Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation

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1 Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation Martin Kluckow, MBBS, FRACP, and Nick Evans, DM, MRCP From the Department of Perinatal Medicine, King George Vth Hospital, Royal Prince Alfred Hospitals, Camperdown, Australia Objective: To identity early echocardiographic markers allowing prediction of subsequent symptomatic patent ductus arteriosus (PDA). Methods: One hundred sixteen preterm infants (<1500 gm) requiring mechanical ventilation underwent echocardiography at a mean postnatal age of 19 hours (range, 7 to 31 hours). Four potential markers were studied: the left atrial to aortic root ratio, pulsed Doppler measurement of left ventricular output, the minimum diameter of the color Doppler signal within the course of the duct (ductal diameter), and the direction of postductal aortic diastolic flow. Subsequent ductal closure or significant patency (if suspected clinically) was confirmed echocardiographically. Results: A significant PDA developed in 42 infants (36%). Ductal diameter was the most accurate echocardiographic marker in predicting subsequent significant PDA. With a ductal diameter of 1.5 mm or greater there were 34 true-positive, 11 false-positive, 63 true-negative, and 8 false-negative results, giving a positive likelihood ratio of 5.5 and a negative likelihood ratio of 0.22 for prediction of development of a PDA requiring treatment. The sensitivity was 81% and the specificity was 85%. Only one infant older than 28 weeks of gestational age had a significant PDA, and limiting the analysis to infants younger than 29 weeks of gestation further improved the predictive accuracy of ductal diameter. The positive likelihood ratio was 8. I and the negative likelihood ratio was 0.19, with a sensitivity of 83% and a specificity of 90%. Conclusion: Color Doppler measurement of the internal ductal diameter allows early prediction of significant PDA in preterm infants. (J PEDIATR 1995;I 27:774-9) Our serial echocardiographic color Doppler flow study of the patent ductus arteriosus in preterm infants 1 showed that a ductus that eventually became significant was usually of larger diameter when visualized early in the postnatal period than one that closed spontaneously. If early prediction were Submitted for publication Jan. 19, 1995; accepted July 3, Reprint requests: Nick Evans, DM, Department of Perinatal Medicine, King George Vth Hospital, Missenden Rd., Camperdown, New South Wales 2050, Australia. Copyright 1995 by Mosby-Year Book, Inc /95/$ possible, then earlier selective treatment of these presymptomatic infants with prophylactic indomethacin would be feasible. I PDA Patent ductus arteriosus LA/AO Left atrial/aortic [ratio] CI Confidence interval The aim of this study was to test prospectively the accuracy of color flow Doppler measurement of ductal diameter within the first 30 hours of life in predicting a subsequently significant PDA. 774

2 The Journal of Pediatrics Kluckow and Evans Volume 127, Number 5 METHODS One hundred sixteen premature infants weighing less than 1500 gm and with respiratory symptoms likely to require ventilation for more than 24 hours underwent echocardiographic studies between 7 and 31 hours of life (mean, 19 hours). Two study enrollment periods were included in the analysis. The first (48 babies) had echocardiograms obtained on a daily basis for the first 7 days; measurements were done early, but occasionally the investigator knew the outcome with respect to a significant PDA. The hypothesis that the internal ductal diameter on color flow Doppler echocardiography in the first 30 hours of life could predict a subsequently significant PDA was developed only after analysis of these data, thereby making any bias unlikely. In the second period of study (68 babies), echocardiograms were obtained within the first 30 hours of life and again at 7 days to confirm ductal closure. An additional echocardiogram was obtained earlier than 7 days only if requested by the clinician. The measurements of the initial echocardiogram were completed soon after the scan, and the investigator was masked with regard to clinical outcome. Echocardiographic data collection. An Acuson 128/ XP10 (Acuson, Inc., Mountain View, Calif.) ultrasonography machine incorporating color flow, pulsed wave, and continuous wave Doppler was used. Structural normality of the heart was established during the course of the scan. One infant had a ventricular septal defect and was excluded from further analysis. All studies were recorded on videotape for later review and performance of measurements, thus limiting the actual scanning time to 10 to 15 minutes. Four echocardiographic markers were measured. Left atrial~aortic root ratio. The LA/AO ratio was measured in the parasternal long-axis view at the level of the aortic valve by a standardized method. 