Aerosolized diuretics for preterm infants with (or developing) chronic lung disease

Luc P Brion; R A Primhak; W Yong

doi:10.1002/14651858.CD001694.pub2

. 2006 Jul 19;2006(3):CD001694. doi: 10.1002/14651858.CD001694.pub2

Aerosolized diuretics for preterm infants with (or developing) chronic lung disease

Luc P Brion ^1,^✉, R A Primhak ², W Yong ³

Editor: Cochrane Neonatal Group

PMCID: PMC6769054 PMID: 16855973

Abstract

Background

Lung disease in preterm infants is often complicated with lung edema.

Objectives

To determine the risks and benefits of aerosolized diuretic administration in preterm infants with or developing chronic lung disease (CLD). Primary objectives are to assess effects on short‐term outcome (changes in need for oxygen or ventilatory support) and effects on long‐term outcome. Secondary objectives are to assess changes in pulmonary mechanics and potential complications of therapy.

Search methods

We used the standard search method of the Cochrane Neonatal Review Group. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 to 1998) and EMBASE (1974 to 1998). We hand searched several abstract books of national and international American and European Societies. The searches of MEDLINE (search via PubMed), CINAHL, EMBASE and The Cochrane Library were updated in July 2009.

Selection criteria

We included trials in which preterm infants with or developing CLD and at least five days of age were randomly allocated to receive an aerosolized loop diuretic.

Data collection and analysis

We used the standard method for the Cochrane Collaboration. We combined parallel and cross‐over trials and, whenever possible, transformed baseline and final outcome data measured on a continuous scale into change scores using Follmann's formula.

Main results

Eight studies met selection criteria. Most studies focused on pathophysiological parameters and did not assess effects on important clinical outcomes or potential complications of diuretic therapy. No study assessed the amount of diuretic effectively delivered to the patient. Furosemide was the only diuretic used in the eight studies included in this review.

Among preterm infants < 3 weeks of age developing CLD, not enough information is available to assess the effect of aerosolized furosemide on outcome or lung function.

Among infants > 3 weeks with CLD, a single aerosolized dose of 1 mg/kg of furosemide may transiently improve pulmonary mechanics. Not enough information is available to assess the effect of chronic administration of aerosolized furosemide on oxygenation and pulmonary mechanics.

Authors' conclusions

In preterm infants > 3 weeks with CLD administration of a single dose of aerosolized furosemide improves pulmonary mechanics. In view of the lack of data from randomized trials concerning effects on important clinical outcomes, routine or sustained use of aerosolized loop diuretics in infants with (or developing) CLD cannot be recommended based on current evidence.

Randomized controlled trials are needed to evaluate clinically important effects of aerosolized diuretics.

Plain language summary

Aerosolized diuretics for preterm infants with (or developing) chronic lung disease

There is no evidence of benefit from routine use of inhaled diuretics in preterm babies at risk of chronic lung disease. Lung disease in babies born early (preterm) is often complicated with excess accumulation of water in the lungs. Medications that reduce body water (diuretics) might help the baby recover from lung disease. In theory, giving the diuretic as an inhaled mist (aerosol) could drain water from the lung more than from the rest of the body, which could reduce adverse effects. The review found several small trials of a single type of diuretic (furosemide). A single dose improved lung function, but only temporarily. No information was available about long term outcome.

Background

This review is part of a group of three closely related reviews on diuretics in preterm infants with chronic lung disease (CLD), developing CLD or at high risk of CLD (Brion 1999 a,b). The present review will describe the evidence about administration of aerosolized diuretics in preterm infants with CLD, developing CLD or at high risk of CLD. The other two reviews (Brion 1999a,b) will discuss the use of systemic loop diuretics and the use of diuretics acting on distal segments of the renal tubule (thiazides and spironolactone).

Description of the condition

Rationale for administering aerosolized diuretics to neonates with CLD:   Reduction of lung edema:   Early stages of chronic lung disease (CLD) of prematurity are associated with lung edema. 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 pulmonary compliance (and thus tidal volume if using a pressure‐limited ventilator) but also increase airway resistance by narrowing terminal airways (Northway 1967). Diuretics may accelerate lung fluid reabsorption and improve pulmonary mechanics in patients with lung edema via two types of mechanisms: (1) an immediate, diuresis‐independent lung fluid reabsorption, and (2) a delayed increase in urine output (Brion 1999a). It is possible that the incidence of lung edema in preterm infants may have decreased as a result of changes in therapy introduced in the last decade (Gortner 1991; Sonntag 1996).

