Methods

The study was conducted at the Tokyo Metropolitan Tsukiji Maternity Hospital, Japan, from August 1995 to December 1996, and at the China Medical College Hospital, Taichung, Taiwan, from February to October 1997. Premature infants weighing less than 1500 g at birth, who required assisted ventilation, and had a symptomatic PDA, were enrolled. General guidelines for the treatment of very low birthweight infants were similar in Tokyo and in Taichung. The fluid supply was 60–70 ml/kg on the first day, increasing by 10 ml/kg daily, and adjusted to maintain serum electrolytes within the normal range, until intake reached 120 ml/kg within the first week of life. Respiratory distress syndrome (RDS) was diagnosed according to clinical and chest radiographic findings consistent with RDS and requirements for inspired oxygen of >40% and for mechanical ventilation. The surfactant preparations used were Surfacten TA (Surfacten, Tokyo-Tanabe Company, Japan) in Tokyo and Survanta (Beractant, Abbott Laboratories, Chicago, USA) in Taichung. The dosing schedule was 1 phial Surfacten TA or 4 ml Survanta per kg of body weight. Assisted ventilation was adjusted to maintain partial arterial oxygen tension (PaO₂) between 50 and 80 mmHg, partial arterial carbon dioxide tension (PaCO₂) between 40 and 50 mmHg, and pH between 7.25 and 7.45.

Symptomatic PDA was diagnosed when there was colour Doppler echocardiographic evidence of left to right ductal shunt associated with at least two of the following clinical signs: heart murmur; persistent tachycardia (heart rate >160/min); hyperactive precordial pulsation; bounding pulses; and radiographic evidence of cardiomegaly or pulmonary congestion. The patients were randomly assigned to receive indomethacin treatment according to the usual protocol (protocol group) or to echocardiographic PDA flow pattern (ECHO group).9Excluded from the study were infants with congenital anomalies, congenital infections, and those who died during the first 72 hours of birth. The eligible infants not included during the study period were those admitted when the investigator with echocardiographic skills (BHS) was on leave, or when serial echocardiographic examination could not be performed.

The study protocol was approved by the review boards of both hospitals, and informed consent was obtained from each infant’s parents.

ECHOCARDIOGRAPHIC DATA COLLECTION

In Tokyo, the infants were studied using a Hewlett-Packard 77020A or an Aloka SSD-2000 scanner fitted with a probe which incorporated a 5 MHZ colour and pulsed Doppler transducer. The first echocardiographic study confirmed cardiac normality and the ductus arteriosus was imaged from the high left parasternal view using colour Doppler echocardiography. If PDA was present, the pulsed Doppler gate was placed in the pulmonary end of the ductus, taking care to ensure the angle of insonation was below 20 degrees, and the flow pattern of the shunt was recorded.

The PDA flow was classified as follows: (1) pulmonary hypertension pattern, which has a bi-directional flow profile with a predominant right to left shunt (downward away from the baseline); (2) growing pattern, which also has a bi-directional flow but with a predominant left to right shunt (upward away from the baseline); (3) pulsatile pattern, which has a left to right shunt with a pulsatile profile of peak flow velocity about 1.5 m/second; and (4) closing pattern, which also has a left to right shunt, but with a characteristic continuous profile of peak flow velocity of about 2 m/second (fig1).9

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Figure 1

Doppler flow patterns: (A) pulmonary hypertension pattern; (B) growing pattern; (C) pulsatile pattern; (D) closing pattern; (E) closed pattern.

In Taichung the infants were studied using an Acouson 128XP/10 scanner with 5 or 7 MHZ colour and pulsed Doppler transducer. The ductus arteriosus was imaged as in Tokyo.