2 Three measurements were taken and averaged. Ductus arteriosus diameter. The presence or absence of a PDA was then determined by direct ductal imaging in the high left parasternal view with color Doppler mapping. Color Doppler was set for automatic preprocessing and at the lowest velocity variance setting, and filters were set for maximum ranges for volume and velocity settings with a medium degree of motion discrimination (Acuson 128/ XP10, filter setting 3). The maximum velocity was usually between 0.64 m/sec and 0.8 m/sec. The color gain was set to obtain an optimal color flow image within the course of the ductus and to eliminate any peripheral color interference. If a PDA was present, the minimal diameter (i.e., point of maximum constriction) of the color flow jet within the course of the ductus was measured by a frame-by-frame analysis of the videotape (Figure). Three to five of the best quality end-systolic frames with the clearest discrete ap- pearance of the ductus were averaged to obtain the measurement of the ductal diameter. 3 lntraobserver error on measurements of ductal diameter was assessed by repeating the measurements on 27 echocardiographic studies stored on videotape without first ascertaining the previous measurement. The coefficient of variation between measurements was 12%. Left ventricular output. In each infant the left ventricular outflow tract was imaged from the apical view modified to incorporate the full length of the ascending aorta. 4 The pulsed Doppler range gate was placed distal to the aortic valve and aligned along the long axis of the aorta with the incorporated angle correction, if necessary. If the angle of insonation was greater than 20 degrees, the transducer was maneuvered to minimize the angle further. The flow velocity time signal was recorded and the maximum velocity time integral was averaged from five consecutive pulsed Doppler complexes with laminar flow. The heart rate was measured from peak-to-peak intervals of the Doppler velocity time signals. The internal diameter of the ascending aorta at the site of flow analysis was measm'ed at the end of systole by using frame-by-frame analysis of the two-dimensional image taken from a parastemal long axis view. Three to five cardiac cycles were averaged. The incorporated cardiac calculation software package on the Acuson was used to determine the left ventricular stroke volume with the formula velocity time integral x ( x [outflow diametela/4]). The left ventricular output was calculated as left ventricnlar stroke volume times the heart rate and the left ventricular output index as left ventricular output divided by body weight. Postductal aortic diastolic flow. The descending aorta was imaged from the high left parasternal or suprastemal position. The insertion of the ductus arteriosus into the aorta was determined by color flow Doppler mapping. The pulsed Doppler range gate was placed distal to the duct insertion in the descending aorta and the flow velocity time signal was recorded. The postductal aortic diastolic flow was classified into three groups: anterograde throughout diastole, no clear direction to diastolic flow, and retrograde throughout diastole. 3 Clinical management. Clinicians responsible for the care of each infant were not told the first day' s echocardiographic results unless there was clinical suspicion of the presence of apda. Infants were assessed daily, and decisions regarding the need for further investigations were made on the basis of physical signs, ventilatory requirements, and chest x-ray films. Our primary outcome measure was the development of a significant PDA defined as (1) a PDA that manifested with characteristic physical signs and symptoms such as a heart murmur, hyperdynamic precordial impulse or periph-

3 7 7 6 Kluckow and Evans The Journal of Pediatrics November 1995 Fi~ltlre. Measurement of ductal diameter is taken at the point of maximal constriction (arrows) within the course of the ductus when visualized with color Doppler flow mapping. Both of the measurements in the Figure were taken at approximately 24 hours of age. A, Small PDA (1.0 nun) in an infant in whom a significant PDA did not develop. B, Large PDA (2.3 mm) in an infant in whom symptoms developed 24 hours after the scan. MPA, Main pulmonary artery; LPA, left pulmonary artery; Desc Ao, descending aorta. eral pulses, low blood pressure, or apnea, often in association with respiratory instability, together with (2) echocardiographic confirmation of the presence of a hemodynamically significant PDA, defined as one that was widely patent (>-1.5 mm) with left-to-right shunt and retrograde or no postductal aortic diastolic flow) Standard management of a significant PDA in our unit includes fluid restriction and administration of indomethacin (0.1 mg/kg daily for 6 days) if not contraindicated. Any PDA that falls to respond to medical management and remains symptomatic is surgically ligated. Surfactant (Exosurf, Wellcome Foundation, Raleigh-Durham, N.C.) was administered as rescue therapy (two doses 12 hours apart) if the alveolar/arterial oxygen ratio