Reduction of bronchoconstriction:   Reactive airway disease may result from narrowing of the terminal airways secondary to interstitial edema (see 1.1) and from bronchial smooth muscle hypertrophy (Northway 1967). Infants with BPD may develop reactive airway disease (Denjean 1992) and benefit from bronchodilator therapy. Reactive airway disease in those infants may persist into childhood (Bader 1987).

Both in children and in adults, aerosolized diuretic administration (furosemide, acetazolamide and amiloride) has been shown to alleviate reactive airway disease mediated by various stimuli (exercise, fog, metabisulfite, antigen) but not bronchoconstriction at rest or that secondary to metacholine challenge (Editorial 1990; O'Donnell 1992; Mochizuki 1995). In contrast, a randomized double‐blind, placebo‐controlled trial with parallel design failed to show any therapeutic effect of aerosolized furosemide in wheezing infants (Van Bever 1995).

Furosemide decreases smooth muscle contractility in vitro whether applied to the intraluminal (mucosal) or extraluminal side of the airway (Iwamoto 1997). Several possible mechanisms of diuretic action (specifically, furosemide) on airway smooth muscle contractility have been proposed. First, furosemide, by inhibiting the basolateral Na‐K‐2Cl cotransporter of the epithelial cells (Frizzell 1979; Welsh 1983; Lavallee 1997), could modify the osmotic and ionic environment, thereby possibly affecting the activation of mast cells and sensory epithelial nerves (Bienenstock 1988). Second, furosemide has been shown to decrease the release of inflammatory mediators, including leukotrienes and histamine produced by lung tissue in vitro (Anderson 1991) and interleukin‐6 by peripheral blood mononuclear cells (Yuengsrigul 1996). Third, furosemide could release bronchodilator prostaglandins from airway epithelium, as shown with vascular endothelium (Lundergan 1988) or kidney (see Brion 1998). The action of furosemide on bronchospasm has been shown to be reduced by indomethacin by some (Pavord 1992) but not all authors (Rodwell 1997). Finally, loop diuretics could inhibit cholinergic and excitatory non‐cholinergic non‐adrenergic contraction of bronchial muscle (Elwood 1991).

Therefore, one may speculate that aerosolized diuretic administration might decrease bronchoconstriction in those infants with BPD who also have reactive airway disease.

Description of the intervention

Pharmacokinetics and pharmacodynamics of diuretics:   So far, the only diuretic administered to neonates in aerosolized form is furosemide. Because of the long half‐life of loop diuretics in immature infants (Peterson 1980; Vert 1982), a prolonged washout period (without diuretic administration) is needed if one wishes to eliminate any residual diuretic activity before initiating a clinical trial or between exposures in cross‐over trials.

Only a small fraction of aerosolized furosemide reaches the terminal bronchioles and alveoli. Medication deposition in the lung may range between 1 and 15% (Fok 1994, O'Riordan 1994). Critical components may include (1) the type of nebulizer, which affects the size of the droplets (2) characteristics of the tubing, including length and temperature gradient, (3) the side flow which if too high will lead to bypassing the patient into the expiratory limb of the tubing, (4) humidity of inhaled gas and (5) whether the patient is ventilated or not (Cameron 1990; Fok TF 1994; Kugelman 1997; O'Riordan 1994, Prabhu 1997).

Unless all these characteristics are provided, it may be difficult to estimate the amount of medication effectively received by the patient. Thus, negative data might result from either lack of efficacy of the medication on the lung, lack of delivery to the distal airway, or both.

Some of the effects on lung function may result from systemic absorption, as shown by increased urine output in some (Aufricht 1997; Seidenberg 1992) but not all studies.

Potential toxicity of diuretic administration include the following:   (1) hypovolemia, increased drug‐induced nephrotoxicity (resulting at least in part from hypovolemia), hyponatremia, hypokalemia, hypochloremia, hyperuricemia and metabolic alkalosis.   (2) hypercalciuria (leading to nephrolithiasis, nephrocalcinosis and bone demineralization) and hyperphosphaturia (leading to osteopenia)   (3) increased incidence of patent ductus arteriosus   (4) cholelithiasis   (5) neurosensory hearing loss, resulting from high serum levels of furosemide associated with long half‐life in immature infants.

How the intervention might work

Summary and rationale for aerosolized diuretic administration in CLD in preterm infants:   Diuretic administration could improve pulmonary mechanics by three separate mechanisms:   ‐immediate diuresis‐independent reabsorption of lung fluid   ‐decrease in bronchospasm in patients with reactive airway disease   ‐delayed reabsorption of lung fluid mediated by a decrease in extracellular volume secondary to increased diuresis

The first two mechanisms would be expected to improve lung mechanics by local action, whereas the third mechanism requires systemic absorption. The rationale for using aerosolized diuretics is to try to alleviate lung disease without causing side effects secondary to systemic absorption.

