Methods

Blinding of randomization: No. Thirty‐nine infants were entered into the study. Within each of 3 birthweight categories (< 1,000 g, 1,000‐1,500 g and >1,500 g), patients were randomized by blocks of 2: within each block, one patient was randomly allocated to treatment or control, and the other patient was entered into the other group. The method of randomization is not documented.
Blinding of intervention: no. Control patients did not receive a placebo.
Complete follow‐up: No. Three infants were excluded from the analysis. Of 39 randomized infants, 2 infants had an exclusion criterion described in the protocol of the study, i.e., proven sepsis (one in the treatment group, one in the control group). The third infant (treatment group) died of massive intracranial hemorrhage at 24 hours of life. Thus, after removing two infants who met criteria for exclusion, the number of patients randomized to furosemide was 20 and the number of patients in the control group was 17.
Blinding of outcome: not documented
Parallel design
Washout period: not documented.

Participants

Total number of patients entered into the study: 39
Entry criteria: (1) Prematurity (2) postnatal age < 24 hours (3) RDS defined as grunting, intercostal retractions, cyanosis in room air, and reticulogranular appearance with air bronchogram on chest radiograms (4) FiO2 > 0.4 to maintain pAO2 > 50 torr.
Exclusion criteria: Sepsis, renal failure (serum creatinine > 1.8 mg/dl)
Data are provided on 19 infants in the furosemide group and 17 in the control group. Patients were enrolled between January and December 1982. Maternal steroid administration occurred in 3 patients in the treatment group and 1 in the control group. All patients in the treatment group and 16 in the control group required mechanical ventilation. Average gestational ages were 30.8±2.6 weeks in the treatment group and 30.6±2.5 weeks in the control group. Average weights were 1459±462 g and 1468±482 g, respectively. The first dose of furosemide was administered at 13±4 hours of life. Maternal steroid administration occurred in 3 experimental infants and in 1 control. There was no significant difference between the treatment and control group for the following variables: gender distribution, location of birth, incidence of cesarean section, Apgar scores at 1 and 5 minutes, and baseline urine output to intake ratio (O/I), FiO2, alveolar‐arterial O2 gradient, and peak inspiratory pressure.
Average fluid intake was similar in the two groups: 88 and 85 ml/kg/day, respectively, on the first day, 106 and 101 ml/kg/day on the second day and 133 and 133 ml/kg/day on the third day.
All patients were followed until discharge.

Interventions

Four doses of furosemide versus control.
Patients were randomly allocated to receive either four doses of 1 mg/kg furosemide every 12 hours intravenously (treatment group, n=21), or no diuretic (control group, n=18).

Outcomes

Major outcomes: urine output to intake ratio (O/I) per 8‐hour period, ventilator requirement, duration of oxygen therapy
Other outcomes: survival, echocardiographic signs of PDA, clinically significant PDA.
One of 20 patients in the furosemide group died of massive intracranial hemorrhage at 24 hours; all the other randomized patients survived. Patients in the furosemide group had significantly higher O/I than those in the control group between 32 and 48 hours. Diuresis (defined as O/I>1) occurred at 32 hours in the furosemide group and 56 hours in the control group. In the treatment group, FiO2 was transiently lower than in the control group at 32‐56 hours of life, alveolar‐arterial O2 gradient was lower at 40 and 48 hours, and peak inspiratory pressure was lower at 32 hours and 48‐64 hours. The average duration of O2 therapy (12 days) was not significant between the 2 groups. Two patients in the furosemide group and one in the control group required O2 for > 1 month. The duration of mechanical ventilation was significantly shorter in the treated group than in the control group (171±47 vs 290±94 hours, respectively, p<0.05).
Three patients in each group developed a murmur suggestive of PDA. No patient in the treatment group and one in the control group required treatment for a decompensated PDA. Echocardiographic data were similar in the two groups.
Subgroup analysis showed higher O/I in treatment group than in control group among infants weighing 1,000‐1,500 g and those weighing > 1,500 g but not in those weighing < 1,000g. Among patients weighing 1,000‐1500 g substantial differences were observed between treatment and control groups in FiO2, alveolar‐arterial gradient and peak inspiratory pressure. Among those weighing 1,500‐2,000 g only minimal differences occurred between the two groups. No differences were observed among those weighing < 1,000 g.

