Acta PBdiatr 81: 672-5. 1992
Atrial natriuretic peptide in the diagnosis of patent ductus arteriosus FJ Weir, A Smith, P Littleton, N Carter and PA Hamilton Department of Child Health. St George's Hospital Medical School, London, UK
Weir FJ, Smith A, Littleton P, Carter N, Hamilton PA. Atrial natriuretic peptide in the diagnosis of patent ductus arteriosus. Acta Paediatr 1992;81:672-5. Stockholm. ISSN 0803-5253 The aim of this study was to measure plasma atrial natriuretic peptide in preterm infants with a patent ductus arteriosus before and after closure with indomethacin. Atrial natriuretic peptide was measured in 28 preterm infants with clinical and echocardiographic evidence of a patent ductus arteriosus and in eight preterm infants who did not develop clinical evidence of a patent ductus arteriosus. Plasma concentration of atrial natriuretic peptide was measured by radioimmunoassay. In 18 infants the patent ductus arteriosus closed after one course of indomethacin; atrial natriuretic peptide levels decreased from median 1240 pg/ml (range 201-5483 pg/ml) to 266 pg/ml (range 62-1 108 pg/ml). In four infants the patent ductus arteriosus closed after two courses of indomethacin and two infants had surgical ligation after indomethacin treatment failed. The patent ductus arteriosus closed spontaneously in four infants (atrial natriuretic peptide median level 152 pg/ml, range 61-495 pg/ml). In the eight infants without patent ductus arteriosus, atrial natriuretic peptide level was median 224 pg/ml (range 38-876 pg/ml). Measurement of plasma atrial natriuretic peptide concentration has a role in predicting when indomethacin treatment is indicated. 0 Atrial natriureticpeptide, indomethacin,patent ductus arteriosus, preterm infants PA Hamilton, Department of Child Health, St George's Hospital, Cranmer Terrace, London S WI70RE.
UK
Treatment of a patent ductus arteriosus (PDA) with Patients and methods indomethacin reduces morbidity (1) but is not without side effects and the diagnosis of a clinically significant Infants of less than 33 weeks' gestational age were PDA that should be treated is difficult to determine by studied. The diagnosis of a PDA was suspected on the clinical examination alone (2). Echocardiography con- basis of auscultation and assessment of the pulses, and firms the early diagnosis (3) but cannot distinguish confirmed by two-dimensional and Doppler echocarwhich ducts will close spontaneously and is not readily diography performed within 24 h of clinical diagnosis using a Hewlett-Packard Sonos 1000. Indomethacin available in every unit. Atrial natriuretic peptide (ANP) is a polypeptide treatment was begun on the same day if there was produced from a prohormone that is stored in secretory evidence of failure or exacerbation of respiratory disgranules in the cardiac atria (4). Recent work has tress and there were no contraindications. Echocardiosuggested that ANP may have an important role in graphy was repeated within three days of treatment to preterm neonates as the peak plasma ANP concentra- confirm duct closure. Three doses of indomethacin 0.2 mg/kg (one course) tion coincides with the maximal diuretic phase of respiratory distress syndrome (RDS) ( 5 ) and correlates were given iv at eight-hourly intervals and infants were with sodium excretion (6). ANP levels are increased in fluid restricted, usually to 120 ml/kg/day. Arterial blood the first few days of life in preterm infants (7) and samples were obtained from indwelling arterial cathextremely high levels have been observed in infants with eters at the same time as clinically indicated blood samples. Samples were taken when a PDA had been PDA (8). It has been shown that ANP concentrations are diagnosed, then once daily while the duct was clinically related to the size of the left-to-right shunt across a PDA apparent until treatment, and at one, two and four days (9) and to atrial size (lo), and that levels decrease after after treatment. Samples were obtained three times daily in a group of infants with RDS but no PDA, for surgical closure of the PDA (10, 1 1). The aim of this study was to determine if, in preterm comparison. Each blood sample was placed in a tube containing infants, a high plasma ANP concentration correlates with the presence of a PDA which is clinically significant EDTA and immediately spun in a high-speed microcenand requires medical intervention and if levels decrease trifuge; the plasma was stored at -20 "C until assay. ANP concentration was measured by radioimmunoafter successful closure with indomethacin.
A N P andpatency of the ductus arreriosus
ACTA PRDIATR 81 (1992)
assay using h-ANP 1-28 antiserum (Peninsula Laboratories) as described previously (12). The plasma sodium concentration was recorded daily and the plasma osmolality was measured on each sample. Statistical analyses of the plasma ANP concentration results were performed using the Wilcoxon non-parametric test. Statistical analyses of the serum sodium and plasma osmolality results were performed using Fisher’s modified least significant difference test to the 0.05 degree level, and Gabriel’s test for confirmation of the results from Fisher’s test. Approval for this study was received from the hospital Ethics Committee.
