Abstract
This chapter reviews the epidemiology and current state of prophylactic and therapeutic pharmacologic management of the patent ductus arteriosus (PDA) in the very preterm neonate. Until now, the optimal management of PDA has been controversial in the scientific community, with no clear consensus or generally accepted guidelines for management. Most of the dispute stems from several sources: the natural history of PDA, uncertainty about immediate treatment effects, unpredictable side effects of pharmacologic and surgical therapy, and lack of information on long-term outcomes associated with treatment. The wide variations in PDA management reported worldwide reflect our poor understanding of these uncertainties. Although efforts are underway to expand our current understanding of the condition, clinicians should continue to consider the risks and benefits of different treatment options when deciding the correct clinical course of action.
Keywords
epidemiology, ibuprofen, indomethacin, neonate, paracetamol, patent ductus arteriosus, pharmacological management, preterm, treatment efficacy
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The clinical management of patent ductus arteriosus (PDA) in the very preterm neonate remains a controversial topic because the risks and benefits of medical or surgical interventions remain unclear.
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Nonsteroidal antiinflammatory drugs (NSAIDs) (indomethacin and ibuprofen) and acetaminophen are the most common and effective pharmacologic agents used for PDA closure.
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No major differences in the efficacy between the three agents have been reported in comparative effectiveness trials as far as closure of the PDA is concerned. However, there are differences among the drugs in their ability to directly affect cerebral perfusion and their side-effect profiles vary as well.
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Wide variations in the timing, dosage, and type of pharmacologic agent have been reported internationally.
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Conservative and pharmacologic management have become increasingly popular, resulting in less use of surgical ligation.
This chapter reviews the epidemiology and current state of pharmacologic management (prophylactic and therapeutic) of the patent ductus arteriosus (PDA) in the very preterm neonate. Until now, the optimal management of PDA has been controversial in the scientific community, with no clear consensus or generally accepted guidelines for management. Most of the dispute stems from several sources: the natural history of PDA, the hemodynamic significance of PDA (especially concerning its impact on cerebral oxygenation and its potential long-term consequences on neurodevelopment), variable efficacy of the available treatments, unpredictable side effects of pharmacologic and surgical therapy, and the lack of information on long-term outcomes associated with treatment. The wide variations in PDA management reported worldwide reflect our poor understanding of these uncertainties. Although efforts are underway to expand our current understanding of the condition, clinicians should continue to consider the risks and benefits of different treatment options when deciding the correct clinical course of action.
Apart from pharmacologic therapy, conservative management and surgical ligation of PDA are also used. Conservative management through watchful waiting may involve fluid restriction and supportive therapy. In contrast, pharmaceutical agents used for PDA either specifically reduce hemodynamically significant shunt effects or stimulate complete ductal closure. Pharmacologic agents stimulate PDA closure via inhibition of prostaglandin production, which plays a significant role in maintaining ductal patency in utero and during the first one to two postnatal weeks. These agents are specifically designed to target either cyclooxygenase (COX) or peroxidase (POX), the second and third enzymes, respectively, in the process of prostaglandin synthesis. These agents include the COX inhibitors indomethacin and ibuprofen and the POX inhibitor acetaminophen (paracetamol) ( Fig. 23.1 ). Adding to the complexity of pharmacologic management is the question of when to treat, which may include prophylactic (treat all without assessing), early asymptomatic (detect and treat early before PDA becomes significant during first week after birth), and symptomatic (treat when PDA becomes clinically and hemodynamically significant) treatment.