Notes

The authors used two‐way analysis of variance followed by Scheffe post‐hoc test.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of randomization is not documented

Allocation concealment (selection bias)

High risk

Blinding of randomization: No. Thirty‐nine infants were entered into the study. Within each of 3 birthweight categories (< 1,000 g, 1,000‐1,500 g and >1,500 g), patients were randomized by blocks of 2: within each block, one patient was randomly allocated to treatment or control, and the other patient was entered into the other group.

Blinding (performance bias and detection bias)
All outcomes

High risk

Blinding of intervention: no. Control patients did not receive a placebo.

Blinding of outcome: not documented

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Complete follow‐up: No. Three infants were excluded from the analysis. Of 39 randomized infants, 2 infants had an exclusion criterion described in the protocol of the study, i.e., proven sepsis (one in the treatment group, one in the control group). The third infant (treatment group) died of massive intracranial hemorrhage at 24 hours of life. Thus, after removing two infants who met criteria for exclusion, the number of patients randomized to furosemide was 20 and the number of patients in the control group was 17.

Methods

Blinding of randomization: yes. Randomization was done by computer.
Blinding of intervention: yes. Theophylline or placebo was prepared by a doctor from the neonatology section, not involved in patient care, using syringes with identical appearance.
Complete follow‐up: yes.
Blindness of outcome: yes.
The medical and nursing staff were blinded to the patient assignment.

Participants

Of 54 eligible patients, 50 were entered into the study and randomly allocated to placebo or to theophylline.
Entry criteria: Inborn preterm neonates <= 32 weeks gestational age, RDS within 6 hours of life, needing mechanical ventilation or nasal continuous positive airway pressure.
Exclusion criteria: kidney and/or urinary tract congenital abnormalities, congenital heart defects, prenatal exposure to inhibitors of angiotensin converting enzyme or non‐steroidal anti‐inflammatory drugs (NSAIDs), and chromosomal disorders or multiple malformations.
Patients assigned to placebo (n=25) had an average gestational age of 28.7±1.6 weeks and a birthweight of 1157±354 g. Patients assigned to theophylline (n=25) had an average gestational age of 28.7±2.0 weeks and an average birthweight of 1192±378 g.

Interventions

Patients in the treatment group were allocated to receive i.v. theophylline 1 mg/kg daily; controls were allocated to receive an equal volume of placebo (5% dextrose in water) for three days. The first dose was given soon after it had been confirmed that inclusion criteria had been met.

Outcomes

Death, BPD, Death or BPD, PDA, IVH, severe IVH, oligoanuria (urine output <1 ml per kg per hour) , serial measurements of urine output, serial serum creatinine values, blood urea nitrogen, hyponatremia, hyperkalemia, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, length of stay.

Notes

Several infants received other medications that could affect outcomes of interest in this review. Eight infants in the theophylline group and twelve in the control group received furosemide, 21 in each group received dopamine, nine in the theophylline group and twelve controls received dobutamine, six in the theophylline group and four controls received ibuprofen, one control received indomethacin, and eight in the theophylline group and nine controls received caffeine.

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. Theophylline or placebo was prepared by a doctor from the neonatology section, not involved in patient care, using syringes with identical appearance.

Blindness of outcome: yes. The medical and nursing staff were blinded to the patient assignment.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

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).

Methods

Blinding of randomization: yes. Method of randomization is not provided.
Blinding of intervention: yes. Furosemide and placebo was dispensed in numbered vials.
Complete follow‐up: yes
Blinding of outcome: yes
Parallel design
Washout period: yes. No patient had received diuretics before entering into the study.

