Although transient tachypnea of newborn (TTN) is usually observed in term or near-term infants, it constitutes an important part of the respiratory distress cases observed in the neonatal intensive care unit (NICU) accounting for 5–30% of all NICU admissions [
Some recent studies suggested that a defect in the pulmonary epithelial sodium transport, occurring due to the dysfunction of some ion channels on alveolar epithelial cells and causing a delay in resorption of fetal lung fluid, may be responsible for the pathogenesis of TTN [
Na+ absorption by ENaC is activated at the time of birth, Na+ moves into the interstitium via basolateral Na+-K+-ATPase, and water flows passively along this osmotic gradient through paracellular and intracellular spaces [
Water channel aquaporin 5 (AQP5) facilitates the majority of water transport across the apical membrane of alveolar epithelia. AQP5 expression has been observed to be higher in tracheal aspirates of TTN cases, possibly as a compensatory mechanism, while
Cardiac influences of TTN, such as ventricular dysfunction, increased pulmonary vascular, and central venous pressure, are described [
Endogen glycosides (digoxin-like immunoreactive substance (DLIS)), first described by Gruber et al. [
The aim of this study is to investigate the cardiac, pulmonary, and hemodynamic effects of DLIS in TTN and if it may have a role in the pathogenesis of disease.
In this prospective study, 15 patients with TTN, who were hospitalized in Ege University Children’s Hospital, Neonatal Intensive Care Unit (NICU), between April 2000 and June 2003, were included. Fifteen healthy control infants were also prospectively included in the study for comparison. One gestational age matched infant was taken as a control for every TTN patient. The study was approved by the local Ethics Committee. An informed written consent was obtained from the parents before inclusion of their children in the study.
Infants born at ≥34-week gestational age, with clinical signs, chest X-ray findings, and clinical course consistent with TTN, were enrolled. Infants with respiratory distress were diagnosed as TTN, if they fulfilled the following criteria [
The subjects were excluded from the study under the following criteria: digoxin treatment for the infant or mother, persistent hypoglycemia, infants of diabetic mothers, hypoglycemia, polycythemia, meconium aspiration, congenital heart disease, hemodynamically significant patent ductus arteriosus (PDA), major congenital anomalies, perinatal or postnatal asphyxia (5-minute Apgar score < 7, pH < 7.10, and HCO3 < 15 mmol), preeclampsia, prolonged rupture of membranes (>18 hours), chorioamnionitis, and other causes of respiratory distress (intrauterine pneumonia, aspiration, respiratory distress syndrome, pneumonia, meconium aspiration, polycythemia, hypoglycemia, and early onset sepsis).
All the study group infants had the same intravenous fluid, total parenteral nutrition (TPN), and follow-up protocols. After obtaining the informed consent from families on the 1st day (day of admission) before the initiation of any medical treatment and on the 7th day, plasma DLIS levels together with hemogram (Cell-Dyn 3700SL, Hemocounter, Germany), blood gas analysis (Phox Plus L Autoanalyser, Nova Biomedical, USA), serum sodium (Na+), potassium (K+), urea, creatinine, (Synchron CX9 Clinical System Autoanalyser, Beckman Coulter, USA), and blood and urine osmolarity (Freezing-point Technology, The Advanced Micro-Osmometer, USA), were measured.
During the study days, 24-hour urine was collected, and the quantity and fractioned Na+ excretion (FeNa+) were calculated [
Serum C-reactive protein (CRP) (Nephelometry, Dade-Behring, BNII, Germany) and blood culture antibiogram (Bact-T Alert, Biomérieux, France) were also evaluated in order to exclude pneumonia and infection.