Epidemiology of Patent Ductus Arteriosus Treatment
Variations in the management of PDA in very preterm and very low birth weight infants have been well reported in North America, Europe, Australia, and Asia. These differences have been described for all aspects of treatment, including if, when, and how to treat PDA. Surveys conducted over the past 20 years regarding the practitioner’s approach to treatment of PDA have yielded consistently variable results. In North America a survey of 100 Canadian neonatologists in 1998 revealed a wide variation in practices regarding management of PDA both within and between centers. Fluid restriction and indomethacin were used for treatment by 89% of neonatologists surveyed, whereas surgery was reserved for patients unresponsive to pharmacologic agents or who had contraindications. Use of echocardiography for diagnosis of PDA also varied among clinicians. Almost a decade later, 56 fellowship program directors in the United States were surveyed regarding the management of PDA. A quarter of respondents were using prophylactic indomethacin for prevention of interventricular hemorrhage (IVH) and 9% used indomethacin to treat asymptomatic PDA. In cases of persistent PDA, three-quarters of respondents indicated use of more than one course of indomethacin, with nearly half reporting usage of two courses and half reporting three courses, if needed. Most respondents were keen on administering indomethacin for patients younger than 2 weeks and used echocardiographic criteria to determine PDA treatment.
Hoellering and Cooke also surveyed Australian and New Zealand neonatologists in 2007 for management of PDA in neonates of 28 weeks’ gestation or less or birth weights less than 1000 g. Expectant (or conservative) management of PDA was favored by 35% of clinicians, whereas 32% used echocardiographic-targeted prophylaxis, 16% used presymptomatic treatment, and 17% used a prophylactic approach; however, nearly half of participating units reported using more than one approach, often depending upon the preference of the individual practitioner. Interestingly, 86% of physicians used long courses of indomethacin and nearly one-quarter of respondents indicated that their approach was not influenced by published literature. This raises important questions regarding the level of effect that individual units or practitioners have on the outcomes of neonates with PDA.
In a survey of 24 European Societies of Neonatology and Perinatology, Guimaraes and colleagues reported data on 45 responses from 19 countries. The majority of neonatal units used intravenous indomethacin (71%), followed by intravenous ibuprofen (36%) and oral ibuprofen (29%); some units reported use of multiple agents. Approximately half of the centers used a second course and a quarter used a third course of pharmacotherapy in the event of persistent patency of the ductus. Nearly all (96%) units treated hsPDA, but a quarter would also treat non-hsPDA. Only one neonatal unit preferred surgical ligation as the first line therapy. In France, nearly three-quarters of the 49 neonatal units surveyed between 2007 and 2008 reported the use of both clinical and echocardiographic criteria to decide on treatment for PDA, whereas the remaining relied on echocardiographic criteria alone. Most units also used echocardiography to diagnose PDA, but the criteria used to describe hsPDA differed. All units used ibuprofen to treat PDA, with the majority of units using a standard course (see section “Ibuprofen” later). Between one-half to two-thirds of centers indicated a tendency to use a second course when either the first course failed or if the duct reopened after successful closure. In the event of contraindications to medical treatment or ductal malformation, 39% of units considered surgery as the primary treatment.
Irmesi et al. recently collated information from published randomized trials of PDA management around the world. They identified that treatment with indomethacin and ibuprofen was more prevalent in the United States and Canada, whereas ibuprofen was the most often used agent in Europe. Worldwide variations in treatment were further validated in an international survey of investigators from 317 neonatal units in 11 high-income countries. Japan, Finland, and the Tuscany region of Italy all routinely perform echocardiographic screening for PDA. Treatment rates of PDA based on routine echocardiography results alone, regardless of a patient’s clinical status, ranged between 11% and 87% (11% of units in Canada; 13% in Illinois; 20% in Israel; 33% in Sweden; 41% in Spain; 50% in Switzerland; 58% in Australia and New Zealand; 75% in Finland; 75% in Tuscany, Italy; and 87% in Japan) among those who conduct echocardiography screening. Acetaminophen was used as the primary treatment for PDA in nine units (one unit each in Australia/New Zealand and Canada; two units in Illinois; and five units in Israel).