Participants

Total number of patients entered into the study: 69
Entry criteria: birthweight < 2,500 g, clinical diagnosis of RDS with radiographic confirmation, need for mechanical ventilation, postnatal age < 30 hours
Exclusion criteria: previous diuretic treatment, known or suspected cardiac or renal disease
Thirty‐five patients were randomized to furosemide prophylaxis and thirty‐four to the control group. Gestational ages were 31.5±2.3 weeks in the treatment group and 31.3±2.3 weeks in the control group. Mean birthweights were 1.66±0.41 kg and 1.63±0.45 kg, respectively. Patients in the furosemide group received the first dose of furosemide at 24 hours (maximum 30 hours for outpatients) of life. Both groups had similar Apgar scores at 1 and 5 minutes, mean airway pressure, alveolar‐arterial O2 gradient and cardiovascular stability index. Nevertheless, the rate of colloid infusion at 18‐24 hours of life, i.e. at or before the time of entry into the study, tended to be higher in the furosemide group than in the control group (6.3±9.5 ml/kg/hour vs 3.8±6.0 ml/kg/hour). Fluid intake (crystalloids) was 60‐80 ml/kg/day initially and maintained at 80‐100 ml/kg/day during mechanical ventilation. Patients with hypotension or poor peripheral perfusion received 5‐10 ml/kg colloids followed if needed by dobutamine or dopamine. Patients were treated in radiant warmers until completion of initial stabilization and procedures, and then in incubators.
Patients remained in the study until day 7.

Interventions

Prophylactic and PRN furosemide vs PRN furosemide
Patients were randomly allocated to the prophylactic furosemide group (n=35) or to the control group (n=34). Patients in the prophylactic furosemide group received four doses of 1 m/kg of furosemide every 12 hours starting at 24 hours of life (maximum 30 hours for outpatients) with additional PRN doses of furosemide. Patients in the control group received similar doses of placebo (0.9% saline); in addition, they received PRN doses of furosemide. Indications for PRN doses included (1) edema or oliguria (<1 ml/kg/hour for 2‐3 hours) in the presence of poor or deteriorating pulmonary function or (2) congestive heart failure defined as cardiomegaly on chest radiography, with hepatosplenomegaly or peripheral edema.
However, the total dose of furosemide administered during the first 3 days of life was significantly greater in the treatment group than in the control group (4.8±1.4 mg/kg vs 1.5±1.7 mg/kg, p<0.001). The dose of furosemide prescribed afterwards was similar in the two groups.

Outcomes

Major outcome: mean airway pressure on day 7, incidence of hemodynamic instability, requirement for inotropic therapy, hypovolemia, mortality.
Other outcomes: PRN furosemide administration, incidence of PDA, urine output, plasma volume (Evans blue distribution volume) at 48 and 96 hours, IVH.
Three patients died in each group. Eleven of 35 patients in the treatment group received additional PRN furosemide during the first 3 days of life, compared with 21 of 34 in the control group (p<0.05).
Mean airway pressure and alveolar‐arterial pressure gradient were similar in both groups at 5 and 7 days of age.
Cardiovascular stability index worsened during the study in the furosemide group but not in the control group. Patients in the furosemide group had higher heart rate and required a higher rate of dobutamine administration than those in the control group. The incidence of PDA was as follows: In the treatment group, 14 patients had a clinically significant PDA, 8 received indomethacin and 3 underwent surgical ligation. In the control group, 8 developed a significant PDA, 5 received indomethacin and one underwent surgical ligation.
Patients in the furosemide group had higher urine output than controls. At 96 hours of life, patients in the furosemide group had a greater % loss from birthweight than controls (9.9±7.2% vs 6.0±7.7%, respectively, p<0.05). In both groups, the amount of colloids effectively administered decreased from 6 ml/kg/hour at 12 hours of life to 2 ml/kg/hour at 96 hours. Patients in the furosemide group had less increase in plasma volume between 48 hours and 96 hours of life than those in the control group (7.8±12.0 vs 0.1±10.7 ml/kg, p<0.02).
Median grade of IVH was 1 (range 0‐4) in the treatment group and 0 (range 0‐4) in the control group.

Notes

The study design included sequential analysis of mean airway pressure on day 7. The study was terminated after enrolling 50 patients, because an interim analysis showed a strong suggestion of adverse cardiovascular effects in the treatment group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomization is not provided

Allocation concealment (selection bias)

Low risk

Blinding of randomization: yes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes. Furosemide and placebo was dispensed in numbered vials. Blinding of outcome: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Methods

Blinding of randomization: yes. Randomization was done using a random sampling of numbers.
Blinding of intervention: yes. Drug and placebo were drawn up in the pharmacy and administered without the knowledge of the investigators.
Complete follow‐up: yes
Blinding of outcome: yes
Parallel design
Washout period: no patients received diuretics before entering the study.