Why it is important to do this review

This review incorporates minor additions in updating the existing review which was published in The Cochrane Library, Disk Issue 3, 1999 (Brion 1999d).

Objectives

The aim of this review is to assess risks and benefits of aerosolized diuretic administration in preterm infants with or developing chronic lung disease.   Primary objectives are to assess:   (1) short‐term improvement: changes in mean airway pressure, need for artificial ventilation, need for continuous positive airway pressure, failure to tolerate extubation, and oxygen supplementation   (2) long‐term improvement: mortality, duration of need for oxygen supplementation and respiratory support, bronchopulmonary dysplasia (BPD) defined as need for oxygen supplementation at 28 days of life, death or BPD, chronic lung disease at 36 weeks of postmenstrual age (gestational age + postnatal age), length of stay, and number of rehospitalizations during the first year of life.   Secondary objectives are to assess changes in pulmonary mechanics after treatment and potential complications of diuretic administration.

Methods

Criteria for considering studies for this review

Types of studies

We included only randomized controlled studies. Randomization needed to involve the allocation of all patients either to a specific treatment (patients on diuretic vs controls on placebo or another therapy), or to a specific time of administration of the diuretic (diuretic first vs placebo first).

Types of participants

Participants needed to be:   (1) Preterm infants   (2) With oxygen dependency (> 21% O2 to maintain pulse oximetry > 90% or paO2 > 50 mm Hg) or ventilator dependency secondary to lung disease beyond five days of life.   Although BPD is usually defined by the need for oxygen supplementation at four weeks of age, CLD already starts during the first few days of life in patients with RDS (Northway 1967). For the present study, we only included studies with entry criteria of oxygen or ventilator dependence beyond five days, to avoid overlap with a systematic review of the use of diuretics in patients with RDS (Brion 1999c). Thus, patients eligible for this study included those with CLD, those developing CLD and those at high risk of CLD.

Types of interventions

The intervention needed to include the administration of an aerosolized loop diuretic. Eligible studies were those that assessed either the administration of an aerosolized diuretic compared to placebo (or no treatment), the administration of an additional aerosolized diuretic compared to a single diuretic in controls, the administration of a different diuretic from that in controls, or administration of a diuretic using another mode compared to control therapy (typically enteral or intravenous furosemide).

Types of outcome measures

Outcome measures had to include an assessment of the effect of diuretic administration on at least one of the following variables:

Primary outcomes

1. Primary outcome variables:   1.1. Short‐term improvement: changes in mean airway pressure, need for artificial ventilation, need for continuous positive airway pressure, failure to tolerate extubation, and changes in concentration of inhaled oxygen   1.2. Long‐term improvement: mortality, duration of need for oxygen supplementation and respiratory support, BPD, death or BPD, chronic lung disease at 36 weeks of postconceptional age (gestational age + postnatal age), length of stay, and number of rehospitalizations during the first year of life.

Secondary outcomes

2. Secondary outcome variables:   2.1. Potential complications: Incidence of alkalosis, hyponatremia, hypochloremia, bone demineralization (measured by using bone radiogram or densitometry), nephrocalcinosis, nephrolithiasis, cholelithiasis, neurosensory hearing loss.   2.2. Pulmonary function: Changes in resistance, compliance, tidal volume for patients on pressure‐limited ventilation, expiratory flow.

Search methods for identification of studies

See: Collaborative Review Group search strategy

Electronic searches

1. Published manuscripts:   We searched the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 1998 in August 1998, MEDLINE (1966 ‐ 1998), EMBASE (1974 ‐ 1998) and . We did not limit the search to any language.

We used the following keywords:{<bronchopulmonary dysplasia> or <chronic lung disease>}   and <explode diuretics>, limited to <human> and limited to <infant, newborn> or <infant>.

Additional searches of MEDLINE done using {<bronchopulmonary dysplasia> or <chronic lung disease>} and <diuretic> in January 2001, April 2003 and April 2006 did not yield any additional eligible studies. Search of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003 and Issue 1, 2006) did not yield any additional eligible studies.

2. Database of the Neonatal CRG of the Cochrane Collaboration:   We screened all publications coded under diuretics as intervention in September, 1998.

In July 2009, the search was updated as follows:   MEDLINE (search via PubMed), CINAHL, EMBASE and The Cochrane Library were searched from 2006 to 2009.   Clinicaltrials.gov was searched with no date restrictions.   Search terms: bronchopulmonary dysplasia or chronic lung disease and diuretics. Limits: human, newborn infant and clinical trial.   No language restrictions were applied.