Apart from the survey data described previously, reports of actual practices in the management of PDA have been published. For instance, data on outborn extremely low birth weight neonates in a Pediatric Health Information System showed a steady decline in indomethacin use and increase in ibuprofen use (from 12.8% to 38.9%) between 2007 and 2010. In another study, Hagadorn and colleagues examined trends in the management of PDA in 19 U.S. Children’s hospitals between 2005 and 2014 and linked the data to neonatal outcomes. Approximately three-quarters of infants with PDA were treated with pharmacologic management or surgery, with wide variation noted among hospitals. There was a steady decline in the number of neonates treated over the years, with the odds of treatment decreasing by 11% in each year of the study period. The trend of reducing treatment was temporally associated with a decline in mortality; however, the incidences of bronchopulmonary dysplasia (BPD), periventricular leukomalacia, retinopathy of prematurity (ROP,) and acute renal failure increased over that time. In a population-based cohort study, Edstedt Bonamy et al. evaluated regional variations and its relationship with outcomes in PDA management across 19 regions in 11 European countries between 2011 and 2012. The proportion of neonates ≤31 weeks’ gestation who received PDA treatment varied from 10% to 39% between units, and it was independent of perinatal characteristics of patients. Variations in PDA treatment rate did not correlate with neonatal outcomes.
In Canada, conservative management of PDA in neonates between 23 and 32 weeks’ gestation increased from 14% to 38% between 2006 and 2012, whereas using pharmacotherapy alone and surgical treatment alone decreased from 58% to 49% and 7.1% to 2.5%, respectively, and both pharmacotherapy and surgical ligation dropped from 21% to 10% (all P < .01) during the same time period. With an increase in conservative management, there was a reduction in the composite outcome of mortality or major morbidity between 2009 and 2012 compared with 2006 and 2008; however, there remains the possibility of confounding bias. Slaughter et al. attempted to adjust for residual confounding by incorporating clinician preference-based variation in practice as an instrument in their analyses. They reported that although an infant’s chance of receiving pharmacotherapy increased by 0.84% for each 1% increase in the hospital’s annual pharmacotherapy rate for treatment of PDA, there was no association between pharmacotherapy and mortality and mortality or BPD in neonates of ≤28 weeks’ gestation. This finding suggests that conservative management of PDA may be a rational approach for the population examined. However, we still do not know how to approach the individual patient ( Chapter 21 ).
In a prospective cohort from France, Rozé et al. evaluated the role of early screening (before day 3 of postnatal life) in neonates <29 weeks’ gestation. The authors determined that screened infants were more likely to be treated for PDA than unexposed infants (55% vs. 43%; odds ratio [OR] 1.62, 95% confidence interval [CI] 1.32 to 2.00). Screened neonates were at lower odds of mortality (OR 0.73, 95% CI 0.54 to 0.98) and pulmonary hemorrhage (OR 0.60, 95% CI 0.38 to 0.95). However, when instrumental variable analyses using unit preference for early screening was conducted, there was no association between early screening and mortality (OR 0.62, 95% CI 0.37 to 1.04), suggesting that questions about screening, prophylaxis, and treatment could only best be answered in well-designed randomized trials. The variations reported above in both survey designs and in studies comparing the evolution of approaches and their relationship with outcomes indicate that the management of PDA is widely variable within neonatal units and at regional, national, and international levels.
Pharmacologic Interventions
Pharmacologic interventions for PDA can be divided into two groups: agents used for symptomatic treatment (i.e., management of heart failure) and agents that induce PDA closure. Based on symptoms associated with heart failure, diuretics such as furosemide have been used to reduce overall fluid overload and pulmonary edema formation. Thus far, three randomized controlled trials (RCTs) of furosemide for symptomatic PDA have been conducted, but none of them demonstrated any benefit. On the contrary, increased prostaglandin synthesis following administration of furosemide may contribute to ductal patency. Diuretics, particularly furosemide, are also associated with various side effects, including electrolyte imbalance, nephrocalcinosis, and hearing impairment. The symptoms of heart failure associated with PDA in preterm neonates are usually managed by restricting fluid intake. Alternatively, digoxin is occasionally used for the management of heart failure; however, justification of its use has been theoretical due to limited clinical evidence available.
