Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease

Early stages of bronchopulmonary dysplasia (BPD) or CLD of prematurity are associated with alveolar and interstitial edema (Brown 1978; Edwards 1979; Northway 1967; Reid 1979). Factors involved in this edema include increased capillary permeability resulting from lung injury, congestive heart failure due to patent ductus arteriosus, and fluid overload (Brown 1978; Zimmerman 1995). This edema could not only reduce lung compliance (and thus tidal volume if using a pressure-limited ventilator) but also increase airway resistance by narrowing terminal airways (Northway 1967).

1. Diuretics may accelerate lung fluid reabsorption and improve pulmonary mechanics in patients with lung edema via two types of mechanisms:
1.1 An immediate, diuresis-independent lung fluid reabsorption: This may result (1) from systemic venodilatation, which increases systemic vein capacitance (Dikshit 1973), (2) from decreased pulmonary shunt in the absence of any change in wedge or oncotic pressure (as described in oleic acid-induced pulmonary edema) (Ali 1979), (3) from pulmonary venodilation which decreases wedge pressure, thereby increasing transpulmonary fluid absorption (Demling 1978) or decreasing fluid filtration, and in turn decreasing lung lymph flow (Bland 1978). Furosemide-induced pulmonary vasodilation may result from an increase in prostaglandins (Lundergan 1988).
1.2. A delayed increase in urine output (Aufricht 1997), which reduces extracellular volume including interstitial volume (O'Donovan 1989), and may reduce afterload (Wilson 1981) and increase oncotic pressure (Sola 1981). The effects of diuretics on the kidney, in contrast with those on the lung, have been studied extensively and well characterized (Brion 1994), and will not be reviewed here. If diuretic administration is repeated for several days, hormonal and renal adaptation mechanisms eventually will limit the diuretic response. Addition of a diuretic acting upon another segment of the nephron is often able to overcome this tolerance.

2. Pharmacokinetics of loop diuretics in premature infants:
The discussion will be limited to possible causes for systematic bias in relevant studies.

First, half-life of loop diuretics is prolonged in very low birth weight infants (Chemtob 1989; Lopez 1990; Mirochnick 1988; Peterson 1980; Shankaran 1990; Vert 1982 ). In one series, furosemide half-life, often > 24 hours in patients with a postconceptional age < 31 weeks, decreased to < 12 hours in most infants by 33 weeks and to four hours by term age (Mirochnick 1988). Because of that long half-life in immature infants, a prolonged washout period (without diuretic administration) is needed if one wishes to eliminate all diuretic effect before initiating a clinical trial or between exposures in cross-over trials.

Second, bioavailability of a single dose of enteral furosemide in preterm infants ranges between 84.3% (range 56 - 106%, postconceptional age 39.1 weeks) (Mirochnick 1988) and less than 20% (postnatal age four months) (Peterson 1980). Nevertheless, average steady state (duration 7 - 14 days) maximum plasma concentrations achieved using 1 mg/kg intravenous doses every 12 hours (23.1 ± 13.8 µg/ml at a postconceptional age of 30.1 ± 6.0 weeks) are similar to those achieved using 2 mg/kg enteral doses (20.0±6.5 µg/ml at a postconceptional age of 29.5 ± 2.0 weeks) (Mirochnick 1988). Thus, an enteral dose of 2 mg/kg furosemide is usually considered equivalent to an intravenous dose of 1 mg/kg in premature infants (Mirochnick 1988, Engelhardt 1986).

3. Potential effects of diuretic administration on other systems include the following:
3.1. Changes in water and electrolyte handling: These may include an increase in urine output and in the excretion of Na, K and Cl, a decrease in extracellular volume and thus changes in water distribution in the body, hypovolemia, increased drug-induced nephrotoxicity (resulting at least in part from hypovolemia), hyponatremia, hypokalemia, hypochloremia, hyperuricemia and metabolic alkalosis. Hyponatremia is common in very low birth weight infants treated with thiazides (Horgan 1996), which do not affect urinary concentration mechanisms, in contrast with loop diuretics. Hypochloremia and alkalosis have been associated with mortality in premature infants with BPD (Giacoia 1991; Perlman 1986); however, causality has not been proven.