Searching other resources

Published abstracts:   We searched the abstracts of the following national or international societies (1991 ‐ 1998 unless otherwise specified):   # American Academy of Pediatrics 1990 ‐ 1998 (published in American Journal of Perinatology [1990 ‐ 1995] and in Pediatrics [1996 ‐ 1998])   # American Society of Nephrology (published in Journal of the American Society of Nephrology)   # American Thoracic Society 1991 ‐ 98 (published in American Review of Respiratory Disease [1991 ‐ 1993] and in American Journal of Respiratory and Critical Care Medicine [1994 ‐ 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).   Details of the search can be found in a related review (Brion 1999a).

Additional searches of the abstracts of the UK Neonatal Society and the European Respiratory Society, done up to March 2006, and of the US Society for Pediatric Research (2000 ‐ 2006) did not yield any additional eligible studies.

Clinical trials registries were also searched for ongoing or recently completed trials (clinicaltrials.gov; controlled‐trials.com; and who.int/ictrp)

Data collection and analysis

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

Selection of studies

Only randomized controlled trials fulfilling the selection criteria described in the previous section were included. Selection was done separately by two investigators (LPB and RP); any disagreement was resolved by discussion.

Data extraction and management

Two investigators extracted, assessed and coded separately all data for each study, using a form that had been designed specifically for this review. We transformed graphical data into numerical data using a millimetric ruler and an electronic spreadsheet. We replaced any standard error of the mean by the corresponding standard deviation (SD). As much as possible we homogenized units among studies; in some cases this required using a specific formula to estimate the SD of a ratio or a product (Baird 1995; Armitage 1994).

In December 1998, we sent to each author an itemized letter requesting additional information about design, patients, methods, or original outcome data (if missing, incomplete or presented in graphical form). We obtained additional data from three authors: Dr. Ohki, Dr. Kugelman and Dr. Stefano (c/o Ms. Leef). Dr. Ohki kindly provided us with additional data, specifically, mean and standard deviation of measurements of pulmonary mechanics at baseline, one hr and two hr, as well as mean and standard deviation of the values at 1 hr and 2 hr expressed as percent of baseline. Dr. Kugelman provided us with description of methods, other medications received by the patients, and the order of medication administered. Dr. Stefano provided us with information on prior exposure to diuretics, method of aerosolization and ventilator parameters.

All calculations within the spreadsheet and entries into RevMan were done by one review author (LPB) and subsequently checked for accuracy by another review author (WY and RP). Any disagreement was resolved by discussion.

Conversion of values into SI units:   To obtain gas pressure in kPa, we multiplied the value in cm H2O by 0.10 or that in mm Hg by 0.13   To obtain calcium:creatinine ratio in mM:mM, we multiplied the ratio in mg:mg by 2.84   To obtain calcium in mM/L, we multiplied the value in mg/dl by 0.25

Assessment of risk of bias in included studies

The standard methods of the Cochrane Neonatal Review Group were employed. The methodological quality of the studies were assessed using the following key criteria: allocation concealment (blinding of randomization), blinding of intervention, completeness of follow‐up, and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, can't tell. Two review authors separately assessed each study. Any disagreement was resolved by discussion. This information was added to the Characteristics of Included Studies Table.

In addition, following issues were evaluated and entered into the Risk of Bias table:

1. Sequence generation: Was the allocation sequence adequately generated?

2. Allocation concealment: Was allocation adequately concealed?

3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?

4. Incomplete outcome data: Were incomplete outcome data adequately addressed?

5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?

6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

We used the standard method of the Cochrane Neonatal Review Group, using a fixed effect model.   For dichotomous variables we analyzed the odds ratio (OR) to combine parallel trials with cross‐over trials, using for cross‐over trials an alternate odds ratio approach with an imputed correlation (Elbourne 2002). If the imputed correlation for all cross‐over trials was zero, we analyzed relative risk (RR) and risk difference (RD).     For continuous variables we combined parallel trials with cross‐over trials using the inverse variance method (Handbook version 4.2.5, pages 117 and 159). We obtained the weighted mean difference (WMD) and its standard error (using a correlation coefficient of 0.4 for cross‐over trials, or 0.3 for sensitivity analysis) between change scores in the treatment group and in the control group. Change scores were obtained either from the mean of individual differences between baseline and final values, from mean and SD (or standard error) values of change (or percent of baseline) provided by the authors, or from the means and SD of baseline and final values. In the latter case, the variance (var) of change was estimated using Follmann's (Follmann 1992) method, described in version 3.0.2 of the Cochrane Collaboration Handbook (page 213):   Var(change)=Var(pretest) + Var(posttest) ‐ 2 x SD(pretest) x SD (posttest) x pretest‐posttest correlation coefficient.   We searched the literature for values of pretest‐posttest correlation coefficient (r) for each test, interval and patient group. If such data were not available, we assumed a value of 0.4, and conducted a sensitivity analysis by successively using r = 0.3 and r = 0.5.