was less than The average oxygenation index on the first day was calculated from arterial blood gas samples by the formula mean airway pressure times percentage of inspired oxygen divided by arterial partial pressure of oxygen. Statistical analysis. The sensitivity, specificity, and likelihood ratios were calculated for each of the four echocardiographic markers at optimum accuracy. The positive like- lihood ratio is the increase in the posttest probability that a PDA will occur when the test results are positive, compared with the pretest probability or actual incidence of PDA. The negative likelihood ratio is the decrease in this probability when the test results are negative. The higher the positive likelihood ratio and the lower the negative likelihood ratio, the greater the accuracy of the test. 5 The Mann-Whitney U test and stepwise logistic regression analysis were performed with a PC statistics package (SPSS/PC+, SPSS, Inc., Chicago, Ill.). Differences were considered significant at p less than Informed parental consent was obtained in all cases except when there was a clinical indication for an echocardiogram. The study was approved by the Royal Prince Alfred Hospital Ethics Committee. RESULTS Population. During the two study periods (February 1992 through March 1993 and June 1993 through July 1994) a total of 145 infants admitted to our neonatal intensive care unit metthe entry criteria for the study. Of these, 21 (14%) were

4 The Journal of Pediatrics Kluckow and Evans Volume 127, Number 5 not studied because neither of the investigators was available to perform echocardiography; 124 infants (86%) were entered into the study. Of these, eight were excluded from the analysis--three because they were scanned after 48 hours of age, one because of the presence of a ventricular septal defect, and four who died in the first 2 days, leaving 116 infants in the analysis. The babies had a mean gestation period of 27.4 weeks (range, 24 to 34 weeks) and a mean birth weight of 1028 gm (range, 512 to 1490 gin). Prenatal corticosteroids were administered to the mothers of 105 babies (91%). Exogenous surfactant was administered to 72 babies (62%). A significant PDA developed in 42 babies (36%), and 40 were treated with indomethacin, of whom two later required surgical ligation. Two infants had contraindications to indomethacin therapy and were successfully treated with conservative medical treatment. The mean age at which a significant PDA was diagnosed and first treated was 5.0 days (range, 1 to 15 days). All but one of the treated infants met our clinical and echocardiographic criteria for a significant PDA. At the time of diagnosis the mean ductal diameter was ram, the mean left ventricular output index was ml/kg per minute, the mean LA/AO ratio was , and all had absent or retrograde postductal aortic diastolic flow. One infant who was treated with indomethacin did not fulfill our echocardiographic criteria (PDA of 1.0 mm and anterograde flow); the symptoms that were ascribed to the small PDA were actually secondary to sepsis. The incidence of PDA fell with increasing gestational age; only one infant older than 28 weeks had a PDA. LA/AO ratio, left ventricular output, and postductal aortic diastolic flow. The sensitivity, specificity, and positive and negative likelihood ratios using these echocardiographic markers to predict a significant PDA were calculated at various cutoff points. An LA/AO ratio of 1.5 or greater was found to be the optimal cutoff point, with a sensitivity of 29% and specificity of 91%. The positive likelihood ratio was 3 (95% confidence interval, 1.32 to 7.24) and negative likelihood ratio 0.8 (95% CI, 0.63 to 0.96), both only just statistically significant. A left ventricular output index of more ihan 300 ml/kg per minute had a sensitivity of 26% and specificity of 92%, with similar positive and negative likelihood ratios. Thus when either of these two markers was increased a later PDA was more likely, but when normal they were of minimal use. The finding of altered postductal aortic diastolic flow (unclear direction to flow or retrograde flow) gave a sensitivity of 68% and specificity of 85% with better and significant positive and negative likelihood ratios of 4 (95% confidence interval, 2.5 to 8.0) and 0.4 (95% CI, 0.2 to 0.6), respectively. Ductal diameter. Ductal diameter was the most accurate marker. Multiple analyses of different ductal diameters were made, and the cutoff point of a ductal diameter at 1.5 mm or greater was found to be the most accurate predictor of subsequent significant ductal patency. Of the 45 infants with early ductal diameters of 1.5 mm or more, 34 eventually had a significant PDA (true-positive results) and 11 did not (false-positive results). Of the 71 infants with early ductal diameters less than 1.5 mm, 8 eventually had a PDA (falsenegative results) and 63 did not (tree-negative results). The sensitivity was 81% (95% CI, 69% to 93%) and specificity was 85% (95% CI, 77% to 93%). The positive likelihood