Participants

Total number of patients entered into the study: 12
Entry criteria: RDS, postnatal age < 72 hours, peripheral edema, FiO2 > 0.4 to maintain pO2 > 50 torr.
Exclusion criteria: not documented
Seven infants were randomized to furosemide and 5 to placebo. Mean gestational ages were 32.1±2.5 weeks in the furosemide group and 34.8±1.2 weeks in the control group (p<0.05). Mean birthweights were significantly lower in the furosemide group, 1,707±485 g, than in the control group, 2,286±418 g (p<0.05). Postnatal ages were 31±9 hours and 36±14 hours, respectively. Patients in the furosemide group had a lower initial FiO2 than those in the control group (0.49±0.01, vs. 0.61±0.02, respectively, p<0.05). In each group, 4 patients received continuous positive airway pressure (CPAP) and 1 received mechanical ventilation. Blood gases were similar in the 2 groups before treatment.
The protocol specified indications to start CPAP and mechanical ventilation, and progressive increase in fluid intake from the first to the third day (65, 80 and 100 ml/kg/day on the first, second and third day, respectively). Patients in the furosemide group received 81±9 ml/kg/day, compared with 71±12 ml/kg/day in the control group. Ventilatory settings and FiO2 were not modified during the study.
The study lasted from the time of baseline observation until 6 hours after drug administration.

Interventions

Single dose of furosemide vs placebo
Patients were randomized to receive either a single dose of 2 mg/kg of furosemide intravenously (n=7), or placebo (5% glucose in 0.225% sodium chloride, n=5).

Outcomes

Blood gases, urine output, echographic measurement of the PDA.
There was no significant different difference in blood pO2, pCO2 and pH between the two groups after treatment.
Echocardiographic measurements were not different between the two groups (data not provided in the manuscript).
Patients in the furosemide group but not those in the control group developed after treatment an increase in urine output, natriuresis and calciuria. One patient in the furosemide group developed acute hypovolemia (hypotension, metabolic acidosis and a rise in hematocrit), which was treated with colloid administration.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was done using a random sampling of numbers

Allocation concealment (selection bias)

Low risk

Blinding of randomization: yes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes. Drug and placebo were drawn up in the pharmacy and administered without the knowledge of the investigators.
Blinding of outcome: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Methods

Blinding of randomization: not documented. The method of randomization is not provided.
Blinding of intervention: no. Control patients did not receive a placebo.
Complete follow‐up: yes
Blinding of outcome: not documented
Parallel design
Washout period: no patient received diuretic before entering the study.

Participants

Total number of patients entered into the study: 20
Entry criteria: RDS
Exclusion criteria: not documented
Seven infants were randomized to furosemide and 13 to the control group. Mean gestational ages were 31.7±3.4 weeks in the furosemide group and 31.8±2.6 weeks in the control group. Mean birthweights were 1830±97 g and 1616±420 g, respectively. The first dose of diuretics was given at 2 hours of life. Patients in the furosemide group had more severe RDS than those in the control group. Positive pressure was required in 5 of 7 infants in the furosemide group (2 on mechanical ventilation and 3 on CPAP) and 3 of 13 patients in the control group (all on mechanical ventilation) (p = 0.062). Five of 7 patients in the furosemide group required Na bicarbonate to correct metabolic acidosis, compared with none in the control group (p<0.001). Fluid intake was similar in the 2 groups: 51 ml/kg/day (range 29‐79) in the furosemide group and 48 ml/kg/day (range 35‐61) in the control group. Average calcium intake in the furosemide group was three times as high as in the control group.
Patients were followed during the first 24 hours of life.

Interventions

Three doses of furosemide vs control
Patients were randomly assigned to either receive 3 doses of 1.5 mg/kg of furosemide intravenously, one each at 2, 6 and 12 hours of age (n=7), or no treatment (n=13).

Outcomes

Outcome variables included blood gas analyses, mortality and fluid balance. No information is provided on mean airway pressure, duration of mechanical ventilation or O2 administration.
Four patients died in the furosemide group, and 2 in the control group. At 6 hours of life, arterial blood pO2 in 100% O2 was 163±66 mm Hg (n=7) in the furosemide group, compared with 215±55 mm Hg (n=11) in the control group (NS).
Patients in the furosemide group had significantly higher urine output, natriuresis and calciuria than those in the control group. No patient developed renal failure. The 2 patients in the furosemide group who did not receive sodium and calcium supplements had higher natriuresis and calciuria than patients in the control group. Blood pO2 and pCO2 did not change significantly in the treatment group after furosemide administration.