The amount of fluid given to the mother before delivery, demographic characteristics (sex, birth weight, gestational age, delivery type, and antenatal steroids), clinical characteristics (Apgar scores at 1st and 5th minutes), respiratory rate on admission (
One mL venous blood samples were collected in sodium EDTA tubes for plasma DLIS measurements. According to the recommendations of the manufacturing company, sera were stored at −20°C until the study day within the maximum storage duration of six months. DLIS levels were measured with Enzyme Multiplied Immune Technology method (COBAS Mira Ins., Branchburg, NJ, USA) using Hitachi 912 (Japan). In this type of assay, a sample of interest with the analyte is added to a fixed quantity of enzyme-bound drug and the antidrug antibody. After the addition of substrate, absorbance measurements are taken at time intervals to determine the speed of the enzyme reaction. The more the free analyte in the sample, the faster the enzyme reaction because only the unbound enzyme-drug complexes are capable of binding the substrate. The method can be used for whole blood, serum, or urine. Enzyme multiplied immunoassays can be fully automated with a fast throughput of clinical samples especially in laboratories specialized in monitoring therapeutic drugs [
All patients were echocardiographically evaluated on calm setup and supine position by the same pediatric cardiologist using Hewlett-Packard Sonos 1000 System Echocardiography Device (USA) with 7.5 Mhz transducer. Structural two-dimension evaluation of heart was completed with M-mode, two-dimensional, and Doppler echocardiographic evaluation of hemodynamic functions. All evaluations were video recorded and repeated three times for each investigation on the 1st and 7th days of life, and the mean values were calculated and recorded. Left and right ventricle evaluations were performed on the short axis parasternally, on the mitral valve level with M-mode. For left and right ventricles (LV, RV), end diastolic diameters (LVEDD and RVEDD) and end systolic diameters (LVESD and RVESD) were also measured. Parasternal long axis measurements of aorta and left atrial diameter (LAD), at the aortic valve level during systole period, were estimated (LA/Aorta). Fractional shortening (FS) was calculated by using
Mean blood pressure (mBP, mmHg) measurements were made 3 times on the study days with oscillometric technique (ARGUS LCM, Schiller AG, Switzerland) when the infants were in supine position in calm awake state. Heart rate (HR) recorded during echocardiographic study was also used.
All data were analyzed using the SPSS 17.0 Software for Windows (SPSS Int. Co., USA). All values were provided as median, minimum-maximum, and mean ± standard deviation. The statistical evaluations were performed using paired
Out of 1296 patients hospitalized in NICU during the three-year study period, 61 infants (4.7%) were diagnosed with TTN. The study group consisted of 15 eligible patients, who were granted permission for inclusion in the study by their parents. Fifteen healthy infants, born in the same hospital and having similar demographic characteristics, were also evaluated as control group.
The amount of fluid given to the mother before delivery, demographic characteristics (sex, birth weight, gestational age, delivery types, and antenatal steroids), and clinical characteristics (Apgar scores at 1st and 5th minutes,