For those studies providing mean and SD of baseline values and of the percent change from baseline, we obtained the mean change by multiplying percent change by the average baseline. Variance of change was calculated using established guidelines (Baird 1995; Armitage 1994), as described elsewhere (Brion 1999a).

Assessment of heterogeneity

Tests of between‐study heterogeneity (chi‐square analysis and I² statistic) were used to determine if pooling of data was appropriate. If there was inconsistency in the direction of the effect we presented the data of the meta‐analysis and discussed possible mechanisms involved in heterogeneity among the studies.

Data synthesis

The analysis was performed using Review Manager software (RevMan 5) supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we used the Mantel‐Haenszel method. For measured quantities, we used the inverse variance method. All meta‐analyses were done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

Planned comparisons and subgroup analyses:

We planned the following comparisons based on type of intervention:   1. Comparison of aerosolized diuretic administration versus placebo   2. Comparison of aerosolized diuretic administration versus intravenous administration   3. Comparison of various doses of furosemide by aerosol

For studies in which controls did not receive placebo but another intervention, we arbitrarily considered as 'control' 1) intravenous administration of furosemide, or 2) intermittent administration of a single diuretic.

Subgroup analyses:

1. Mean postnatal age:   Within each of the above groups, subgroups were determined based on mean postnatal age. The initial plan was to use a cut‐off value of four weeks, based on the usual definition of bronchopulmonary dysplasia. However, using this value would have made it impossible to classify two of the twenty studies included in this group of three related reviews on diuretics in preterm infants with (or developing) CLD (Singhal 1983; Robbins 1993).Therefore, we selected a mean postnatal age of three wk as the cut‐off for all three reviews.

2. Mean gestational age:   We planned to use subcategories based on mean gestational age if mean values in various studies were observed to differ by more than four weeks.

3. Presence of an endotracheal tube:   Pre‐determined sub‐categories were used for intubated patients vs. non‐intubated patients. The presence of an endotracheal tube is expected to increase total resistance and to decrease dead space. Patients requiring an endotracheal tube are likely to be sicker and thus to have lower pulmonary compliance and to require more oxygen than the other patients.

Results

Description of studies

A total of nine studies were considered for this review. One was eliminated because it did not involve random allocation to diuretic administration (Suresh 1992). Thus, eight studies were included in the present review. Details reported by the authors are provided in the table. All studies but one were cross‐over studies.

Almost all studies included in this review included dynamic measurements of pulmonary mechanics with or without an esophageal balloon. Static measurements were done in only one study (Ohki 1997). 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 four weeks. Main categories (based on intervention) and subcategories (based on postnatal age and mechanical ventilation) are described below:

1. Administration of furosemide by aerosol versus placebo:   This group included four studies, one with parallel design (Robbins 1993), and three with cross‐over design (Raval 1994; Ohki 1997; Kugelman 1997). Average gestational age ranged between 25 and 29 weeks, so that only one group was considered for the analysis. All patients required mechanical ventilation at study entry.

1.1. Average postnatal age < 3 weeks

Raval 1994: cross‐over design with pooled data.   This study was available as abstract only; additional data were provided by the authors. Six infants did not receive any diuretics before the study period. One patient in the control group had received diuretics two weeks before the study, and three patients had received one dose of furosemide during the last five days preceding the study (two in the control group and one in the treated group). Patients were randomized to receive either a daily dose of 1 mg/kg of furosemide for two days followed by placebo, or vice‐versa. There was no washout period between the two phases. An 'acorn' nebulizer with a capillary was placed in line on the ventilator circuit and the medication was mixed with 2 ml of normal saline and delivered at 6 L/min flow. The authors measured dynamic pulmonary mechanics. Change scores for tidal volume were estimated using Follmann's formula.

1.2. Average postnatal age > 3 weeks

Kugelman 1997: cross‐over design with pooled data.   Patients were randomized to receive either a single dose of 1 mg/kg of furosemide followed by placebo, or vice‐versa. The washout period before the study was only six hours for thiazides, spironolactone, and furosemide. A 24 hour‐washout period was documented at the time of cross‐over. Change scores for tidal volume were estimated using Follmann's formula; those for compliance, resistance and transcutaneous pO2 were calculated from the authors' primary data.

Ohki 1997: 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. A washout period of 48 hours was documented both before the study and at the time of crossover.