Notes

Values of blood PO2 and PCO2 before and after treatment are provided in the furosemide group but no comparable data are provided in the control group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The method of randomization is not provided

Allocation concealment (selection bias)

Unclear risk

Blinding of randomization: not documented

Blinding (performance bias and detection bias)
All outcomes

High risk

Blinding of intervention: no. Control patients did not receive a placebo. Blinding of outcome: not documented

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Complete follow‐up: yes

Methods

Blinding of randomization: yes. Sixty envelopes were prepared and kept under the control of an independent observer.
Blinding of intervention: unclear. Control patients were treated similarly to experimental patients but did not receive furosemide. The authors do not mention whether control patients received a placebo.
Complete follow‐up: no. Sixty patients were randomized. Four patients were excluded from the study before analysis: 2 patients (one in each group) with group B streptococcus sepsis, and 2 patients in the control group who died within 24 hours after birth with IVH and seizures.
Blinding of outcome: not documented
Parallel design
Washout period: not documented

Participants

Total number of patients entered into the study: 60
Entry criteria: Birthweight maximum 2000 g, clinical and radiologic evidence of RDS, mechanical ventilation within 4 hours of age, normal blood pressure and good peripheral capillary filling.
Exclusion criteria: not defined in the protocol.
Final analysis included 29 patients randomized to furosemide and 27 randomized to the control group. Average gestational ages were 30.5±2.6 weeks in the furosemide group and 30.7±1.9 weeks in the control group. Birth weights were 1257±343 g and 1277±286 g, respectively. Postnatal ages at study entry were 7.3±3.5 hours and 7.0±3.5 hours, respectively. Mean airway pressure, FiO2 and alveolar‐arterial O2 gradient were similar in both groups.
Fluid intake increased daily from 80 ml/kg/day on the first day to 150 ml/kg/day on the fifth day, with an additional 20 ml/kg/day for patients on phototherapy. Fluid intake was similar in the 2 groups. Patients were treated in servocontrolled incubators.
All parameters were followed for 72 hours after study entry. In addition, patients were assessed clinically for PDA until discharge from the hospital.

Interventions

Three doses of furosemide vs control.
Patients were randomly assigned to receive either 3 doses of 1 mg/kg of furosemide intravenously at approximately 24‐hour intervals (n=30), or no furosemide (n=30).

Outcomes

Major outcome: failure to extubate at 72 hours
Other outcomes: incidence of BPD (defined as respiratory distress with radiographic changes of at least stage 3 from Northway classification), incidence of clinical PDA, incidence of IVH, mean airway pressure, FiO2.
Five of 29 patients in the furosemide group died (6 of the original 30), compared with 4 of 27 in the control group (7 of the original 30). Sixteen of 29 patients in the furosemide group and 23 in the control group failed extubation within 72 hours after initiation of the study. Mean airway pressure at the end of the study was significantly lower in the furosemide group than in the control group, but FiO2 and alveolar‐arterial gradient were similar. Clinical diagnosis of PDA was made in 10 of 29 patients in the furosemide group and 12 of 27 in the control group. BPD developed in 9 of 29 patients in the furosemide group and 9 of 27 patients in the control group. Duration of O2 therapy, time to regain weight and duration of hospitalization were not significantly different between the 2 groups.
IVH was observed in 7 of 29 patients in the furosemide group (7 of the 30 initially enrolled patients) and 8 of 27 (10 of the 30 initially enrolled patients) in the control group. During the study, patients in the furosemide group had higher urine output, fractional excretions of sodium and chloride but not potassium than those in the control group. At the end of the study, patients in the furosemide group had lost a higher percentage of body weight than those in the control group.

Notes

No echographic results are presented. Treatment for PDA is not documented.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Sixty envelopes were prepared and kept under the control of an independent observer.

Allocation concealment (selection bias)

Low risk

Blinding of randomization: yes

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding of intervention: unclear. Control patients were treated similarly to experimental patients but did not receive furosemide. The authors do not mention whether control patients received a placebo. Blinding of outcome: not documented

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Complete follow‐up: no. Sixty patients were randomized. Four patients were excluded from the study before analysis: 2 patients (one in each group) with group B streptococcus sepsis, and 2 patients in the control group who died within 24 hours after birth with IVH and seizures.