Clinical Review & Education
Review
Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates Amish Jain, MBBS, MRCPCH; Prakesh S. Shah, MD, MSc, FRCPC
Patent ductus arteriosus (PDA) poses a diagnostic and therapeutic dilemma for clinicians. Diagnosis of persistent PDA and determination of its clinical and hemodynamic significance are challenging. Although the condition has been associated with substantial neonatal morbidities such as intraventricular hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis, most therapeutic approaches have failed to show improvement in these outcomes. As such, clinicians have tended toward conservative management strategies; however, the benefits and risks of such an approach are unclear. In this review, we explore various clinical diagnostic modalities, echocardiographic parameters for assessment of shunt presence, shunt volume and its effect on cardiovascular and hemodynamic status, and challenges in determining if a PDA is hemodynamically significant and clinically relevant. From the therapeutic aspect, we review current evidence on conservative, pharmacological, and mechanical (surgical or nonsurgical ligation) approaches to PDA closure. Dose, route, duration, and comparison of pharmacological strategies are reviewed, with implications for future research. JAMA Pediatr. doi:10.1001/jamapediatrics.2015.0987 Published online July 13, 2015.
D
iagnosis and management of patent ductus arteriosus (PDA) in preterm neonates represent a highly debated topic. Physiological studies have shown several hemodynamic alterations that normalize after successful ductal closure. Epidemiological studies have also demonstrated significant associations between a large PDA and neonatal outcomes, including intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and mortality. However, trials of treatment to date have not shown improvements in outcomes. Variability in approaches to evaluation and management of PDA has been suggested as one explanation for these inconsistent findings. In this review, we summarize evidence for PDA diagnosis methods and appraise the currently available therapeutic interventions.
Diagnosis and Evaluation Clinical Examination A clinical diagnosis of PDA in preterm neonates is typically made according to a high index of suspicion and the presence of 1 or more characteristic clinical signs. In several cases, a PDA shunt has been shown to be already left to right and of high volume as early as 6 hours of age.1 However, typical clinical signs are absent at this early stage. Furthermore, exclusive use of clinical signs for diagnosing PDA during the first week after birth has limitations (Table 1), with poor to moderate interobserver agreement.2-7 Lower blood pressures are the only consistently reported clinical finding associated with a large PDA on day 1 after birth.4 This lag is due to the lower shunt velocity and delayed adaptation of the immature myocardium to changes in preload. An increase in shunt velocity coinciding with declining pul-
Author Affiliations: Department of Paediatrics, Mount Sinai Hospital, and University of Toronto, Toronto, Ontario, Canada. Corresponding Author: Prakesh S. Shah, MD, MSc, FRCPC, Department of Paediatrics, Mount Sinai Hospital, Room 19-231F, 600 University Ave, Toronto, ON M5G 1X5, Canada ([email protected]).
monary vascular resistance produces a characteristic systolic murmur.7 Subsequent myocardial adaptation leads to tachycardia, increased stroke output, and contractility, which manifest clinically as hyperactive precordium, increased pulse volume, and wide pulse pressure. A chest radiograph may also reveal signs of pulmonary overcirculation and left heart dilatation. Among clinical signs, the presence of a murmur has the highest specificity for the presence of a PDA but lacks sensitivity. The study7 by Skelton et al reported that a murmur was heard in 11% of neonates with closed ducts and in 24% with a small PDA, indicating that isolated use of this clinical sign to diagnose a large PDA can lead to significant misclassification.