3.2. Changes in mineral reabsorption: Hypercalciuria, associated with the use of many diuretics, is most prominent with loop diuretics and spironolactone. Hypercalciuria may lead to nephrolithiasis, nephrocalcinosis and bone demineralization. A 48 fold increased risk of nephrocalcinosis has been associated with a 10mg/kg cumulative dose of furosemide during a NICU hospitalization (Gimpel 2010). Many infants with nephrocalcinosis have long-term glomerular and tubular renal dysfunction (Downing 1992; Ezzedeen 1988). In contrast, thiazides, metolazone and K-sparing diuretics other than spironolactone enhance calcium reabsorption by the renal tubule and thus cause hypocalciuria and even may cause hypercalcemia. Nevertheless, administration of thiazide does not prevent hypercalciuria in patients receiving a loop diuretic (Campfield 1997).

An increase in phosphaturia is observed with all diuretics. This phosphaturia may contribute to a negative phosphate balance, which is a major factor involved in osteopenia of prematurity.

3.3. Cardiovascular system: Diuretic administration may have both beneficial and harmful effects on the cardiovascular system.
Diuretics are useful to treat pulmonary edema due to congestive heart failure and to treat systemic hypertension, a common complication of BPD. In contrast, administration of furosemide increases the incidence of patent ductus arteriosus compared to thiazide diuretic administration in patients with RDS (Green 1983). In addition, furosemide administration simultaneous with indomethacin therapy results in a trend towards a 10% higher risk of failure of ductal closure in response to indomethacin (Brion 1998).

3.4. Gastrointestinal tract: Cholelithiasis is associated with furosemide administration (Randall 1992).

3.5. Neurosensory hearing loss: This may result from high serum levels of furosemide associated with long half-life in immature infants.

Based on the above, one may speculate that enteral or intravenous administration of furosemide could improve pulmonary mechanics by two separate mechanisms:
-immediate diuresis-independent reabsorption of lung fluid
-delayed reabsorption of lung fluid mediated by a decrease in extracellular volume secondary to increased diuresis.
Both these mechanisms would be expected to improve lung compliance (and tidal volume with pressure-limited ventilation).

Furosemide is reported to be one of the top 10 reported drugs used in NICU’s treating critically ill neonates (Clark 2006). Despite their widespread use, there are surprisingly few studies looking at short and long term improvement in infants with CLD treated with loop diuretics. In addition, these drugs have many side effects including nephrocalcinosis which can contribute to long term renal morbidity (Downing 1992; Ezzedeen 1988).

Types of studies

Types of participants

Types of interventions

Types of outcome measures

See: Collaborative Review Group search strategy
The standard search method of the Cochrane Neonatal Review Group was used.

Published manuscripts:
MEDLINE (1966 to 1998), EMBASE (1974 to 1998) and the Cochrane Controlled Trials Register (CCTR) from The Cochrane Library (Issue 3, 1998) in August 1998 were searched. The search was not limited to any language.
The following keywords were used: {<bronchopulmonary dysplasia> or <chronic lung disease>} and <explode diuretics>, limited to <human> and limited to <infant, newborn> or <infant>.

A new MEDLINE search was done on August 20, 2000 using the keywords {<bronchopulmonary dysplasia> or <chronic lung disease>} and <diuretics>, limited to <human> and limited to <infant, newborn>, and publications starting January 1, 1998. This search did not yield any additional relevant randomized trials.

An additional search of MEDLINE done using {<bronchopulmonary dysplasia> or <chronic lung disease>} and <diuretic> in April 2003, March 2007 and repeated in December 2010 did not yield any additional eligible studies. An additional EMBASE search in April 2007 and December 2010 did not yield any additional eligible studies.

A new search was completed in December 2010 in CINAHL, clinicaltrials.gov, and controlled-trials.com. No additional eligible studies were obtained.