As previously mentioned, the three main pharmacologic agents used to stimulate PDA closure include indomethacin, ibuprofen, and acetaminophen (paracetamol), each of which is described next. The complexity of management of PDA is summarized in Fig. 23.2 , where strategies that have been tested in randomized trials are delineated.
Indomethacin
Mechanism of Action
Indomethacin is a potent and nonselective inhibitor of the COX enzyme and promotes PDA closure by inhibiting the synthesis of prostaglandins, including prostaglandin E2 (see Fig. 23.1 ). The half-life of indomethacin is 4 to 5 hours longer on average in preterm neonates less than 32 weeks’ gestation compared with those greater than 32 weeks’ gestation (17.2 ± 0.8 vs. 12.5 ± 0.5 hours) and thus, prolonged accumulation can occur in very preterm neonates.
Route, Dose and Frequency
Although the most common route of administration of indomethacin is intravenous, it has been used orally, rectally, and intraarterially. Six studies of oral use (ranging between 9 and 74 neonates) have reported PDA closure rates of 66%–67%. Intraarterial use in 26 neonates was successful in 76% of cases, whereas a 66% closure rate was observed in a small group of neonates treated either orally ( n = 1) or rectally ( n = 5). Both of these routes have not been widely used due to concerns of damage to mucosal layers from local direct effects of indomethacin, as well as the effects on prostaglandin synthesis inhibition affecting mucosal integrity of the gastrointestinal track, especially the ileum.
Intravenous indomethacin has been used in various dosing regimens. Although the majority of studies use three standard doses of 0.1 to 0.2 mg/kg/dose 12 to 24 hours apart, many modifications of this strategy have been carried out. In one study, dose escalation of indomethacin starting from 0.2 mg/kg and increasing to 1 mg/kg in nonresponders resulted in a 98.5% PDA closure rate. It should be noted that higher doses are typically associated with increased risk of side effects, which were not addressed in the study quoted. In another study a high-dose (0.2 to 0.5 mg/kg/dose) and low-dose (0.1 mg/kg/dose) regimen of indomethacin were compared in cases of persistent PDA following conventional treatment with the three conventional doses described previously. Although the authors reported no difference in PDA closure rates (55% vs. 48%, respectively), the infants exposed to the higher dosage displayed increased rates of renal compromise and moderate to severe retinopathy.
The usual duration for one course of indomethacin treatment is 48 to 72 hours. For some neonates, ductal closure can be a lengthy remodeling process and may need prolonged treatment. Five randomized trials compared PDA closure rates in neonates treated with a prolonged course of indomethacin versus routine treatment using a three-dose course and reported no difference in PDA closure rates but identified that an increased risk of necrotizing enterocolitis (NEC) was associated with longer indomethacin exposure (relative risk [RR] 1.87, 95% CI 1.07 to 3.27). Some practitioners advocate for an echocardiogram to be performed after the last dose (third dose of a routine course) and to continue treatment until the duct closes. However, based on concerns of adverse side effects, a prolonged course is not recommended by most.
Typically, indomethacin is administered as a slow infusion to avoid rapidly rising concentrations characteristic of bolus infusions. The potential impact of indomethacin concentration on cerebral, renal, and splanchnic blood flow has led to recommendations for infusion to be carried out over a 20- to 30-minute time period. Studies have reported reduced blood flow, and similar or higher closure rates (81% vs. 43%, P = .03), with bolus infusion compared with continuous infusion. However, as suggested by a previous systematic review, the evidence may be too limited to draw a conclusion regarding the superiority of either approach. Pharmacokinetic data from a small series of neonates suggest that in neonates who had lower plasma levels, faster clearance, and shorter half-life, the drug was less effective. In addition, there was a 20-fold variation in the plasma levels 24 hours after indomethacin administration among neonates.
