do not respond to pharmacologic therapy, surgical ligation or interventional closure of the ductus is performed. A recent meta-analysis that reviewed published data on prolonged versus short courses of indomethacin for the treatment of sPDA showed that prolonged indomethacin treatment has reduced the rate of PDA reopening.5 However, most of the studies that used prolonged indomethacin therapy applied low doses of the drug.6–9 Seyberth et al10 postulated that an effective threshold serum indomethacin level for successful ductal closure has to be reached. Nonresponders thus may need higher doses of indomethacin. However, there is concern that high doses of indomethacin may increase the risk for severe side effects. Two case reports on indomethacin overdosing in premature infants who were treated for PDA reported only a transient impairment in renal function without any other severe side effects.11,12 One of these infants received a 100-fold overdose of indomethacin (20 mg/kg), leading to serum indomethacin levels of almost 10000 µg/L, which is ~10-fold over the proposed upper limit of the therapeutic range of ~1000 µg/L. The overdose led to the successful closure of the PDA accompanied by transient renal failure (oliguria and hyponatremia) but without other severe side effects.11

So far, no studies on effectiveness and side effects of high-dose indomethacin in the treatment of premature infants with sPDA have been reported. We report here on a high-dose indomethacin treatment strategy in infants who were <33 weeks’ gestation and had sPDA, hypothesizing that this strategy may lead to an efficient and sustained closure of the ductus.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Infants and Design
The retrospective study was conducted at the Perinatal Centre of the University Hospital of Heidelberg (Heidelberg, Germany) and included all preterm infants who were <33 weeks of gestation, were born between January 1993 and December 2002, and had sPDA that was treated with indomethacin. A total of 1267 infants who were <33 weeks’ gestation were born during this period, and 167 (13%) infants received a diagnosis of sPDA and were treated with indomethacin.

Diagnosis of sPDA
Clinical and radiographic signs of sPDA included (1) unexplained worsening of ventilator settings; (2) a systolic or continuous murmur; (3) widening of the blood pressure amplitude or low blood pressure; and (4) cardiac enlargement, increased pulmonary vascularity, or pulmonary edema on chest radiography. The clinical diagnosis of sPDA was confirmed by echocardiography using an ATL-interspec scanner (Advanced Technology Laboratories, Solingen, Germany) with a 7.5-MHz probe. Echocardiographic criteria for sPDA included an increased left atrial diameter compared with aortic root (left-atrium-to-aortic-root ratio: >1.2), visualization of the ductus (>1 mm), and evidence of left-to-right blood flow through the open duct. Color and pulsed wave spectral Doppler scanning was applied to assess the direction and velocity of ductal flow. Ductal closure was documented by no ductal blood flow on color Doppler scanning.

Indomethacin Treatment Regimen
Infants with sPDA were treated according to the flowchart shown in Fig 1. After the diagnosis of an sPDA was made, treatment was started with 0.2 mg/kg indomethacin (Indocid PDA; Merck Sharp & Dohme Limited, Herdtfordshire, UK). Indomethacin (1 mg) was dissolved in normal saline (0.9%) to a final concentration of 0.1 mg/mL and infused over 30 minutes. The same dose was repeated 12 hours and 24 hours later. Echocardiography was conducted 24 to 36 hours after initiation of therapy. In case of PDA closure or filiform residual, 2 additional doses at 48 hours and 72 hours completed the intermediate-dose treatment regimen (Fig 1).


Figure 1
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  		Fig 1. Flow diagram for the treatment of sPDA using intravenous indomethacin.

 
In infants with echocardiographic evidence of PDA at 24 to 36 hours, the intravenous dose of indomethacin was gradually increased by steps of 0.1 mg/kg and given in intervals of 12 hours. Daily echocardiography was performed to monitor the presence of an open ductus. After echocardiographic evidence of a closed ductus, indomethacin was repeated 24 hours and 48 hours later with the same dose used for the last indomethacin infusion. When the open ductus persisted after reaching a single dose of 0.4 mg/kg, we continued to increase the single dose every 12 hours by 0.2-mg/kg steps until a maximum dose of 1 mg/kg was reached.