673
Table 2. Plasma ANP concentrations,
ANP @g/ml) (median (range))
Group A No PDA
224 (38-876)
Spontaneous closure
152 (61-495)
B
C Before indomethacin After indomethacin (closed)
1240 (201-5483) 266 (62-1 108)**
D Before 1st course Before 2nd course After closure
616 (138-1926) 888 (328-1520) 271 (90-604)
E
. Before 1st course
Results The infants were divided into five clinical groups: group A: RDS but no clinical evidence of PDA; group B: PDA closed spontaneously; group C: PDA closed after one course of indomethacin; group D: PDA closed after two courses of indomethacin; group E: PDA surgically ligated after two courses of indomethacin. The clinical details of the infants studied are shown in Table 1. There were no statistical differences between the groups for birth weight or gestational age. The infants had a median (range) age of 3 (1-8) days in group A. At diagnosis of the PDA, the infants in group B were aged 13 (3-60) days, in group C 6 (2-17) days, in group D 6 (4-8)days and in group E 4 (2-6) days. At first treatment with indomethacin the infants were aged 7 (2-1 7) days in group C, 7 (5-8) days in group D and 6 (5-7) days in group E. No correlation was observed between plasma ANP concentration and postnatal age in the group A infants. Table 2 shows the plasma ANP concentrations. These represent the mean values for each individual before or after treatment. For completeness, group C includes two infants in whom only pretreatment levels were obtained. Analysis of significance is unchanged if these two patients are excluded. There was no statistically significant difference in the plasma ANP concentration between group A and group B (spontaneous closure). In group C (one course of indomethacin), the plasma ANP concentration was significantly higher before closure than after closure (Fig. 1) and significantly higher than
Table I . Infant details.
Group A B C D E
326 (186-595) 465 (216-798) 749 (368-1004) I79 (48-399)
Before 2nd course Before ligation After ligation
No. of infants
Gestation (weeks) (median (range))
Birth weight (kg) (median (range))
8 4 18 4 2
27 (25-29) 26 (24-3 I ) 26 (24-31) 26 (25-30) 28 (24-33)
0.89 (0.69-1.33) 1.10 (0.73-1.74) 0.85 (0.63-1.82) 0.92 (0.81-1.46) 1.27 (0.84-1.70)
** p
Atrial natriuretic peptide in the diagnosis of patent ductus arteriosus FJ Weir, A Smith, P Littleton, N Carter and PA Hamilton Department of Child Health. St George's Hospital Medical School, London, UK
Weir FJ, Smith A, Littleton P, Carter N, Hamilton PA. Atrial natriuretic peptide in the diagnosis of patent ductus arteriosus. Acta Paediatr 1992;81:672-5. Stockholm. ISSN 0803-5253 The aim of this study was to measure plasma atrial natriuretic peptide in preterm infants with a patent ductus arteriosus before and after closure with indomethacin. Atrial natriuretic peptide was measured in 28 preterm infants with clinical and echocardiographic evidence of a patent ductus arteriosus and in eight preterm infants who did not develop clinical evidence of a patent ductus arteriosus. Plasma concentration of atrial natriuretic peptide was measured by radioimmunoassay. In 18 infants the patent ductus arteriosus closed after one course of indomethacin; atrial natriuretic peptide levels decreased from median 1240 pg/ml (range 201-5483 pg/ml) to 266 pg/ml (range 62-1 108 pg/ml). In four infants the patent ductus arteriosus closed after two courses of indomethacin and two infants had surgical ligation after indomethacin treatment failed. The patent ductus arteriosus closed spontaneously in four infants (atrial natriuretic peptide median level 152 pg/ml, range 61-495 pg/ml). In the eight infants without patent ductus arteriosus, atrial natriuretic peptide level was median 224 pg/ml (range 38-876 pg/ml). Measurement of plasma atrial natriuretic peptide concentration has a role in predicting when indomethacin treatment is indicated. 0 Atrial natriureticpeptide, indomethacin,patent ductus arteriosus, preterm infants PA Hamilton, Department of Child Health, St George's Hospital, Cranmer Terrace, London S WI70RE.