In patients on furosemide, change scores for pulmonary function tests were estimated by the mean of two results. First we used Baird and Armitage's method with the exact unpublished average and SD baseline values (see table of included studies) and percent values of baseline provided by Y. Ohki. Second, we calculated the mean of change scores for individual data extracted from figures 4‐6. For patients in the control group, only the first method was available. Change scores for blood pH were estimated using Follmann's formula.

Robbins 1993: parallel design.   This study was available as abstract only. Patients were randomized to receive either 1 mg/kg of furosemide (the interval is not mentioned in the abstract) for seven days, or placebo. No washout period was documented. Change scores for tidal volume were estimated using Follmann's formula.

2. Administration of furosemide by aerosol versus intermittent intravenous furosemide administration in controls:   This group included two studies (Rastogi 92, Prabhu 97), both with a cross‐over design. Patients in these studies had similar gestational ages (26 ‐ 27 weeks) and postnatal ages (˜ four weeks). All patients required mechanical ventilation at study entry.

Prabhu 1997: cross‐over design with pooled data.   Patients were randomized to receive either 1 mg/kg of furosemide followed by placebo, or vice‐versa. No patients had received any diuretics before the study. Bronchodilators were held for four hrs before the study. Change scores for tidal volume were estimated using Follmann's formula.

Rastogi 1992: cross‐over design with pooled data.   Patients were randomized to receive either 1 mg/kg of furosemide followed by placebo, or vice‐versa. No washout period was documented. Change scores for tidal volume were estimated using Follmann's formula.

3. Comparison of various doses of aerosolized furosemide:   This group includes two studies (Prabhu 98 and Rastogi 94). They had similar gestational ages and postnatal ages. One study compared a dose of 1 mg/kg furosemide with lower doses (Rastogi 94). The other study compared a dose of 1 mg/kg with 2 mg/kg (Prabhu 98). Therefore, we did not combine these two studies.

Prabhu 1998: cross‐over design with pooled data.   Patients were randomized to receive either 1 mg/kg followed by 2 mg/kg of furosemide, or vice‐versa. No diuretics or glucocorticosteroids were used before study in any patient. Bronchodilators were held for four hours before the study. Change scores for tidal volume were estimated using Follmann's formula.

Rastogi 1994: cross‐over design with pooled data.   Patients received furosemide at doses of 0.1, 0.25 and 0.5 mg/kg in random order. A washout period of 72 hr was documented before the study. Serial values were only provided after a dose of 1 mg/kg, so that change scores could not be calculated for any of the lower doses.

Risk of bias in included studies

1. Administration of furosemide by aerosol versus placebo:   1.1. Average postnatal age < 3 weeks:   Raval 1994:   This study was exempt of any of the four types of bias analyzed.     1.2. Average postnatal age > 3 weeks:   Kugelman 1997:   This study was exempt of any of the four types of bias analyzed.

Ohki 1997:   Randomization and outcome, but not intervention (nurses prepared the medication), were blinded.

Robbins 1993:   This study was exempt of any of the four types of bias analyzed.

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

Prabhu 1997:   Blinding is not documented.

Rastogi 1992:   Blinding is not documented.

3. Comparison of various doses:

Prabhu 1998:   Blinding is not documented.

Rastogi 1994:   Blinding was not documented.

Effects of interventions

1. Limitations of the scope of available studies:   Most studies focused on short‐term pathophysiological parameters (pulmonary mechanics) and failed to assess the primary outcomes defined in this review (e.g., mean airway pressure or percent inspiratory oxygen) or the potential complications of diuretic therapy. No studies reported on need for or duration of mechanical ventilation or oxygen supplementation, need for continuous positive airway pressure, BPD, death or BPD, chronic lung disease at 36 weeks of postconceptional age, mortality, length of stay, or number of rehospitalizations during the first year of life.

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.

No study assessed the amount of diuretic effectively delivered to the patient.

2. Calculation of WMD and estimation of the pretest‐posttest correlation coefficient (r):   For most variables, r was assumed to be 0.4. Unless specified otherwise, sensitivity analysis using a value of 0.3 or 0.5 did not significantly alter the CI and the summary results.

Limited data on dynamic measurements in preterm infants (Kugelman 1997) suggest that r is higher for dynamic compliance (0.8 for a 1‐hour or a 2‐hour period) than for resistance (0.4 for a 2‐hour, 0.7 for a 1‐hour period). We used these values in our calculations of change scores with the Follmann's formula for several studies that analyzed the evolution of dynamic pulmonary mechanics over a period of maximum two hours (Prabhu 1997; Prabhu 1998; Rastogi 1992; Robbins 1993). Sensitivity analysis was done using r=0.4 (vs. 0.7‐0.8 as the expected value) or 0.3 (vs. 0.4 as the expected value).