INDOMETHACIN TREATMENT FOR PATENT DUCTUS ARTERIOSUS

Protocol group

Colour Doppler echocardiographic examination was performed daily 12–24 hours after birth until the ductus arteriosus closed. Infants were examined at least twice daily for clinical signs of PDA, and diagnosis and treatment protocols were made by the attending clinician. The management protocol for a symptomatic PDA in both units included fluid restriction and intravenous administration of indomethacin (0.2 mg/kg for the first dose, then 0.1 mg/kg in infants less than 48 hours old, 0.2 mg/kg in infants over 48 hours, every 12 hours for another two doses) if not contraindicated.9 10 A follow up echocardiogram was obtained between 24 to 36 hours after completion of the course of indomethacin treatment. If the PDA remained open, as documented on colour Doppler echocardiography, a second course of indomethacin was given and the echocardiogram was repeated 24 to 36 hours afterwards, and then every 24 hours until closure. If the PDA had not closed and the patient remained symptomatic after the second course of indomethacin, surgical ligation was considered. Surgery was also performed in infants with symptomatic PDA in whom indomethacin was contraindicated.

ECHO group

Infants in this group also received colour Doppler echocardiographic and clinical assessments. Similarly, indomethacin was given when a symptomatic PDA was diagnosed. Pulsed Doppler echocardiography was performed immediately before indomethacin treatment to determine the PDA flow pattern. A follow up echocardiogram was obtained 24 hours after the start of the first dose of indomethacin. The echocardiographer (BHS) was blinded to the clinical status of the infants. PDA flow pattern and the treatment regimen were decided by the attending clinician. Subsequent doses of indomethacin were given only if the pulsatile or growing PDA flow pattern persisted on follow up pulsed Doppler echocardiograms obtained every 24 hours. The subsequent dose of indomethacin was withheld if the closing or closed pattern was documented. If a closing or closed pattern was not observed after six doses of indomethacin, surgical ligation was considered. Surgery was also considered in infants with symptomatic PDA in whom indomethacin was contraindicated.

OUTCOME MEASURES

General clinical data, total doses of indomethacin, PDA outcome, and the presence of complications associated with prematurity and indomethacin treatment, as well as neonatal mortality and the incidence of chronic lung disease were recorded. Complications associated with indomethacin occurring during treatment or within 48 hours of its completion, such as hypoglycaemia, impaired urine output, necrotising enterocolitis and gastrointestinal bleeding, were also recorded. Hypoglycaemia was diagnosed if blood glucose fell to below 40 mg/dl; impaired urine output was defined as a fall to less than half that before treatment started. Necrotising enterocolitis was considered if there were signs of abdominal distension and ileus, and was confirmed by a roentgenogram showing a fixed dilated loop, pneumatosis, portal or hepatic venous air or pneumoperitoneum. Gastrointestinal bleeding was considered if the aspirate had the appearance of coffee grounds, or if there was fresh blood from the gastric tube.

Cranial sonograms were obtained on days 1, 7, 28, and, if necessary, when intraventricular haemorrhage (IVH) was suspected. IVH grading was performed according to Papile et al. 11 PDA outcome was categorised as: (1) failure of closure, if the PDA remained open as documented on echocardiography for at least 10 days or if surgical ligation was required for symptomatic PDA, because of unresponsiveness or contraindication of indomethacin treatment, or (2) reopening of PDA, if there was clinical and echocardiographic evidence of PDA after initial closure. Neonatal mortality was defined as death within 28 days of age. Chronic lung disease was defined as requirement for supplemental oxygen at 28 days of age, with respiratory distress and characteristic signs on chestx-ray picture.

STATISTICAL ANALYSIS

Our previous study showed that about half of the infants, similar to those enrolled in this study, had at least one of the major complications associated with indomethacin treatment.10 12To examine whether PDA flow pattern is an effective guide to indomethacin treatment, we estimated that the sample should comprise 45 infants in each group, to achieve a power of 80% at a level of p=0.05. We expected a decrease in the complication rate associated with indomethacin treatment from 50% to 20%, when PDA flow pattern was adopted as a guide to treatment. The observed PDA incidence was 60% in infants weighing under 1500 g, therefore, a total of 150 infants were needed for the study. Categorical variables were analysed using Student’s t test, and the comparisons of complication rates were carried out using χ² analysis.