UK
Treatment of a patent ductus arteriosus (PDA) with Patients and methods indomethacin reduces morbidity (1) but is not without side effects and the diagnosis of a clinically significant Infants of less than 33 weeks' gestational age were PDA that should be treated is difficult to determine by studied. The diagnosis of a PDA was suspected on the clinical examination alone (2). Echocardiography con- basis of auscultation and assessment of the pulses, and firms the early diagnosis (3) but cannot distinguish confirmed by two-dimensional and Doppler echocarwhich ducts will close spontaneously and is not readily diography performed within 24 h of clinical diagnosis using a Hewlett-Packard Sonos 1000. Indomethacin available in every unit. Atrial natriuretic peptide (ANP) is a polypeptide treatment was begun on the same day if there was produced from a prohormone that is stored in secretory evidence of failure or exacerbation of respiratory disgranules in the cardiac atria (4). Recent work has tress and there were no contraindications. Echocardiosuggested that ANP may have an important role in graphy was repeated within three days of treatment to preterm neonates as the peak plasma ANP concentra- confirm duct closure. Three doses of indomethacin 0.2 mg/kg (one course) tion coincides with the maximal diuretic phase of respiratory distress syndrome (RDS) ( 5 ) and correlates were given iv at eight-hourly intervals and infants were with sodium excretion (6). ANP levels are increased in fluid restricted, usually to 120 ml/kg/day. Arterial blood the first few days of life in preterm infants (7) and samples were obtained from indwelling arterial cathextremely high levels have been observed in infants with eters at the same time as clinically indicated blood samples. Samples were taken when a PDA had been PDA (8). It has been shown that ANP concentrations are diagnosed, then once daily while the duct was clinically related to the size of the left-to-right shunt across a PDA apparent until treatment, and at one, two and four days (9) and to atrial size (lo), and that levels decrease after after treatment. Samples were obtained three times daily in a group of infants with RDS but no PDA, for surgical closure of the PDA (10, 1 1). The aim of this study was to determine if, in preterm comparison. Each blood sample was placed in a tube containing infants, a high plasma ANP concentration correlates with the presence of a PDA which is clinically significant EDTA and immediately spun in a high-speed microcenand requires medical intervention and if levels decrease trifuge; the plasma was stored at -20 "C until assay. ANP concentration was measured by radioimmunoafter successful closure with indomethacin.
A N P andpatency of the ductus arreriosus
ACTA PRDIATR 81 (1992)
assay using h-ANP 1-28 antiserum (Peninsula Laboratories) as described previously (12). The plasma sodium concentration was recorded daily and the plasma osmolality was measured on each sample. Statistical analyses of the plasma ANP concentration results were performed using the Wilcoxon non-parametric test. Statistical analyses of the serum sodium and plasma osmolality results were performed using Fisher’s modified least significant difference test to the 0.05 degree level, and Gabriel’s test for confirmation of the results from Fisher’s test. Approval for this study was received from the hospital Ethics Committee.
673
Table 2. Plasma ANP concentrations,
ANP @g/ml) (median (range))
Group A No PDA
224 (38-876)
Spontaneous closure
152 (61-495)
B
C Before indomethacin After indomethacin (closed)
1240 (201-5483) 266 (62-1 108)**
D Before 1st course Before 2nd course After closure
616 (138-1926) 888 (328-1520) 271 (90-604)
E
. Before 1st course
Results The infants were divided into five clinical groups: group A: RDS but no clinical evidence of PDA; group B: PDA closed spontaneously; group C: PDA closed after one course of indomethacin; group D: PDA closed after two courses of indomethacin; group E: PDA surgically ligated after two courses of indomethacin. The clinical details of the infants studied are shown in Table 1. There were no statistical differences between the groups for birth weight or gestational age. The infants had a median (range) age of 3 (1-8) days in group A. At diagnosis of the PDA, the infants in group B were aged 13 (3-60) days, in group C 6 (2-17) days, in group D 6 (4-8)days and in group E 4 (2-6) days. At first treatment with indomethacin the infants were aged 7 (2-1 7) days in group C, 7 (5-8) days in group D and 6 (5-7) days in group E. No correlation was observed between plasma ANP concentration and postnatal age in the group A infants. Table 2 shows the plasma ANP concentrations. These represent the mean values for each individual before or after treatment. For completeness, group C includes two infants in whom only pretreatment levels were obtained. Analysis of significance is unchanged if these two patients are excluded. There was no statistically significant difference in the plasma ANP concentration between group A and group B (spontaneous closure). In group C (one course of indomethacin), the plasma ANP concentration was significantly higher before closure than after closure (Fig. 1) and significantly higher than
Table I . Infant details.
Group A B C D E
326 (186-595) 465 (216-798) 749 (368-1004) I79 (48-399)
Before 2nd course Before ligation After ligation
No. of infants
Gestation (weeks) (median (range))
Birth weight (kg) (median (range))
8 4 18 4 2
27 (25-29) 26 (24-3 I ) 26 (24-31) 26 (25-30) 28 (24-33)
0.89 (0.69-1.33) 1.10 (0.73-1.74) 0.85 (0.63-1.82) 0.92 (0.81-1.46) 1.27 (0.84-1.70)
** p