Serial data in patients on furosemide (Ohki 1997) yielded a higher value of r for static compliance (0.84 for 1‐hour and 0.90 for a 2‐hour period) and resistance (0.87 for a 1‐hour and 0.91 for a 2‐hour period) than for tidal volume (0.48 for a 1‐hour and 0.32 for a 2‐hour period). We did not use these values of r for calculating change scores; we used instead additional original data provided by Dr. Ohki.

WMD for tidal volume (Kugelman 1997) was calculated using Follmann's formula while assuming r = 0.4 for tidal volume, whereas WMDs for compliance and resistance were calculated from individual differences between baseline and final values. WMDs for Ohki's data were calculated using original mean and SD of percent values from baseline provided by the author.

We report sensitivity analysis only when it affected the results of the study.

Effects of aerosolized furosemide:   Comparison 1: Administration of furosemide by aerosol versus placebo   Introduction:   The effects of a two‐day treatment with aerosolized furosemide on pulmonary mechanics were assessed in 22 patients < 3 weeks of age enrolled in one study (Raval 1994). Data on ventilatory support (n = 19 measurements in each group, provided by Dr. Stefano) showed identical values at the time of entry into the study and trends toward higher peak pressure, higher PEEP and higher FiO2 after furosemide administration than after placebo.   The effect of a single dose of furosemide on pulmonary mechanics in patients > 3 weeks of age was analyzed in three studies (Kugelman 1997; Ohki 1997; Robbins 1993). Measurements of pulmonary mechanics 30 minutes after furosemide administration were obtained in only five patients > 3 weeks of age (Robbins 1993). Seventeen patients were assessed one hour and two hours after aerosol administration (Kugelman 1997; Ohki 1997).   One trial assessed the effects of a seven day treatment with a daily dose of aerosolized furosemide in patients > 3 weeks of age (Robbins 1993).

Outcome 1.1: Change in transcutaneous pO2 and Outcome 01.02: Change in blood pH   Furosemide administration did not significantly affect transcutaneous pO2 after one and two hours (n = 9 patients) (Kugelman 1997) or Outcome 1.2 blood pH after one hour (n = 8 patients) (Ohki 1997).

Outcome 1.3: Change in compliance   In patients < 3 weeks of age furosemide significantly decreased compliance 20 min after a single dose on the second of therapy (WMD ‐0.21 ml/cm H2O/kg, CI ‐0.38, ‐0.04) (Raval 1994).

In patients > 3 weeks of age, furosemide did not significantly affect compliance at 30 minutes (Robbins 1993). It increased compliance at one hour and two hours in one study (Ohki 1997) but not in the other one (Kugelman 1997). Both tests for heterogeneity (chi‐square and I‐squared) were statistically significant for compliance at one hour and at two hours. Heterogeneity of response to furosemide could have resulted from differences in (1) washout period at study entry (48 hours for Ohki's study vs 6 hours for Kugelman's study) or at the time of cross‐over (48 hours vs 24 hours, respectively), (2) blinding of intervention (only in the second study), (3) method of measuring mechanics of the total respiratory system (static for Ohki's study vs. dynamic without esophageal balloon for Kugelman's study), and (4) method of furosemide delivery (ultrasonic nebulizer [Ohki] vs. neonatal nebulizer with a relatively high side flow of 5 ‐ 6 L/min [Kugelman]). Method of furosemide delivery is unlikely to account for heterogeneity, because the neonatal nebulizer used in the second study has been successfully used to deliver other medications, including B2 agonists, ipratropium bromide, and beclomethasone in ventilated infants with BPD (Kugelman 1997). Washout period is unlikely to account to heterogeneity because subgroup analysis of patients randomized to furosemide first and those randomized to placebo first in Kugelman's study (using data kindly provided by Dr. Kugelman) showed similar results.

Outcome 1.4: Change in resistance   Furosemide did not significantly affect resistance in any of the studies (Kugelman 1997; Ohki 1997; Raval 1994; Robbins 1993), in any of the summary statistics or any of the subgroup analyses.

Outcome 1.5: Change in tidal volume   One trials showed no significant effect of furosemide on tidal volume 20 min after the dose. One trial (Kugelman 1997) showed no significant effect of furosemide on tidal volume, and the other trial (Ohki 1997) showed a significant increase in tidal volume after furosemide. Although meta‐analysis showed that furosemide significantly improved tidal volume after one hour (WMD 1.86 ml/kg, CI 1.14, 2.59) and two hours (1.11 ml/kg, CI 0.28, 1.94), both the I squared test and the chi‐square test showed significant heterogeneity. Severity of lung disease was similar in both studies (FiO2 0.30 vs 0.35, peak inspiratory pressure 20 vs 22 cm H2O).