Monitoring of Side Effects
Before starting with the first dose of indomethacin, plasmatic coagulation parameters, platelet count, serum creatinine, and electrolytes were assessed. Therapy was initiated when coagulation parameters were normal and platelet counts were >40000/µL. Serum sodium was checked daily, and serum creatinine was checked at least once during indomethacin treatment. After treatment had been finished, serum creatinine was assessed again to monitor renal function after therapy. Oral feeding was continued throughout the indomethacin treatment.13 Infants were observed closely for signs of intraventricular hemorrhage, gastrointestinal (GI) bleeding or perforation, and necrotizing enterocolitis (NEC). In case of adverse events, indomethacin treatment was withheld until clinical status improved.

Treatment of Infants With Symptomatic PDA
We did not try to achieve ductal closure by fluid restriction but reduced daily fluid intake by 30% at the onset of indomethacin therapy. Thereafter, fluid and electrolyte administration was adjusted daily according to the daily measured body weight and serum electrolytes, aiming to keep weight constant during therapy. Low serum levels of sodium were treated with additional fluid restriction. When urine output declined below 1 mL/kg per hour, furosemide 0.5 to 1 mg/kg was given. Cranial ultrasonography was performed every other day. Intraventricular hemorrhage was classified according to Papile et al.14 Periventricular leukomalacia was defined as periventricular hyperechogenicity that progressed to the formation of periventricular white matter cysts. The diagnosis of NEC was made according to the modified Bell’s criteria.15

Statistical Analysis
Numeric data between the intermediate-dose and high-dose indomethacin groups were compared by Student’s t test or Wilcoxon rank-sum test as appropriate, including adjustments for multiple testing. Continuous numeric data are given as median (range) and 95% confidence intervals. Fisher’s exact test was used for the comparison of proportions. Statistical significance was set at P < .05. All statistical analyses were performed with SAS version 8.1 (The SAS Institute Inc, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Efficacy of Treatment
From January 1993 until December 2002, 167 infants who were <33 weeks’ gestation and had sPDA underwent treatment with indomethacin. Twenty-one (12%) infants who were treated with indomethacin were excluded because of accompanying congenital heart disease (n = 9), congenital renal disease (n = 4), other congenital diseases (n = 8), or maternal disease (n = 3). Seventeen additional infants were excluded because the available charts were incomplete. None of the excluded infants underwent surgical closure of the ductus. Clinical characteristics of the remaining 129 study infants who were included in the analysis are listed in Table 1.


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  		TABLE 1. Clinical Data of the Study Group

 
After clinical and echocardiographic diagnosis of sPDA was made, indomethacin therapy was started according to the flow diagram in Fig 1. Echocardiographic reassessment of the ductus was conducted after the third dose. In infants with closed or significantly reduced diameter of the ductus, the treatment was terminated after 2 additional doses (0.2 mg/kg at 48 and 72 hours). Ductal closure then was documented by no ductal flow on color Doppler scanning. In nonresponders, indomethacin was continued every 12 hours with single doses increased by 0.1-mg/kg steps from 0.2 mg/kg to 0.4 mg/kg and by 0.2-mg/kg steps from 0.4 mg/kg to 1.0 mg/kg (Fig 1). The decision to increase the dose of indomethacin was based on daily echocardiography. We successfully treated 73 (57%) of 129 infants with a maximum single dose of 0.2 mg/kg indomethacin, 39 (30%) of 129 infants received >0.2 to ≤0.4 mg/kg, 8 (6%) of 129 were treated with >0.4 to ≤0.6 mg/kg, 6 (5%) of 129 received >0.6 to ≤0.8 mg/kg, and finally 3 (2%) of 129 (including the 2 infants who had to undergo interventional closure of the ductus) were treated with >0.8 to ≤1 mg/kg indomethacin.

In infants who did not respond to intermediate-dose therapy, the continuation of intravenous indomethacin led to ductal closure in all but 2 (98.5%) infants. When we analyzed the total amount of indomethacin given (Fig 2), we found that a total dose of 1.5 mg/kg was sufficient to close the duct in 53% of affected infants (Fig 2). At a total dose of ≤4 mg/kg, 87% of sPDAs were closed (Fig 2).


Figure 2
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  		Fig 2. Ductal closure rate correlated to the total dose (mg/kg) of indomethacin given to infants with sPDA. The gray area represents ductal closure rates within the intermediate-dose group; the white area represents the ductal closure rate for the high-dose group.