Efficacy
Indomethacin is a potent medication for PDA closure, with historically proven rates of ductal closure. Closure rates following an initial course vary from 48% to 98.5% depending upon dose, duration, and method of administration. Many times a repeat course is provided when either a PDA fails to close following the first course or reopens after initial closure. The success rates with a second course are approximately 40%–50%. Very rarely is a third course of indomethacin attempted, because exposure to more than two courses has been associated with periventricular leukomalacia. It is unclear what pathologic mechanisms play a role in this association, but the indomethacin-induced prolonged decrease in cerebral blood flow might contribute to this phenomenon. The efficacy of indomethacin declines with decreasing gestational age and increasing postnatal age. Data regarding efficacy of indomethacin beyond 2 months of age suggest its ineffectiveness at this age. Similarly, it is unclear whether indomethacin is as useful in the treatment of periviable neonates of 22 and 23 weeks’ gestation because the efficacy decreases with decreasing gestational age. Of note is that most efficacy studies had very few infants in this gestational age range.
Timing of Administration
Indomethacin administration has been defined as prophylactic, early asymptomatic, and symptomatic treatment. Prophylactic use is employed in the first 12 hours after birth irrespective of the presence of a PDA. Because approximately half of preterm neonates with a gestational age of ≤28 weeks close their ductus arteriosus spontaneously, this strategy predisposes many neonates to overtreatment. The underlying basis of prophylactic administration is to reduce the impact of a PDA on hemodynamic instability before it becomes of sufficient size and to reduce the incidence and/or severity of peri/intraventricular hemorrhage (P/IVH). A systematic review and meta-analysis of 19 studies identified a significant reduction in the incidence of symptomatic PDA (RR 0.44, 95% CI 0.38 to 0.50) and need for surgical ligation of a PDA (RR 0.51, 95% CI 0.37 to 0.71) with prophylactic use compared with placebo. Indomethacin use was also associated with reduced rates of any P/IVH (RR 0.88, 95% CI 0.80 to 0.98) and severe P/IVH (RR 0.66, 95% CI 0.53 to 0.82). However, there was no improvement in neurodevelopmental outcomes during early childhood despite a reduction in the severity of P/IVH. This has created diverse opinions and practices regarding the use of prophylactic indomethacin in routine clinical settings. Certain subgroups, such as males and neonates less than 27 weeks’ gestation, have been identified as potential candidates for prophylactic indomethacin. In addition, units with a higher underlying rate of P/IVH might use this approach because in this situation the benefits likely outweigh the risks of prophylactic indomethacin administration.
Using indomethacin during the “early asymptomatic phase” significantly lowers the number of patients exposed to the drug compared with prophylactic measures described previously, yet several patients who would have had a spontaneous closure will still be exposed. A systematic review of three RCTs reported a reduction in symptomatic PDA (RR 0.36, 95% CI 0.19 to 0.68) and duration of oxygen therapy following indomethacin use in the early asymptomatic phase; however, there was no difference in any other neonatal complications and no assessment of long-term neurodevelopmental outcomes. An RCT compared treatment with indomethacin and a placebo within the first 12 hours after delivery in infants who positively screened for a “large” PDA, irrespective of their effects on hemodynamic status. The trial was stopped prematurely due to unavailability of indomethacin. There was a significant reduction in pulmonary hemorrhage (2% vs. 21%), early P/IVH (4.5% vs. 12.5%) and need for later medical treatment of PDA (20% vs. 40%) with early asymptomatic treatment. However, there was no difference in the primary outcome of death or abnormal head ultrasound findings.