Demographic and clinical characteristics of TTN and control groups.
TTN ( |
Control ( |
| |
---|---|---|---|
Gestational age (week) |
|
|
>0.05 |
(Mean ± SD) (min.–max.) | (36–39) | (35–38) | |
Birthweight (gram) |
|
|
>0.05 |
(Mean ± SD) (min.–max.) | (2550–3120) | (2450–3420) | |
Delivery type (C/S) ( |
10 (66.67%) | 10 (66.67%) | >0.05 |
Sex (male) ( |
9 (60%) | 9 (60%) | >0.05 |
Apgar 1st (median) (min.–max.) | 8 (7–10) | 8 (7–10) | >0.05 |
Apgar 5th (median) (min.–max.) | 9 (8–10) | 9 (8–10) | >0.05 |
Arterial blood gas pH |
|
|
>0.05 |
(Mean ± SD) (min.–max.) | (7.21–7.41) | (7.21–7.38) | |
Antenatal fluid to mother (mL/kg/hour) |
|
|
>0.05 |
(Mean ± SD) (min.–max.) | (0–21) | (0–26) | |
Antenatal steroids ( |
8 (53.33%) | 7 (46.6%) | >0.05 |
CRP (mg/dL) |
|
|
>0.05 |
(Mean ± SD) (min.–max.) | (0.10–0.80) | (0.21–0.70) | |
Sepsis or pneumonia ( |
0 | 0 | >0.05 |
Time of inclusion (hour) |
|
|
>0.05 |
(12–20) | (12–22) | ||
RR0 (/min.ute) |
|
|
<0.05 |
(Mean ± SD ) (min.–max.) | (60–90) | (44–54) | |
RRmax.(/min.ute) |
|
|
<0.05 |
(Mean ± SD) (min.–max.) | (65–105) | (48–56) | |
Duration of tachypnea (DoT) (hour) |
|
— | — |
(Mean ± SD) (min.–max.) | (48–144) | ||
Respiratory assistance ( |
— | — | |
Only O2 support | 11 (73.3%) | ||
nCPAP | 2 (13.3%) | ||
Mechanical ventilation | 2 (13.3%) | ||
Duration of hospitalization (hour) |
|
|
<0.05 |
(Mean ± SD) (min.–max.) | (240–926) | (16–120) | |
Pneumothorax ( |
2 (13.3%) | — | — |
DLIS1 (ng/mL) |
|
|
<0.01 |
(Mean ± SD) (min.–max.) | (0–1.30) | (0–0.80) | |
DLIS7 (ng/mL) |
|
|
<0.05 |
(Mean ± SD) (min.–max.) | (0–0.76) | (0–0.45) |
S/C: caesarian section.
CRP: serum C reactive protein.
RR0: respiratory rate on admission.
RRmax.: max.imum respiratory rate on follow-up.
CPAP: nasal continuous positive airway pressure.
DLIS1: digitalis-like immunoreactive substance at the 1st day.
DLIS7: digitalis-like immunoreactive substance at the 7th day.
The TTN group was found to have higher
Evaluation of fluid and ion balance parameter on the 1st and 7th days of TTN and control groups.
Parameter* | TTN ( |
Control ( |
| |||||
---|---|---|---|---|---|---|---|---|
1st daya | 7th dayb | 1st dayc | 7th dayd | a versus b | c versus d | a versus c | b versus d | |
Na+ (meq/L) |
|
|
|
|
<0.05 | <0.05 | <0.05 | <0.05 |
(138–154) | (128–148) | (132–148) | (128–141) | |||||
K+ (meq/L) |
|
|
|
|
>0.05 | >0.05 | <0.05 | >0.05 |
(3.2–4.6) | (3.2–4.4) | (3.7–4.4) | (3.2–4.3) | |||||
Urea (mg/dL) |
|
|
|
|
>0.05 | <0.05 | >0.05 | <0.01 |
(20–42) | (18–43) | (18–43) | (30–65) | |||||
Creatinine (mg/dL) |
|
|
|
|
>0.05 | >0.05 | >0.05 | >0.05 |
(0.50–1.23) | (0.45–1.20) | (0.55–1.20) | (0.56–1.30) | |||||
Blood osmolarity (mosm/L) |
|
|
|
|
<0.05 | >0.05 | <0.05 | >0.05 |
(295–316) | (285–308) | (275–306) | (280–311) | |||||
Urine osmolarity (mosm/L) |
|
|
|
|
>0.05 | >0.05 | >0.05 | <0.05 |
(320–490) | (245–440) | (330–468) | (324–460) | |||||
FeNa+ (%) |
|
|
|
|
<0.001 | <0.01 | <0.001 | <0.01 |
(2.10–2.89) | (1.32–2.20) | (1.20–2.65) | (1.0–2.11) | |||||
Diuresis (mL/kg/hour) |
|
|
|
|
<0.001 | >0.05 | <0.05 | >0.05 |
(2.0–4.3) | (1.5–2.8) | (1.1–4.4) | (1.3–4.4) |
On the 1st day, the TTN group had higher DLIS levels (
According to the time, DLIS (ng/mL) levels of TTN and control groups for (a versus b) and (a versus c)
DLIS levels decreased on the 7th day compared to the 1st day of life (
Evaluation of hemodynamic and echocardiogram parameter on the 1st and 7th days of TTN and control groups.