 
Only 2 infants (twins at 28 weeks of gestation) did not respond to the pharmacologic therapy, although they received a total dose of 30 mg/kg and 33 mg/kg, respectively. Both infants underwent interventional closure of the open ductus at the age of 1 year. It is interesting that both patients had unexpectedly low serum trough levels of indomethacin (2400 µg/L and 2700 µg/L, respectively) despite the high doses given. Reopening of the ductus occurred in 14 (11%) infants studied. In these infants, indomethacin therapy was restarted and, when necessary, followed by increasing doses of indomethacin according to the flow diagram in Fig 1. The ductus was closed successfully in all 14 infants with reopened ductus. In addition, in infants in whom indomethacin therapy had to be interrupted for >36 hours because of adverse effects (n = 3; 1 infant because of thrombocytopenia, 1 infant with NEC grade 1, and 1 infant with gastric perforation caused by a gastric tube), later continuation of therapy led to ductal closure in all of them.

Taken together, these results provide strong evidence that the escalating stepwise approach to high-dose indomethacin is effective in permanently closing an sPDA. In addition, this treatment strategy dramatically lowers the number of infants who have to undergo surgical ligation or interventional closure of the duct.

Intermediate-Dose Versus High-Dose Indomethacin Therapy
To investigate the characteristics and potential side effects of a high-dose and long-term indomethacin therapy, we compared the 68 infants with intermediate-dose therapy (up to 1.5 mg/kg total dose of indomethacin) with the 61 infants who received high-dose indomethacin treatment (>1.5 mg/kg). Clinical characteristics and outcome of the 2 groups are summarized in Tables 2 and 3, respectively. Infants who required high-dose indomethacin treatment had a similar gestational age as infants in the intermediate-dose indomethacin group. Antenatal glucocorticoid prophylaxis and the incidence of respiratory distress syndrome were also similar in both groups.


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  		TABLE 2. Clinical Data of the Intermediate-Dose Group and High-Dose Group

 

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  		TABLE 3. Clinical Outcome

 
The most common causes of death in both groups (Table 3) were refractory hypoxemia or overwhelming infections. There were no significant differences in the incidences of NEC, GI bleeding or perforation, intraventricular hemorrhage grades 3 and 4, and periventricular leukomalacia between intermediate- and high-dose groups, as assessed by Fisher’s exact test, indicating that high doses of indomethacin did not cause an increase in morbidity and mortality. Of note, high doses of indomethacin did not lead to a significant increase in the incidence of GI perforation, which has been reported as a severe complication during indomethacin treatment.16

Analysis of renal function (Table 4) demonstrated a transient increase of serum creatinine in the intermediate-dose group from 92 µmol/L (1.04 mg/dL) before therapy to 120 µmol/L (1.36 mg/dL) during indomethacin therapy (P < .001). In the high-dose group, serum creatinine increased from 92 µmol/L (1.04 mg/dL) before therapy to 110 µmol/L (1.24 mg/dL) during indomethacin therapy (P < .001). Two to 3 weeks after indomethacin treatment, serum creatinine had returned to 63 µmol/L (0.71 mg/dL; P < .001 vs initial value) in the intermediate-dose group and to 74 µmol/L (0.84 mg/dL; P = .026 vs initial value) in the high-dose group. None of the values and changes was significantly different between the 2 groups. Serum creatinine after indomethacin treatment was slightly but insignificantly higher in the high-dose than in the intermediate-dose group (P = .08).


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  		TABLE 4. Laboratory and Clinical Variables During Indomethacin Therapy

 
The decrease in urine output monitored during indomethacin therapy was similar in the intermediate-dose and high-dose groups (Table 4). In addition, the number of infants in the high-dose group who had urine output below 1 mL/kg per hour and required treatment with furosemide was similar to the number of infants in the intermediate-dose group (11% vs 9%, respectively; P = .77). Serum sodium levels during indomethacin treatment were comparable in the intermediate- and high-dose group (Table 4). In addition, the number of infants with serum sodium values <130 mmol/L during indomethacin therapy was similar for the high-dose (38%) and the intermediate-dose groups (37%; P = .91).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study provides substantial evidence that a carefully monitored stepwise approach to the dosing of indomethacin treatment dramatically improved ductal closure rates to nearly 100% when used in preterm infants who were <33 weeks of gestation and had sPDA. This is of considerable clinical relevance, as it strongly reduces the number of infants who have to undergo surgical intervention to close the open duct. We observed that intermediate-dose indomethacin treatment (≤1.5 mg/kg total cumulative dose) in our patients led to a closure rate of 53%. This is lower than ductal closure rates reported by most other groups.5 However, by increasing the dose, we were able to close those open ducts that did not respond to intermediate-dose therapy. This apparent discrepancy with a low closure rate at intermediate-dose indomethacin and almost 100% closure rate at high doses of indomethacin may be related to our treatment protocol, which includes a rapid dose increase of indomethacin in case the ductus remains open early after the beginning of indomethacin treatment. Thus, in some infants with high-dose indomethacin, spontaneous ductal closure may have occurred without continuation of indomethacin treatment, which could explain at least in part the high success rate reported from those studies in which conventional doses of indomethacin were used.5