Echocardiography Although an initial PDA diagnosis typically involves clinical signs, echocardiography is the gold standard and is used for direct assessment of PDA diameter and shunt pattern, as well as indirect assessment of shunt volume, for which several surrogate measures have been proposed (Table 2). For hemodynamically significant PDAs, echocardiographic signs have been shown to precede clinical recognition by 1.8 days.7 PDA Diameter and Shunt Pattern
Patent ductus arteriosus diameter is measured at its narrowest part in end systole and can be expressed either as an absolute value in millimeters or indexed to the diameter of the left pulmonary artery (the ratio of PDA to LPA) or patient body weight (in millimeters per kilogram).8-10 However, the relative benefit of each approach is unknown. Shunt pattern assessment includes establishing directionality and velocity during systole and diastole. For a PDA to cause significant shunting from systemic to pulmonary circulation, the flow
jamapediatrics.com
(Reprinted) JAMA Pediatrics Published online July 13, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Yale University User on 07/13/2015
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Clinical Review & Education Review
Management of Patent Ductus Arteriosus in Preterm Neonates
needs to be unrestrictive and completely or almost completely left to right; the latter is sometimes referred to as a growing pattern.11 The PDAs of less than 1.5 mm in diameter are considered small because they are commonly restrictive, cause a mild increase in pulmonary circulation, and are rarely associated with echocardiographic markers of a high-volume shunt.12,13 Further subclassification of PDAs of at least 1.5 mm as moderate or large is based on incremental probability of a high-volume shunt. Although the diameter correlates well with shunt volume, using an absolute cutoff to describe hemodynamic significance may be misleading given the interobserver measurement variability (10%-15%) and its dynamic nature. Shunt Volume
Direct calculation of shunt volume is not feasible, so it is commonly estimated using surrogate indexes.14 A left-to-right, highvolume PDA shunt causes an increase in antegrade total and diastolic blood flow in branch pulmonary arteries, left atrial and left ventricle end-filling dimensions, mitral valve inflow, and compensatory changes in left ventricle hemodynamics. In the presence of an isolated ductal shunt, the right ventricular output is reflective of systemic blood flow, whereas the left ventricular output equals pulmonary blood flow. Lack of standardized measures limits the interpretation of validation studies1,8,12,13,15-20 involving echocardiographic indexes (Table 3). Only 3 studies to date have reported on some measure of pulmonary blood flow, including (1) the ratio of echocardiographyderived right and left ventricular stroke volumes in the absence of a significant interatrial shunt,19 (2) the ratio of left ventricular output to superior vena cava flow (a ratio ⱖ4 is likely associated with a 50% increase in pulmonary blood flow from the PDA),8 and (3) phase-contrast magnetic resonance imaging–derived left ventricular output, superior vena cava flow, and flow in the postductal descending aorta.17 Correlations between these markers are weak to moderate, with a significant overlap between cases and controls. Diastolic flow reversal in the descending aorta appears to be the most consistent feature of a high-volume PDA shunt. Early Prediction of Hemodynamically Significant PDA
Echocardiography indexes have also been used to identify PDAs that are likely to become hemodynamically significant (Table 4).9-11,21,22 However, the reported sensitivities and specificities ranged from 26% to 100% and from 6% to 100%, respectively.
Biomarkers A more recent development in PDA evaluation is the use of serum biomarkers, in particular brain-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTpBNP).23,24 The inactive precursor proBNP is released from ventricles in response to pressure or volume overload and then cleaved into the metabolically active BNP and inactive metabolite, NTpBNP. The results of studies24-26 have suggested that after the first 48 hours of age in preterm neonates the concentration of both of these biomarkers increases with the emergence of hemodynamically significant PDA and decreases with successful PDA closure; however, there was wide interstudy variability. The reported sensitivity and specificity cutoffs, respectively, ranged from 70 pg/mL (93% and 73%) to 1110 pg/mL (100% and 95%) for BNP and from 1203 pmol/L (100% and 91%) to 4000 E2
At a Glance • Diagnosis and management of patent ductus arteriosus (PDA) in preterm neonates is the most widely debated issue in modern neonatology. • Identifying hemodynamically significant PDA requires comprehensive risk assessment tools, including host factors, duct-related variables, parameters incorporating effects of the duct on other organ systems, and echocardiographic markers. • Indomethacin, ibuprofen, and acetaminophen are the most widely used agents in various forms to close ductal patency; however, the timing and method of administration to achieve improvement in duct-related outcomes remain to be investigated. • Surgical ligation of a PDA is associated with adverse neonatal and infantile outcomes; however, the issue of confounding by indication is not resolved. • Newer approaches of minimally invasive methods of ductal ligation may confer benefit; however, further comparative studies and the development of expertise are needed.
pmol/L (70% and 89%) for NTpBNP. Change in concentration on serial measurements has been shown to correlate with changes in PDA shunts, but the sensitivity remains weak.27 A significant overlap in the range of BNP concentrations has been observed between neonates with no PDA (0-118 pg/mL), small PDA (5-451 pg/mL), moderate PDA (5-1270 pg/mL), and large PDA (33-4510 pg/mL).27 Similarly, a significant overlap has been reported in NTpBNP concentrations, limiting its clinical application. The reasons for such variability remain unknown but may relate to the confounding effect of interatrial shunts and pulmonary hypertension.