Another approach is to treat PDA when it becomes symptomatic or hemodynamically significant. This method prevents unnecessary exposure to indomethacin as far as the PDA is concerned. Early treatment is used to describe the administration of the medication within the first 5 postnatal days, whereas late treatment is considered to occur in the second week after birth. A meta-analysis of four trials conducted between 1980 and 1990 revealed a significant reduction in BPD (OR 0.39, 95% CI 0.21 to 0.76) and duration of mechanical ventilation in infants receiving early versus late symptomatic treatment. Furthermore, in a randomized clinical trial, higher PDA closure rates were noted when treatment was begun on day 6 (73% vs. 44%, P < .001) and day 9 (91% vs. 78%, P < .05) versus later treatment. However, there was no difference in the rate of surgical duct ligation. Infants treated early were more susceptible to side effects, such as lower urine output and higher creatinine levels, and experienced more severe adverse events. Two other studies, one RCT and one before-after study, evaluated early versus late symptomatic treatment and concluded that delays in treatment are feasible and may reduce exposure to pharmacologic agents; yet, an increase in the combined outcome of death or BPD may result.
Side Effects
Indomethacin produces alterations in cerebral, renal, and splanchnic blood flow in a concentration-dependent manner and thus can lead to side effects, including cerebral ischemia, renal dysfunction, and gut ischemia, and it also impairs platelet aggregation. Reduction of blood flow in the renal arteries occurs within the first 30 minutes of indomethacin administration and continues for 2 hours. This can lead to elevations in urea and creatinine levels and even renal failure. Mucosal injury associated with indomethacin is secondary to effects on prostaglandin synthesis. Indomethacin is associated with spontaneous intestinal perforation, especially when given concomitantly with corticosteroids. However, the association of indomethacin with NEC is a subject of debate because the occurrence of NEC could be due to the disturbance of blood flow in the presence of a hsPDA rather than indomethacin alone. Still, indomethacin is also known to reduce splanchnic blood flow during its administration, and therefore this cause-and-effect relationship remains unclear. Because of concerns regarding intestinal blood flow, feeding is either discontinued, held, or sustained depending upon the attending medical team’s preference; however, similar outcomes have been reported with each approach.
Take-Home Message
Of all pharmacologic agents used to manage PDA, indomethacin is the most studied and used and is effective in treating PDA, with successful closure rates of approximately 70% with the first course and 50% with a repeat course. Recommended use includes a routine course of three doses after excluding contraindications, followed by repeat use for persistent PDA, if clinically indicated. Varying side effects, concerns over the impact of oral use on immature gastric mucosa, and the availability of other alternatives have led to a decrease in indomethacin use for treatment of PDA. Finally, the decrease in the rate of P/IVH with the use of prophylactic indomethacin might serve as an indication of its use in patients with higher risk of P/IVH (see Chapter 6 ).
Ibuprofen
Mechanism of Action
Ibuprofen is a nonselective COX inhibitor (see Fig. 23.1 ) that does not alter cerebral perfusion and has a significantly reduced effect on renal and gut perfusion. Ibuprofen inhibits COX-1 and COX-2 in a rapid and reversible manner. It is metabolized in the liver and excreted in urine, and thus physiologic impairment of hepatic or renal function may lead to adverse reactions.
Route, Dose, and Frequency
Ibuprofen can be given orally or intravenously. Although the peak levels are reached earlier with intravenous delivery, the elimination is slower after enteral administration and thus no adjustment in dose has been suggested for route of administration. The usual dose is 10 mg/kg on day 1, followed by two doses of 5 mg/kg 24 hours apart. However, suggestions for variable dosing based on advancing postnatal age (14-7-7 mg/kg for postnatal ages of 4 to 7 days and 20-10-10 mg/kg for postnatal ages >7 days) due to increased clearance of ibuprofen after birth have been made. A reduced rate of failure to close the ductus arteriosus has been observed with high doses of ibuprofen compared with low doses (RR 0.27; 95% CI 0.11 to 0.64). In a study of 60 preterm neonates with hsPDA, Pourarian et al. reported a 70% ductal closure rate in infants treated with an oral high-dose ibuprofen regimen (20-10-10 mg/kg) compared with a 37% closure rate with standard dosing (10-5-5 mg/kg) with no difference in adverse renal or gastrointestinal side effects. Adaptive dosing in the form of continued doses of ibuprofen (up to six doses if PDA was not closed) was associated with an 88% closure rate (similar to indomethacin). Doubling of the doses during the second course was associated with 60% closure rates compared with 10% in infants receiving the same dose when a consecutive treatment protocol was used, underscoring the need for further studies on ibuprofen dosing, pharmacokinetics, and pharmacodynamics.