ratio was 5.45 (95% CI, 3.1 to 9.6) and the negative likelihood ratio was 0.22 (95% CI, 0.12 to 0.42) for prediction of development of a significant PDA. That is, a positive test result increased the probability of a significant PDA by a factor of more than 5, and a negative test result decreased the probability of a clinically significant PDA by a factor of 4. Both of these likelihood ratios were statistically significant. Subgroup characteristics (true- and false-positive resuits, true- and false-negative results). Characteristics of each of these four subgroups were compared with the Mann-Whitney U test. Babies in the false-positive group had heavier birth weights (1212 vs 950 gm, p <0.001), were more mature (29 vs 26 weeks,p <0.001), and tended to have earlier scans (13 vs 17 hours, p <0.03) than those in the true-positive group. The PDA became clinically apparent significandy later in the false-negative group than in the true-positive group (6.8 vs 4.7 days, p = 0.01). Other predictive factors. Logistic regression was used to examine other factors that have previously been suggested as important in predicting a PDA. 6, 7 Gestational age, birth weight percentile, respiratory disease severity as measured by the average oxygenation index in the first 24 hours, need for rescue surfactant, and all of the echocardiographic measurements were entered into a stepwise logistic regression equation with significant PDA as the dependent variable. The two factors identified as significant were ductal diameter first (p <0.0001), and gestational age second (p <0.0001). None of the other echocardiographic measurements was independently significant as either a continuous or a dichotomous variable. Because only one baby of gestational age older than 28 weeks had a clinically significant PDA in our study population, a further analysis of the subgroup of infants younger than 29 weeks was performed. The use of a ductal diameter of 1.5 mm or greater in this group predicted a significant PDA with a sensitivity of 83% (95% CI, 71% to 94%), a specificity of 90% (95% CI, 81% to 98%), a positive likelihood ratio of 8.1 (95% CI, 3.5 to 18.9), and a negative likelihood ratio of 0.19 (95% CI, 0.10 to 0.38). Almost half the infants in the false-positive group in this study were older than 28 weeks, so confining the test to those at highest risk (i.e., 28 weeks or younger) further increased the predictive power.

5 7 7 8 Kluckow and Evans The Journal of Pediatrics November 1995 DISCUSSION This study has demonstrated that early prediction of a significant PDA is possible using the measurement of ductal diameter on color flow Doppler mapping. It seems that the rate of early ductal constriction is closely related to the likelihood of later development of significant PDA. Eleven infants had large ducts on the first day that subsequently closed spontaneously (false-positive group). This group was more mature and had a higher average birth weight. Their greater maturity may enable them to overcome the influence of factors, such as increased serum prostaglandin levels, s that presumably cause a failure of early postnatal ductal constriction in less mature infants. Some infants initially had small or closed ducts that later opened. In these babies the initial constriction worked well but later failed, possibly because of immaturity. The PDAs in this group became clinically apparent significantly later than they did in the tree-positive group. There are strong empirical reasons why early closure of a significant PDA is likely to be advantageous to the preterm infant. Left-to-right shunting through a PDA is associated with adverse outcomes. 9 A ductal shunt decreases lung compliance, 1 resulting in increased early ventilation requirements and possibly increased risk of chronic lung disease.h, 12 A PDA also adversely affects blood pressure TM 14 and systemic perfusion patterns to many organ systems, 15 including the brain. 16 A PDA often becomes apparent at a time when the initial disease process is beginning to resolve, causing interrupted improvement or a worsening of the infant's respiratory status. In addition, the use of exogenous surfactant may increase any left-to-right shunt by acutely increasing pulmonary compliance and reducing pulmonary arterial pressures.17 Randomized studies of prophylactic indomethacin administered in the first 24 hours of life show reduced incidence of both PDA and intraventricular hemorrhage 9 but have failed toshow improvements in respiratory outcome or overall mortality. 9' 13 However, the potential beneficial effect of prophylactic indomethacin may have been masked by several factors, including early treatment in the placebo group (2 to 3 days 18' 19 compared with the mean onset and treatment time of a PDA of 5 days in our group and 7 days in the study by Merritt et al.20) or the fact that a large proportion of the placebo group was also being treated for a significant PDA (56% in the study by Krueger et a1.19). A major concern with the prophylactic approach is that more than 60% of babies given indomethacin have a PDA that is hemodynamically insignificant and that will close spontaneously. 