Defining a Hemodynamically Significant PDA Despite widespread use of the term, there is no consensus on the definition of a hemodynamically significant PDA.28 Echocardiographic criteria used in clinical trials vary from left heart dimensions in 34 studies (the ratio of left atrium to aorta is the most common criterion [cutoff, 1.15-1.70]) to ductal diameter in 8 studies (cutoff, 1.5-2.0 mm). Although PDA diameter exceeding 1.5 mm combined with diastolic flow reversal in the descending aorta appears to represent the best echocardiographic criterion, this only provides semiquantitative evidence of a high-volume shunt, and not its clinical significance. The presence of a large PDA at 3 days of age was associated with IVH (adjusted odds ratio, 4.2; 95% CI, 1.3-14.0) and a composite of death or severe morbidity (adjusted odds ratio, 5.0; 95% CI, 1.4-19.0), but only for neonates of less than 28 weeks’ gestation.29 Neonates with a small PDA had outcomes similar to those with no PDA.29 A PDA disease staging system that incorporates clinical condition and echocardiographic findings has been suggested, but its clinical usefulness has not been evaluated.30 Furthermore, the proposed scoring systems do not account for host factors such as gestational age or preexisting morbidities. Given the heterogeneity in previously conducted studies and the intense debate on what constitutes a hemodynamically significant PDA, it is important to develop and test a comprehensive disease staging system that includes patient characteristics, clinical condition at assessment, and markers of PDA shunt volume, as well as duration of exposure to a PDA shunt.
JAMA Pediatrics Published online July 13, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Yale University User on 07/13/2015
jamapediatrics.com
Management of Patent Ductus Arteriosus in Preterm Neonates
Review Clinical Review & Education
Table 1. Usefulness of Clinical Signs for Assessment of Patent Ductus Arteriosus (PDA) in Preterm Neonates2-7 Parameters Evaluated and Outcome
Result
41 Neonates with BW
Review
Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates Amish Jain, MBBS, MRCPCH; Prakesh S. Shah, MD, MSc, FRCPC
Patent ductus arteriosus (PDA) poses a diagnostic and therapeutic dilemma for clinicians. Diagnosis of persistent PDA and determination of its clinical and hemodynamic significance are challenging. Although the condition has been associated with substantial neonatal morbidities such as intraventricular hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis, most therapeutic approaches have failed to show improvement in these outcomes. As such, clinicians have tended toward conservative management strategies; however, the benefits and risks of such an approach are unclear. In this review, we explore various clinical diagnostic modalities, echocardiographic parameters for assessment of shunt presence, shunt volume and its effect on cardiovascular and hemodynamic status, and challenges in determining if a PDA is hemodynamically significant and clinically relevant. From the therapeutic aspect, we review current evidence on conservative, pharmacological, and mechanical (surgical or nonsurgical ligation) approaches to PDA closure. Dose, route, duration, and comparison of pharmacological strategies are reviewed, with implications for future research. JAMA Pediatr. doi:10.1001/jamapediatrics.2015.0987 Published online July 13, 2015.
D
iagnosis and management of patent ductus arteriosus (PDA) in preterm neonates represent a highly debated topic. Physiological studies have shown several hemodynamic alterations that normalize after successful ductal closure. Epidemiological studies have also demonstrated significant associations between a large PDA and neonatal outcomes, including intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and mortality. However, trials of treatment to date have not shown improvements in outcomes. Variability in approaches to evaluation and management of PDA has been suggested as one explanation for these inconsistent findings. In this review, we summarize evidence for PDA diagnosis methods and appraise the currently available therapeutic interventions.