Published abstracts:
The abstracts of the following national or international societies were searched (1991 to 1998 unless otherwise specified):
# American Academy of Pediatrics 90-98 (published in American Journal of Perinatology [1990 to 1995] and in Pediatrics [1996 to 1998])
# American Society of Nephrology (published in Journal of the American Society of Nephrology)
# American Thoracic Society 1991 to 1998 (published in American Review of Respiratory Disease [1991 to 1993] and in American Journal of Respiratory and Critical Care Medicine [1994 to 1998])
# British Paediatric Association (now Royal College of Paediatrics and Child Health [RCPCH]) Annual Scientific Meeting
# European Respiratory Society
# European Society for Pediatric Research (published in Pediatric Research)
# Neonatal Society [UK]
# Society for Pediatric Research [US] (published in Pediatric Research).

The search was done by hand for most of these societies, and by CD-ROM where available (American Thoracic Society 1998, [American] Society for Pediatric Research 1997-8 and American Society of Nephrology 1997-8). For abstract books or CD-ROMs with keywords, the following keywords were used: bronchopulmonary dysplasia, bumetanide, chronic lung disease, diuretic, furosemide, lung disease chronic, metolazone, spironolactone, and thiazide.

For abstract books that do not include keywords the search was limited to relevant sections, whenever possible. For the American Academy of Pediatrics the sections on Computer and other Technologies, Critical Care and Perinatal Pediatrics were hand searched.

For the American Thoracic Society (1991 to 1993 and 1995 to 1997) sections with a title that included one of the following keywords were searched: airway (pharmacology, dynamics, reactivity, hyperreactivity, hyperresponsiveness), asthma (pharmacology, therapy, treatment), bronchopulmonary dysplasia, BPD, childhood/children, diuretic, edema, fluid, infant, mechanics, neonatal, pediatric(s), pulmonary function tests, or water. For 1994 (no sections) we hand searched all abstracts.

For the European Society for Pediatrics 1991 to 1993 and 1997 to 1998 the sections on Clinical Trials, Epidemiology, Neonatology, and Pulmonology were handsearched.

For years 1992 to 1993 of the Society for Pediatric Research, (volumes 31 and 33 of Pediatric Research) the sections on Developmental Pharmacology, Neonatology-General, Neonatal Pulmonology and Nephrology were hand searched.

Hand searching of the Neonatal Society [UK] and RCPCH abstracts in April 2007 did not yield any additional eligible study.

Cochrane neonatal specialized register:
All publications coded under diuretics as intervention in September, 1998 were screened.
Searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) Issue 1, 2003, Issue 1, 2007, and Issue 4, 2010 did not yield any additional eligible study.

Selection process:
Only randomized controlled trials fulfilling the selection criteria described in the previous section were kept. Selection was done separately by two investigators; any disagreement was resolved by discussion.

The standard method for the Cochrane Collaboration which is described in the Cochrane Collaboration Handbook was used.

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

A total of 27 studies were considered for this review. Eighteen studies were eliminated because they did not involve random allocation to administration of a loop diuretic. One study (Engelhardt 1986) was eliminated because it combined a randomized trial with non randomized data. Two studies (Segar 1992, Shankaran 1994) were eliminated because they did not include any information on the outcomes selected for this systematic review. Thus, six studies were included in the present review. Details reported by the authors are provided in the table.

Almost all studies included in this review included dynamic measurements of pulmonary mechanics with or without an esophageal balloon. Kao and collaborators (Kao 1983) measured resistance by plethysmography.

Main categories (intervention) are shown as first entry in the column labeled 'Interventions.' No subcategories were used based on gestational age, because the maximum range of gestational age within each intervention group was 4 weeks. Main categories (based on intervention) and subcategories (based on postnatal age and mechanical ventilation) are described below:

1. Intravenous or enteral administration of a loop diuretic versus placebo in controls:
Five studies were in this group, including two with parallel design (Najak 83, McCann 85) and three with cross-over design (Kao 83, Rush 90, Singhal 83). Postnatal age ranged between 7 and 101 days; therefore, we classified studies into 2 subcategories based on average postnatal age at study entry: < 3 wk (Najak) vs. > 3 wk (Kao, McCann, Rush, Singhal). Average gestational age ranged between 27 and 30 weeks, so that no subcategories were created for gestational age.