Parameter* | TTN ( |
Control ( |
| |||||
---|---|---|---|---|---|---|---|---|
1st daya | 7th dayb | 1st dayc | 7th dayd | a versus b | c versus d | a versus c | b versus d | |
CO (mL/minute) |
|
|
|
|
<0.01 | >0.05 | <0.05 | >0.05 |
EF (%) |
|
|
|
|
<0.01 | <0.05 | <0.05 | >0.05 |
LVEDD (mm/kg) |
|
|
|
2 |
<0.01 | >0.05 | <0.05 | >0.05 |
LVESD (mm/kg) |
|
|
|
|
<0.001 | >0.05 | <0.001 | <0.01 |
RVEDD (mm/kg) |
|
|
|
|
<0.05 | >0.05 | <0.01 | <0.01 |
RVESD (mm/kg) |
|
|
|
|
<0.05 | >0.05 | <0.05 | >0.05 |
LA/Aorta |
|
|
|
|
<0.001 | >0.05 | <0.001 | >0.05 |
FS (%) |
|
|
3 |
|
>0.05 | >0.05 | >0.05 | >0.05 |
HR (/minute) |
|
|
|
|
<0.001 | >0.05 | <0.001 | >0.05 |
mBP (mmHg) |
|
|
|
|
>0.05 | >0.05 | <0.01 | >0.05 |
DLIS values at the 1st and 7th days were in correlation in theTTN group (
The significant positive correlation was found between DLIS1 levels and plasma DLIS7 ((a)
Plasma DLIS values at the 1st day (DLIS1) were correlated with DoT (
TTN group DLIS1 levels were found to be in negative correlation with blood osmolarity (
For control group, plasma DLIS levels had no correlation with any of the parameters at the 1st and 7th days.
In TTN group, plasma DLIS1 values were positively correlated with CO (
TTN is not always a benign condition. In our study group of 15 cases, about 13.3% required nasal CPAP, another 13.3% required mechanical ventilation, and other 13.3% of cases had pneumothorax. The pathophysiology of TTN is not adequately explained, and a delay in the resorption of fetal alveolar fluid is thought to be a major problem [
Among the adult patients of intensive care unit (ICU), higher mean plasma DLIS levels (
DLIS levels were reported to be high and around 0.41–0.56 ng/mL in the healthy term infants at the time of birth, unrelated to birth weight, sex, and gestational age. These high DLIS levels decrease to immeasurable levels within 14–45 days [
Na+-K+-ATPase mRNA levels are the highest in postnatal first three days (during which the fluid resorption is maximum) and stay high up to the 14th day compared to adult levels [
DLIS has a natriuretic effect in term and preterm neonates [
Atrial natriuretic peptide (ANP) was found to be higher in RDS cases, correlating with the severity and progress of the disease and acting as an endogenous diuretic [
Plasma DLIS levels were related with creatinine levels in adult [
Important hemodynamic changes occur in early postnatal period [
Very few studies investigated the effect of TTN on cardiac functions. Clinically classifying TTN cases into classical (
Urine DLIS levels were found to be related to LV functions (HR,
Na+-K+-ATPase and intracellular calcium have a negative effect on myocardial functions. Therefore, Na+-K+-ATPase inhibitor digoxin is effectively used in this treatment [
In adults, mBP is related to DLIS [
In the present study, for the first time in the literature, higher DLIS levels in correlation with serum osmolarity, diuresis, FeNa+ levels, and severity of disease have been shown in TTN cases. This correlation may indicate that it has a role in the pathophysiology of TTN, but more possibly DLIS levels may have increased as a compensatory mechanism for the volume overload caused due to the already disturbed LV and RV functions.
TTN patients have increased plasma DLIS levels in correlation with disease severity. Its cardiac effect may be a compensatory digoxin-like effect; besides, its natriuretic and diuretic effect may help in an already increased volume load status. However, this compensatory increase may cause a vicious cycle since it inhibits alveolar Na+-K+-ATPase and causes a further delay in the fetal lung fluid absorption.
There is no conflict of interests.