Diagnosis and Evaluation Clinical Examination A clinical diagnosis of PDA in preterm neonates is typically made according to a high index of suspicion and the presence of 1 or more characteristic clinical signs. In several cases, a PDA shunt has been shown to be already left to right and of high volume as early as 6 hours of age.1 However, typical clinical signs are absent at this early stage. Furthermore, exclusive use of clinical signs for diagnosing PDA during the first week after birth has limitations (Table 1), with poor to moderate interobserver agreement.2-7 Lower blood pressures are the only consistently reported clinical finding associated with a large PDA on day 1 after birth.4 This lag is due to the lower shunt velocity and delayed adaptation of the immature myocardium to changes in preload. An increase in shunt velocity coinciding with declining pul-
Author Affiliations: Department of Paediatrics, Mount Sinai Hospital, and University of Toronto, Toronto, Ontario, Canada. Corresponding Author: Prakesh S. Shah, MD, MSc, FRCPC, Department of Paediatrics, Mount Sinai Hospital, Room 19-231F, 600 University Ave, Toronto, ON M5G 1X5, Canada ([email protected]).
monary vascular resistance produces a characteristic systolic murmur.7 Subsequent myocardial adaptation leads to tachycardia, increased stroke output, and contractility, which manifest clinically as hyperactive precordium, increased pulse volume, and wide pulse pressure. A chest radiograph may also reveal signs of pulmonary overcirculation and left heart dilatation. Among clinical signs, the presence of a murmur has the highest specificity for the presence of a PDA but lacks sensitivity. The study7 by Skelton et al reported that a murmur was heard in 11% of neonates with closed ducts and in 24% with a small PDA, indicating that isolated use of this clinical sign to diagnose a large PDA can lead to significant misclassification.
Echocardiography Although an initial PDA diagnosis typically involves clinical signs, echocardiography is the gold standard and is used for direct assessment of PDA diameter and shunt pattern, as well as indirect assessment of shunt volume, for which several surrogate measures have been proposed (Table 2). For hemodynamically significant PDAs, echocardiographic signs have been shown to precede clinical recognition by 1.8 days.7 PDA Diameter and Shunt Pattern
Patent ductus arteriosus diameter is measured at its narrowest part in end systole and can be expressed either as an absolute value in millimeters or indexed to the diameter of the left pulmonary artery (the ratio of PDA to LPA) or patient body weight (in millimeters per kilogram).8-10 However, the relative benefit of each approach is unknown. Shunt pattern assessment includes establishing directionality and velocity during systole and diastole. For a PDA to cause significant shunting from systemic to pulmonary circulation, the flow
jamapediatrics.com
(Reprinted) JAMA Pediatrics Published online July 13, 2015
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Yale University User on 07/13/2015
E1
Clinical Review & Education Review
Management of Patent Ductus Arteriosus in Preterm Neonates
needs to be unrestrictive and completely or almost completely left to right; the latter is sometimes referred to as a growing pattern.11 The PDAs of less than 1.5 mm in diameter are considered small because they are commonly restrictive, cause a mild increase in pulmonary circulation, and are rarely associated with echocardiographic markers of a high-volume shunt.12,13 Further subclassification of PDAs of at least 1.5 mm as moderate or large is based on incremental probability of a high-volume shunt. Although the diameter correlates well with shunt volume, using an absolute cutoff to describe hemodynamic significance may be misleading given the interobserver measurement variability (10%-15%) and its dynamic nature. Shunt Volume
Direct calculation of shunt volume is not feasible, so it is commonly estimated using surrogate indexes.14 A left-to-right, highvolume PDA shunt causes an increase in antegrade total and diastolic blood flow in branch pulmonary arteries, left atrial and left ventricle end-filling dimensions, mitral valve inflow, and compensatory changes in left ventricle hemodynamics. In the presence of an isolated ductal shunt, the right ventricular output is reflective of systemic blood flow, whereas the left ventricular output equals pulmonary blood flow. Lack of standardized measures limits the interpretation of validation studies1,8,12,13,15-20 involving echocardiographic indexes (Table 3). Only 3 studies to date have reported on some measure of pulmonary blood flow, including (1) the ratio of echocardiographyderived right and left ventricular stroke volumes in the absence of a significant interatrial shunt,19 (2) the ratio of left ventricular output to superior vena cava flow (a ratio ⱖ4 is likely associated with a 50% increase in pulmonary blood flow from the PDA),8 and (3) phase-contrast magnetic resonance imaging–derived left ventricular output, superior vena cava flow, and flow in the postductal descending aorta.17 Correlations between these markers are weak to moderate, with a significant overlap between cases and controls. Diastolic flow reversal in the descending aorta appears to be the most consistent feature of a high-volume PDA shunt. Early Prediction of Hemodynamically Significant PDA
Echocardiography indexes have also been used to identify PDAs that are likely to become hemodynamically significant (Table 4).9-11,21,22 However, the reported sensitivities and specificities ranged from 26% to 100% and from 6% to 100%, respectively.