21 Indomethacin has many toxic effects, including reduction of cerebral blood flow22; reduced urine output, which may result in fluid overload; decreased lung compliance; and increased duration of assisted ventilation, z3 Each of these factors may adversely affect the outcome of infants who do not have a PDA. Because of these concerns, many have urged caution in adopting a policy of routine use of prophylactic indomethacin in low birth weight infants despite the potential benefits of prevention of both PDA and intraventricular hemorrhage. 24, 25 A few investigators have given indomethacin to infants identified as having presymptomatic PDAs on the basis of clinical or echocardiographic criteria, or a combination of both, between days 2 and 5. Metaanalysis of these small studies shows a nonsignificant change in respiratory morbidity, probably because of inadequate power. 13 We speculate that earlier and more accurate identification of a highrisk group of babies, all likely to have development of a significant PDA, would allow targeting with early prophylaxis and thus minimize the risk of neurologic and respiratory morbidity. Previous studies have evaluated echocardiographic prediction. Through a combination of Doppler and M-mode criteria Mellander et 1tl.26 found that they could predict a significant PDA with reasonable accuracy by day 3. Walther et al.27 showed by serial Doppler measurements that an increase in left ventricular output predicted the development of physical signs and symptoms of a PDA at least 24 hours before they appeared. Dudell and Gersony 28 used aortic contrast echocardiography to detect ductal patency and were able to predict a significant PDA with 75% accuracy in infants weighing less than 1500 gin. Our technique compares favorably to these methods, correctly predicting a clinically significant PDA in 81% of babies with 85% specificity. The main advantage of our technique is that prediction, and therefore treatment, can occur earlier. An echocardiogram can be performed anytime within the first 30 hours, but preferably between 16 and 28 hours for the most accuracy. The main limitation of color Doppler measurements is that the width of the color jet can be altered by the color settings of the machine; we used a standardized color Doppler procedure to minimize this effect. Measurement of the diameter of the color flow Doppler jet has been used previously in infants with ventricular septal defects. The diameter of each ventricular septal defect as measured by color Doppler flow mapping correlated very closely with the measurement obtained through an angiogram and at surgery. 29 The standard management of a PDA in our unit is to treat when the shunt is significant. In our study group, all 42 of the infants with PDAs were treated appropriately at a mean age of 5.0 days (range, 1 to 15 days) There were no unnecessary treatments, but there was a relative delay in treatment. If all the infants in our study group had been given prophylactic indomethacin, treatment would have been significantly earlier in those with a PDA, but 64% of the infants would have been treated unnecessarily. Targeting treatment by defining at-risk infants as those with a ductal diameter of 1.5

6 The Journal of Pediatrics Kluckow and Evans Volume 127, Number 5 mm or greater would have resulted in appropriate treatment at a mean age of 19 hours for 81% of the babies with significant PDAs. The other 19% had ducts with minimal early hemodynamic impact, which were treated appropriately when they became significant. Only 9% of the babies would have been treated unnecessarily with indomethacin. This latter group had an early large left-to-right shunt through larger-than-average PDAs 3 and may also have benefited from early closure, even though spontaneous closure at a later stage would have occurred. We conclude that it is possible to accurately identify preterm infants at high risk of eventually having significant PDAs and to then treat them with appropriate prophylactic indomethacin. Although the technique described here relies on echocardiography, the increasing availability of such modalities in neonatal intensive care nurseries may allow a more directed approach to indomethacin prophylaxis. A placebo-controlled, randomized trial of early targeted prophylactic indomethacin is needed, and results of such a trial may clarify the role of PDA in respiratory disease and intraventricular hemorrhage. REFERENCES 1. Evans N, Iyer P. Longitudinal changes in the diameter of the ductus arteriosus in ventilated preterm infants. Arch Dis Child 1995;72:F Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58: Evans N, Iyer P. Assessment of ductus arteriosus shunt in preterm infants requiring ventilation: effect of interatrial shunt. J PED]ATR 1994;125: Mandelbaum Isken VH, Linderkamp O. 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