1.1. Postnatal age < 3 weeks

Najak 1983: parallel design.
This study included both intubated and non-intubated patients. Patients were randomized to receive either a single daily dose of 1 mg/kg of furosemide for four days, or placebo. No washout period was documented. Individual change scores were provided for alveolar-arterial O2 gradient.

1.2. Postnatal age > 3 weeks

1.2.1. Non-intubated patients:

Kao 1983: cross-over design with pooled data.
Patients were randomized to receive either a single dose of 1 mg/kg of furosemide followed by a 48-hour washout period and then placebo, or vice-versa. Prolonged washout period before the study is also documented. Change scores were estimated from the % change from baseline using Baird and Armitage's method. For tidal volume, the change score (ml/cm h3O) needed then to be converted into ml/cm h3O/kg using Baird and Armitage's method.

Rush 1990: cross-over design with pooled data.
Patients were randomized to receive, enterally, either alternate-day doses of 4 mg/kg of furosemide for eight days followed by a 48-hour washout period and then placebo for eight days, or vice-versa. Prolonged washout period before the study and at cross-over is documented. Change scores for pulmonary function were estimated using Follmann's formula, while those for % inspired O2 and weight gain were provided in the manuscript. No baseline data were provided for calciuria.

1.2.2. Non-intubated and intubated patients:

McCann 1985: parallel design.
Patients were randomized to receive either 1 mg/kg of furosemide every 12 hours for seven days, or placebo. Prolonged washout period before the study and at cross-over is documented. Change scores were estimated using Follmann's formula.

1.2.3. No information provided about respiratory support:

Singhal 1983: cross-over design with pooled data.
This study was available as abstract only. Patients were randomized to receive either 1.5 mg/kg of furosemide every 12 hours for three doses followed by placebo, or vice-versa. No washout period was documented. Change scores for pulmonary function were estimated using Follmann's formula.

2. Administration of furosemide by continuous intravenous infusion versus intermittent intravenous administration in controls:

Reiter 1998: parallel design.
Eighteen of thirty patients required mechanical ventilation at study entry. Patients were randomly allocated to receive a single dose of furosemide, either (1) by infusion, which included a small bolus of 0.1 mg/kg over two minutes followed by a six-hour infusion of 0.9 mg/kg, or (2) by intravenous bolus of 1 mg/kg over two minutes followed by a six-hour infusion of placebo. Prolonged washout period before the study is documented. Change scores were provided in the manuscript.

Specific assessments of all four types of bias are described in the table of included studies.

1. Intravenous or enteral administration of a loop diuretic, versus placebo in controls:
Of the five studies included in this group, none appeared to be bias-free.

In Kao's study (Kao 1983) blinding was not documented; this could have yielded an increase in the effect of furosemide.

In McCann's study (McCann 1985) blinding was well documented but attrition bias is likely to have affected the data. Of 24 infants entered into the study, seven were removed from the analysis: in the control group, two infants had clinical deterioration. In the furosemide group, one had severe hypochloremia, two had sepsis, one had a surgical shunt for hydrocephalus, and one had CLD following meconium aspiration syndrome. Removing control patients from analysis because of clinical deterioration could have biased the data towards decreasing the effect of furosemide, whereas removing one treated patient from the analysis because of hypochloremia could have biased the results toward decreasing the incidence of electrolyte abnormalities in treated patients.

In Najak's study (Najak 1983) blinding was not documented; this could have yielded an increase in the effect of furosemide. Two of twelve patients randomized to furosemide were subsequently removed from the study because they did not have typical RDS; it is not clear which effect this could have had on the results.

In Rush's study (Rush 1990) blinding was well documented. Of 16 eligible infants, 13 were enrolled (consent signed); two patients were later excluded because of documented infection, as planned in the authors' protocol.

In Singhal's study (Singhal 1983) blinding was well documented.

2. Administration of furosemide by continuous intravenous infusion versus intermittent intravenous administration in controls:
Only one study (Reiter 1998) is in this group. Blinding was well documented. All patients were followed; nevertheless, FiO2 is only provided for patients requiring mechanical ventilation.