There have been several reports about indomethacin overdosage in preterm infants, ranging from a 10-fold to a 100-fold overdose.12 It is interesting that no severe side effects other than transient renal failure have been observed in those infants. Our results demonstrated no significant differences in side effects when we compared the infants who were treated with an intermediate-dose with infants who received high doses of indomethacin. This was true not only for kidney function but also for other reported side effects, such as abdominal problems and platelet dysfunction. It is noteworthy to mention that abdominal side effects, including NEC, have been considered for a long time to be one of the major risks during treatment with indomethacin. This prompted many neonatal centers to stop oral feeding during indomethacin therapy. However, recent data from a retrospective analysis showed that enteral feeding during indomethacin therapy does not lead to an increase in abdominal side effects during therapy.13 In our center, we continue with oral feeding during indomethacin therapy, provided that this does not interfere with fluid restrictions.

Although we did not regularly obtain serum indomethacin levels, we found fairly low indomethacin levels from sporadic measurements performed in infants who received high doses of the drug. This suggests that preterm infants may have widely differing pharmacodynamic responses to indomethacin treatment, leading to a broad range of serum levels for a given indomethacin dose. This observation is important, as an earlier study proposed an effective threshold serum indomethacin level for successful closure of the duct.10 In some infants, indomethacin doses that currently are recommended may not be high enough to reach and sustain the proposed threshold level. In fact, the 2 nonresponders had unexpectedly low serum indomethacin levels for the doses given. It is also noteworthy that these 2 infants were twins, who obviously shared similar properties to metabolize indomethacin. Jackson et al17 proposed that the maintenance of a therapeutic serum level of 475 µg/L to 3500 µg/L over a critical period of 72 hours is essential for the permanent closure of the duct. Additional investigations in our hospital are under way, aiming to correlate serum indomethacin levels with the doses of indomethacin given to close successfully patent ducts in preterm infants with sPDA.

Recently, ibuprofen was shown to be effective in the treatment of sPDA. In addition, studies that compared ibuprofen and indomethacin revealed no difference in ductal closure rates, whereas side effects were significantly reduced in ibuprofen-treated infants.18 However, recently Ahlfors et al19 reported that ibuprofen in dosages used for the treatment of sPDA leads to displacement of bilirubin from albumin in vitro, causing a dramatic increase in free bilirubin. Another group reported 3 infants who were treated with ibuprofen and developed pulmonary hypertension responsive to nitric oxide treatment.20

In summary, our results clearly show that the use of high single doses of indomethacin up to 1 mg/kg leads to ductal closure rates of nearly 100%. This is a significant improvement over conventional treatment regimens with closure rates of 70% to 80% necessitating surgical or interventional treatment for 20% to 30% of patients with sPDA. As we did not observe more side effects in infants who received high doses of indomethacin when compared with intermediate-dose therapy, we strongly advocate the application of this treatment strategy in preterm infants who have sPDA.


   FOOTNOTES
 
Accepted Apr 12, 2005.

Reprint requests to (M.S.) Division of Neonatology, Department of Pediatrics, University of Heidelberg, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany. E-mail: markus.sperandio{at}med.uni-heidelberg.de

No conflict of interest declared.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  17. Jackson JK, Abdel-Rahman SM, Reavey D, Leeks S, Garg U, Hall RT. Use of indomethacin serum concentration in predicting effectiveness of dosing for symptomatic patent ductus arteriosus [abstract]. Hot Topics in Neonatology. Washington DC; 2000:352
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics



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