Green 1983.

Methods	Blinding of randomization: yes. Randomization was done by computer. Blinding of intervention: yes. Diuretic solutions were prepared in the pharmacy and were only identified by patient name and number. Complete follow‐up: no. Of 128 infants with RDS, 27 were ineligible either because they were older than 72 hours or had already received a diuretics. Of 101 enrolled patients, 2 were dropped from the study, one because of coarctation of the aorta and the other because of inaudible heart sounds secondary to severe lung disease. Most information is available only in 66 of the randomized patients, i.e., those who effectively received diuretics (33 furosemide and 33 chlorothiazide). Thus, intention‐to‐treat analysis is not possible. Blinding of outcome: yes Parallel design Washout period: adequate. Only patients who never received diuretics previously were eligible to the study.
Participants	Total number of patients entered into the study: 99 Entry criteria: Birthweight < 2,500 g, RDS, mechanical ventilation, postnatal age < 72 hours. Exclusion criteria: previous diuretic treatment, known or suspected cardiac or renal disease. Patients were entered into the study between December 1979 and June 1981, at which time 99 infants had completed the study. The exact number of patients enrolled in each group is not provided. Patients who did not receive diuretics had an average gestational age of 31.4±2.4 weeks and a birthweight of 1668±484 g. Their mean airway pressure, 11.8±4.3 cm H2O, was lower than in those who received diuretics, 15.0±4.7 cm H2O (p<0.001). Among patients who received diuretics, average gestational ages were 30.3±2.8 weeks in the furosemide group and 30.8±2.8 weeks in the thiazide group. Average birthweights were 1481±471 g and 1532±500 g, respectively. The mean ages at the time of administration of the first dose of diuretic were, respectively, 2.8±1.0 and 2.9±1.4 days. Mean airway pressure (15 cm HO) was similar in the two groups. In patients showing no pulmonary improvement, clinical PDA was treated with diuretics and surgical ligation; indomethacin was not used. Fluid intake was restricted to 60‐80 ml/kg/day in intubated patients. Patients were treated in servo‐controlled isolettes. Patients remained in the study until extubation, ductal ligation or 14 days of age, whichever came first.
Interventions	PRN furosemide vs PRN chlorothiazide. Patients were randomly allocated to the furosemide group or the thiazide group. The numbers by group at randomization are not given by the authors. Criteria for diuretic administration were not rigidly defined in the protocol. Beginning on the second to fourth day of life, a diuretic was usually prescribed by the attending neonatologist if the patient had not initiated spontaneous diuresis (urine output > fluid intake for at least 8 hours) and was not showing satisfactory pulmonary improvement. In addition, patients with clinical evidence of PDA and lack of pulmonary improvement received diuretics as indicated. Diuretic solutions were prepared in the pharmacy in vials identified only by patient and number. Concentrations of furosemide (1 mg/ml) and chlorothiazide (20 mg/ml) were based on furosemide‐to‐chlorothiazide equivalency. In most circumstances, the dosage administered was 1 ml/kg/dose. Twenty of 33 furosemide‐treated patients received multiple doses, and 21 of 33 chlorothiazide‐treated patients received multiple doses. The average total volume of diuretic solution received was 3.8±4.3 ml/kg in the furosemide group and 4.8±3.5 ml/kg in the thiazide group.
Outcomes	Major outcome variable: PDA (NEJM), survival (J Pediatr). Other outcome variables: incidence of ductal ligation, urinary prostaglandin E excretion after diuretic administration, incidence of IVH, duration of mechanical ventilation. Among the 33 patients who did not receive diuretics, 6 died, 10 developed a PDA, and 3 developed an intraventricular hemorrhage. Other outcomes are provided only in the 66 patients who were prescribed diuretics, i.e., 33 patients in each group. Eight patients died in the furosemide group and 13 in the thiazide group. A murmur characteristic of PDA was observed in 22 patients in the furosemide group and 13 in the control group (p<0.05). During the study, 18 patients developed clinical findings of a PDA in the furosemide group and 8 in the thiazide group (p<0.05). Of those, 11 and 7, respectively, underwent surgical ligation. In addition, 6 patients in the furosemide group were later found to have a PDA; thus, the total number of patients developing a PDA during the initial hospital stay was 24 in the furosemide group and 8 in the thiazide group. Weight loss (% of body weight) was greater in furosemide‐treated patients than in thiazide‐treated patients on days 4 and 5. Urinary excretion of prostaglandin E slightly and transiently increased in both groups after diuretic administration on the first day. However, furosemide but not chlorothiazide administration after day 5 doubled urinary excretion of prostaglandin E2. Thirteen developed an IVH in the furosemide group, compared with 11 in the thiazide group. Among survivors, duration of mechanical ventilation was 10.5±10.3 days and 7.3±4.6 days, respectively (NS).
Notes	The study was designed as (1) a sequential analysis of PDA scores in pairs of furosemide‐treated and chlorothiazide‐treated patients (NEJM) and (2) multivariate analysis of factors associated with survival (J Pediatr). Multivariate analysis showed that better survival was related to increasing birthweight, lower initial mean airway pressure, lack of IVH and furosemide usage. PDA was related to birthweight and furosemide usage. IVH was related to low birthweight but not to furosemide. The routes of administration of furosemide and chlorothiazide are not mentioned in the manuscript.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was done by computer
Allocation concealment (selection bias)	Low risk	Blinding of randomization: yes
Blinding (performance bias and detection bias) All outcomes	Low risk	Blinding of intervention: yes. Diuretic solutions were prepared in the pharmacy and were only identified by patient name and number. Blinding of outcome: yes
Incomplete outcome data (attrition bias) All outcomes	High risk	Complete follow‐up: no. Of 128 infants with RDS, 27 were ineligible either because they were older than 72 hours or had already received a diuretics. Of 101 enrolled patients, 2 were dropped from the study, one because of coarctation of the aorta and the other because of inaudible heart sounds secondary to severe lung disease. Most information is available only in 66 of the randomized patients, i.e., those who effectively received diuretics (33 furosemide and 33 chlorothiazide).