Several trials have also compared the efficacy of routes of administration. A systematic review of oral versus intravenous ibuprofen indicated a lower risk of failure to close a PDA with oral ibuprofen use (RR 0.41, 95% CI 0.27 to 0.64). However, it should be noted that oral ibuprofen is associated with higher rates of gastrointestinal hemorrhage. Furthermore, higher rates of sustained closure have been observed after continuous infusion compared with bolus infusion (closure after one or two courses 86% in continuous infusion group versus 68% after one or two courses in the intermittent infusion group; P = .02).
Ibuprofen is available in two preparations, ibuprofen lysine and ibuprofen-tris-hydroxymethyl-aminomethane (THAM). The association of ibuprofen use with pulmonary hypertension was initially thought to be specific to the ibuprofen-THAM preparation; however, in a cohort of 144 neonates who received ibuprofen treatment for PDA, 10 cases developed pulmonary arterial hypertension, of which 7 occurred in the intravenous ibuprofen-THAM group ( n = 100), 2 in the oral ibuprofen group ( n = 40), and 1 who received intravenous ibuprofen lysine preparation ( n = 4). Risk factors for the development of pulmonary arterial hypertension were small for gestational age, maternal hypertension, and oligohydramnios. In one retrospective study from Italy, it was identified that ibuprofen lysine was more effective than ibuprofen THAM in PDA ligation (73% vs. 51%, P = .002) when used prophylactically in neonates of ≤28 weeks’ gestation.
Efficacy
Similar to indomethacin, ibuprofen is also an effective agent for closure of the PDA. The response rate for the first and second course mimics that of indomethacin, with approximate closure rates of 70% and 50%, respectively. A detailed systematic review of studies evaluating the therapeutic use of ibuprofen revealed that oral ibuprofen reduces failure of PDA closure (RR 0.26, 95% CI 0.11 to 0.62) and intravenous ibuprofen reduces the need for rescue treatment (RR 0.71, 95% CI 0.51 to 0.99) in comparison with placebo treatment. Ibuprofen has been compared with indomethacin in several RCTs. A systematic review of these trials indicated that ibuprofen and indomethacin (both oral and intravenous) are similar in terms of their efficacy in ductal closure (RR 1.00, 95% CI 0.84 to 1.20), rates of PDA reopening after the first course (RR 1.28; 95% CI 0.48 to 3.38), need for surgical ligation (RR 1.07, 95% CI 0.76 to 1.50), or need for retreatment with either agent (RR 1.20, 95% CI 0.76 to 1.90). In addition, ibuprofen was associated with a lower incidence of renal dysfunction (as indicated by its effect on urine output and serum creatinine), shorter duration of mechanical ventilation (−2.4 days; 95% CI −3.7 days to −1.0 day), and lower incidence of NEC (16 studies, 948 infants; RR 0.64, 95% CI 0.45 to 0.93). There were no differences in P/IVH, ROP, and survival or neurodevelopmental outcomes between the two agents.
Timing of Administration
Similar to indomethacin, ibuprofen has also been used as a prophylactic agent, with an aim to reduce P/IVH. Use of oral or intravenous ibuprofen prophylactically reduces the incidence of PDA on postnatal day 3 (oral, RR 0.34, 95% CI 0.16 to 0.73; intravenous, RR 0.37, 95% CI 0.29 to 0.47) compared with placebo or no treatment but has no benefit on any other neonatal outcomes.