Biomarkers A more recent development in PDA evaluation is the use of serum biomarkers, in particular brain-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTpBNP).23,24 The inactive precursor proBNP is released from ventricles in response to pressure or volume overload and then cleaved into the metabolically active BNP and inactive metabolite, NTpBNP. The results of studies24-26 have suggested that after the first 48 hours of age in preterm neonates the concentration of both of these biomarkers increases with the emergence of hemodynamically significant PDA and decreases with successful PDA closure; however, there was wide interstudy variability. The reported sensitivity and specificity cutoffs, respectively, ranged from 70 pg/mL (93% and 73%) to 1110 pg/mL (100% and 95%) for BNP and from 1203 pmol/L (100% and 91%) to 4000 E2
At a Glance • Diagnosis and management of patent ductus arteriosus (PDA) in preterm neonates is the most widely debated issue in modern neonatology. • Identifying hemodynamically significant PDA requires comprehensive risk assessment tools, including host factors, duct-related variables, parameters incorporating effects of the duct on other organ systems, and echocardiographic markers. • Indomethacin, ibuprofen, and acetaminophen are the most widely used agents in various forms to close ductal patency; however, the timing and method of administration to achieve improvement in duct-related outcomes remain to be investigated. • Surgical ligation of a PDA is associated with adverse neonatal and infantile outcomes; however, the issue of confounding by indication is not resolved. • Newer approaches of minimally invasive methods of ductal ligation may confer benefit; however, further comparative studies and the development of expertise are needed.
pmol/L (70% and 89%) for NTpBNP. Change in concentration on serial measurements has been shown to correlate with changes in PDA shunts, but the sensitivity remains weak.27 A significant overlap in the range of BNP concentrations has been observed between neonates with no PDA (0-118 pg/mL), small PDA (5-451 pg/mL), moderate PDA (5-1270 pg/mL), and large PDA (33-4510 pg/mL).27 Similarly, a significant overlap has been reported in NTpBNP concentrations, limiting its clinical application. The reasons for such variability remain unknown but may relate to the confounding effect of interatrial shunts and pulmonary hypertension.
Defining a Hemodynamically Significant PDA Despite widespread use of the term, there is no consensus on the definition of a hemodynamically significant PDA.28 Echocardiographic criteria used in clinical trials vary from left heart dimensions in 34 studies (the ratio of left atrium to aorta is the most common criterion [cutoff, 1.15-1.70]) to ductal diameter in 8 studies (cutoff, 1.5-2.0 mm). Although PDA diameter exceeding 1.5 mm combined with diastolic flow reversal in the descending aorta appears to represent the best echocardiographic criterion, this only provides semiquantitative evidence of a high-volume shunt, and not its clinical significance. The presence of a large PDA at 3 days of age was associated with IVH (adjusted odds ratio, 4.2; 95% CI, 1.3-14.0) and a composite of death or severe morbidity (adjusted odds ratio, 5.0; 95% CI, 1.4-19.0), but only for neonates of less than 28 weeks’ gestation.29 Neonates with a small PDA had outcomes similar to those with no PDA.29 A PDA disease staging system that incorporates clinical condition and echocardiographic findings has been suggested, but its clinical usefulness has not been evaluated.30 Furthermore, the proposed scoring systems do not account for host factors such as gestational age or preexisting morbidities. Given the heterogeneity in previously conducted studies and the intense debate on what constitutes a hemodynamically significant PDA, it is important to develop and test a comprehensive disease staging system that includes patient characteristics, clinical condition at assessment, and markers of PDA shunt volume, as well as duration of exposure to a PDA shunt.
JAMA Pediatrics Published online July 13, 2015 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Yale University User on 07/13/2015
jamapediatrics.com
Management of Patent Ductus Arteriosus in Preterm Neonates
Review Clinical Review & Education
Table 1. Usefulness of Clinical Signs for Assessment of Patent Ductus Arteriosus (PDA) in Preterm Neonates2-7 Parameters Evaluated and Outcome
Result
41 Neonates with BW