1. Limitations of the scope of the studies available for this review:
Most studies focused on pathophysiological parameters (pulmonary mechanics) and failed to assess the primary outcomes defined in this review (e.g., need for and duration for mechanical ventilation or oxygen supplementation, BPD, mortality) or the potential complications of diuretic therapy. No studies reported on need for continuous positive airway pressure, chronic lung disease at 36 weeks postmenstrual age, mortality, length of stay, number of rehospitalizations during the first year of life, alkalosis, hyponatremia, bone demineralization, nephrocalcinosis, nephrolithiasis, cholelithiasis, or expiratory flow.

Furthermore, for most outcomes, only one or two studies provided data that could be merged into a meta-analysis, so that only a small number of patients was included in each analysis. Therefore, it is possible that real differences due to furosemide administration could have been missed. For each analysis we report the studies and the number of patients in which the particular outcome is reported.

2. Value of the pretest-posttest correlation coefficient:
Limited data are available in the literature about the value of this correlation coefficient for pulmonary mechanics in preterm infants. Data from Kugelman (Kugelman 1997) yield a strong pretest-posttest correlation for dynamic compliance (0.8 for a one or a two hour period). This value was used for calculating the change score in Singhal's study.

3. Effects of furosemide in preterm infants with or developing CLD
3.1. Intravenous or enteral administration of a loop diuretic, versus placebo in controls:
3.1.1. Oxygenation, oxygen requirement and BPD:
Among patients entered at a postnatal age < 3 weeks, daily furosemide administration improved the change in alveolar-arteriolar gradient within two hours after therapy inconsistently (n = 20) (Najak 1983). The alveolar-arterial oxygen gradient improved more within two hours after the second dose of furosemide than in controls (WMD -16.0 mm Hg, 95%CI -2.8 to -29.2) but not after the first, third or fourth dose of furosemide.

Among patients with a postnatal age > 3 weeks, a two-day furosemide course did not affect oxygen requirement (n = 17) (McCann 1985). In contrast, a seven to eight day course of furosemide significantly improved the percent inspired O2 (WMD -2.7%, 95%CI -1.0 to -4.4, n = 39) (McCann 1985; Rush 1990).

No data were available on total duration of O2 administration, incidence of BPD or chronic lung disease at 36 weeks postmenstrual age.

3.1.2. Failure to wean mechanical ventilation:
Furosemide tended to decrease the risk of failure to extubate within a week (RR 0.53, 95%CI 0.17 to 1.68; RD -0.35, 95%CI -0.87 to +0.17, n = 13) (McCann 1985) and the risk of failure to either wean off the ventilator or to decrease the ventilatory settings (RR 0.12, 95%CI 0.01 to 1.69; RD -0.75, 95%CI -1.18 to -0.32, n = 13). Furosemide tended to improve the change in peak inspiratory pressure (WMD -11 cm h3O, 95%CI -29 to +7.4, n = 8) and the change in rate of mechanical ventilation (WMD -16 cycles/min, 95%CI -41 to +9, n = 8) (McCann 1995).

3.1.3. Pulmonary mechanics:
The effect of a single dose of furosemide was analyzed in two studies: Kao (1983), in which only non intubated patients were studied, and Singhal (1983), in which tracheal intubation was not an entry criterion. Furosemide improved compliance more than placebo after one hour (WMD 0.5 ml/cm h3O/kg, 95%CI 0.3 to 0.7, n = 20) (Kao 1983). This effect was transient: there was no significant difference after two hours (Kao 1983; Singhal 1983) (WMD 0.09, 95%CI -0.17 ml/cm h3O/kg to +0.35), obtained using a pretest-posttest correlation of 0.8 for calculating the change score in Singhal's study. Sensitivity analysis using a pretest-posttest correlation of 0.4 yielded a WMD of 0.05 ml/cm h3O/kg, 95%CI -0.24 to 0.33. Furosemide significantly improved resistance after one hour (WMD -25 cm h3O/L/sec, 95%CI -5 to -45, n = 20) (Kao 1983); the difference at two hours did not reach significance anymore (WMD -10.27 cm h3O/L/sec, 95%CI -24.93 to +3.49, n = 20) (Kao 1983).