Yoo et al. evaluated mortality and neonatal complications following the use of ibuprofen in two groups of neonates, including 14 (15.4%) preterm infants of less than 28 weeks’ gestation with clinical symptoms of hsPDA and 77 (84.6%) asymptomatic neonates with no evidence of hsPDA. Infants in the symptomatic group were of younger gestation (by 1 week) and lower birth weight (by 225 g) and had higher severity of illness scores. They also received more courses of ibuprofen. In a logistic regression analysis after adjustment for severity of illness, birth weight, birth year, and invasive ventilator care ≤2 postnatal days, there were no significant differences in mortality, frequency of secondary ligation, NEC, P/IVH, BPD, or death between the two groups. The authors concluded that treatment of asymptomatic or non-hsPDA may not be warranted.
In a randomized trial of infants of 23 to 32 weeks’ gestation and weighing less than 1250 g, neonates with non-hsPDA were randomized to receive either early ibuprofen ( n = 54) or treatment only when hsPDA was detected ( n = 51). The early ibuprofen group received treatment at a median age of 3 days, whereas the latter group received ibuprofen at a median of 11 days. Approximately half of the patients in the latter group never required ibuprofen. There was no difference in BPD, BPD or death, intestinal perforation, surgical NEC, grades 3 and 4 P/IVH, periventricular leukomalacia, sepsis, or ROP. Therefore this study suggests that infants with non-hsPDA do not benefit from early treatment. Although ibuprofen is an effective treatment for PDA in both forms (oral and intravenous), the impact of early treatment of PDA with ibuprofen on other neonatal conditions and neurodevelopmental outcomes is unknown.
Side Effects
Major side effects of ibuprofen include oliguria, high bilirubin levels, gastrointestinal hemorrhage, and pulmonary hypertension. The use of ibuprofen-THAM has been associated with higher rates of gastrointestinal complications, as well as pulmonary hypertension.
Take-Home Message
Several studies have confirmed that ibuprofen has similar potency for PDA closure as indomethacin but carries a lower profile of side effects. Given that oral ibuprofen is as effective as intravenous ibuprofen and is likely to result in reduced side effects, it may be the preferred agent among practitioners for ductal closure.
Acetaminophen (Paracetamol)
Mechanism of Action
Acetaminophen acts on PDA closure through the inhibition of POX-mediated conversion of prostaglandin G 2 to prostaglandin H 2 (see Fig. 23.1 ). It has no peripheral vasoconstrictive effects, which may be considered as an advantage over the COX inhibitors.
Route, Dose, and Frequency
The compound’s pharmacokinetics, including the route and dose of administration, have not been well studied compared with indomethacin and ibuprofen. Most case reports have evaluated acetaminophen after failure of PDA closure by routine measures. Several studies report the use of 15-mg/kg dose every 6 hours for 2 to 7 days. However, effects on other neonatal and neurodevelopmental outcomes are poorly understood. The requirement for prolonged administration calls into question the efficacy of paracetamol because PDA closure may be related to time rather than drug administration. This is particularly relevant with paracetamol because there is a paucity of placebo-controlled RCTs. Most studies have used oral acetaminophen; however, some have reported on the use of its intravenous formulation, which is not readily available in North America.
Efficacy
A total of seven RCTs ( Table 23.1 ) and several case series and reports have examined the efficacy of acetaminophen. Overall, most of the randomized studies have assessed acetaminophen treatment as a primary medical therapy, whereas the majority of case series and reports have described the use of acetaminophen after failure with COX inhibitors. The efficacy of acetaminophen in randomized studies has been similar to any other comparator treatment via any route. The most current Cochrane review analyzes only the first two published trials and highlights the need for more information on efficacy and long-term safety of the intervention. PDA closure rates range from 70.5% to 100% with acetaminophen use. Because most studies have only described acetaminophen use for PDA in neonates greater than 28 weeks’ gestational age, data for extremely preterm neonates is limited and the efficacy and side effects of acetaminophen in this population remain unanswered.