A one to two day course of furosemide tended to improve pulmonary compliance (WMD 0.17 ml/cm h3O/kg, 95%CI -0.09 to +0.44, n = 59) (Rush 1990, McCann 1985; Singhal 1983), tidal volume (n = 17) (McCann 1985) and resistance (WMD -49 cm/L/sec, 95%CI -128 to +33, n = 39) (Mc Cann 1985, Rush 1990) but none of these comparisons reached significance. Furosemide did not affect minute ventilation or alveolar ventilation (n = 17) (McCann 1985). A 4-6 day course tended to improve compliance and resistance (n = 22) (Rush 1990) but this did not reach statistical significance.

Patients treated for seven to eight days with furosemide had a significant improvement in pulmonary compliance (WMD 0.4 ml/cm h3O/kg, 95%CI 0.1 to 0.7, n = 39) (Mc Cann 1985, Rush 1990) and minute ventilation (WMD 126 ml/kg/min, 95%CI 19 to 233, n = 17) (McCann 1985) than controls. Furosemide tended to improve alveolar ventilation (WMD 67 ml/kg/min, 95%CI -8 to +143, n = 17) (McCann 1985) and resistance (WMD -61.5 cm/L/sec, 95%CI -134.2 to + 11.2, n = 39) (McCann 1985; Rush 1990) but did not affect tidal volume (WMD 0.6 ml/kg, 95%CI -1.7 to +2.9, n = 17) (McCann 1985).

Furosemide tended to decrease the failure to improve the chest radiogram (RR 0.1, 95%CI 0.01 to 1.4, n = 17) (McCann 1985).

3.1.4. Fluids, electrolytes, minerals, kidney:
Severe hypochloremia was observed in 1/12 treated infants and none of 12 controls in one study (McCann 1985). There is no information on the incidence of other electrolyte abnormalities, dehydration, nephrocalcinosis, or nephrolithiasis. A one-week furosemide administration reduced weight gain (-9 g, 95%CI -15 to -2, n = 11) and tended to increase the amount of calciuria (+29 mg/dl, 95%CI -21 to +79, n = 11) but not the calcium/creatinine ratio (Rush 1990).

3.1.5. Long term outcome:
No hearing loss was detected in seven furosemide treated infants and 10 controls (McCann 1985). None of the other long term outcomes, including the primary outcomes defined for this review, were assessed in these studies.

3.2. Administration of furosemide by continuous intravenous infusion versus bolus intravenous administration in controls:
The single available study (Reiter 1998) showed that a slow infusion of furosemide did not improve mean airway pressure compared with a rapid injection of furosemide (n = 18). No patient in the bolus group had any change in mean airway pressure (both mean and SD were 0 at each time point). Among patients in the slow infusion group, furosemide administration yielded no (clinically or statistically) significant changes in mean airway pressure (-0.24±0.81 cm h3O [-0.18±0.60 mm Hg] at 1-4 hours and -0.62±1.12 cm h3O [-0.46±0.83 mm Hg] at 4-12 hours). RevMan is unable to calculate a WMD for these data because SD in control (bolus) group is zero. The slow infusion tended to improve the need for supplemental oxygen (n = 18), but this did not reach statistical significance.

Only limited data are available about the primary outcomes defined for this systematic review. Most of the outcome variables have been reported only in one or two studies and in a limited number of patients. Therefore, some effects of furosemide may have been undetected.

In preterm infants < 3 weeks of age developing CLD, intravenous furosemide administration has either inconsistent effects or no detectable effect.

In infants > 3 weeks of age with CLD, a single intravenous dose of 1 mg/kg of furosemide transiently improves pulmonary mechanics. Chronic enteral or intravenous furosemide administration improves both oxygenation and pulmonary mechanics.

There is little evidence to support any benefit of furosemide administration on need for ventilatory support, length of hospital stay, survival or long-term outcome. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of systemic loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence.

Further studies need to assess the effects of diuretics on survival, duration of O2- and ventilator-dependency, length of stay and long-term outcome.

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

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