Outcome 1.6: Change in minute ventilation   Furosemide did not significantly affect he change in minute ventilation 20 min after the dose, on the second day of treatment, in patients > 3 weeks of age.

Comparison 2: Administration of furosemide by aerosol versus intermittent intravenous furosemide administration in controls

Change in oxygen administration (Outcome 2.1), transcutaneous oxygen monitoring (Outcome 2.2) and ventilatory settings (Outcome 2.3 ‐ 2.5).   Aerosolized furosemide tended to decrease the percent inspiratory oxygen and to improve transcutaneous hemoglobin saturation after two hours (n = 19) (Prabhu 1997). Aerosolized furosemide did not affect peak inspiratory pressure, positive end expiratory pressure or ventilatory rate two hours after treatment (n = 19) (Prabhu 1997).

Outcome 2.6: Change in compliance   Compared with intravenous furosemide, aerosolized furosemide tended to decrease compliance at 30 minutes in one study (Rastogi 1992) and significantly increased compliance in the other study (Prabhu 1997). Aerosolized furosemide significantly improved compliance at one hour (WMD 0.15 ml/cm H2O/kg, CI 0.08, 0.23, n=24 patients) and at two hours (WMD 0.18 ml/cm H2O/kg, CI 0.09, 0.26, n = 24 patients) (Prabhu 1997, Rastogi 1992). Lack of significance at four hours (WMD 0.23, CI ‐0.24, +0.70) may have resulted from the small number of patients available (n = 5 patients) (Rastogi 1992), from lack of a washout period, from overestimating the CI by using r = 0.4 in Follmann's formula, or from other factors that could not be analyzed in this study available as an abstract only.     Outcome 2.7: Change in resistance   Aerosolized furosemide significantly improved resistance in one study (WMD ‐30 cm/L/sec, CI ‐48, ‐12) (Prabhu 1997) and tended to increase resistance in the other study (Rastogi 1992). Meta‐analysis showed no significant effect of aerosolized furosemide compared with intravenous furosemide on resistance between 30 min and two hours (n = 24). At at 30 min, both statistical tests for heterogeneity (chi‐square and I‐squared) were significant. Heterogeneity could have resulted from lack of a washout period in one study (Rastogi 1992) but not the other one (Prabhu 1997), or from overestimating the CI using r = 0.4 in Follmann's formula. Other potential differences could not be analyzed or detected because Rastogi's study is only available as an abstract. Aerosolized furosemide significantly reduced resistance at four hours in one study (Rastogi 1992) using a correlation coefficient of 0.4 for the cross‐over trial (WMD ‐19.3, CI ‐36.9, ‐ 1.7) but not using a correlation coefficient of 0.3 (CI ‐39.7, + 1.1).

Outcome 2.8: Change in tidal volume   Compared with intravenous furosemide, aerosolized furosemide tended to improve tidal volume at 30 min in one study (Prabhu 1997) and to worsen tidal volume in the other one (Rastogi 1992). Meta‐analysis showed significant heterogeneity using the I‐squared test but not the chi‐square test. Aerosolized furosemide significantly improved tidal volume at one hour using a correlation coefficient of 0.4 for the cross‐over trial (WMD 1.34 ml/kg, CI 0.12, +2.57, n = 24 patients) but not using a correlation coefficient of 0.3 (CI ‐0.07,+2.75) (Prabhu 1997; Rastogi 1992). Aerosolized furosemide significantly improved tidal volume at two hours (WMD 1.8 ml/kg, CI 0.5, 3.1, n = 24) but not at four hours (n = 5) (Rastogi 1992).

Comparison 3: 1 mg/kg aerosolized furosemide versus lower doses:   One study compared the effects of 1 mg/kg of furosemide with those of lower doses (n = 8 patients) (Rastogi 1994).

Outcomes 3.1 ‐ 3.3: Failure to improve pulmonary function   The authors found no effect of low doses of furosemide on pulmonary function, in contrast with a standard dose of 1 mg/kg. For this review, we arbitrary limited data entry into MetaView to data corresponding to 1.0 mg/kg (treatment) vs. 0.1 mg/kg (control). Results on pulmonary function would have been similar with any of the other low doses. Since no patient responded to the low dose, the imputed correlation was zero; therefore, we used the values calculated by RevMan for relative risk (RR) and risk difference (RD). In comparison with the lower dose, the standard dose of 1 mg/kg of furosemide significantly decreased the risk of failure to improve compliance within 30 minutes (RR 0.13, CI 0.02, 0.78; RD ‐0.88, CI ‐1.16, ‐0.59) and 4 hours (RR 0.25, CI 0.08, 0.83; RD ‐0.75, CI ‐1.08, ‐0.42). The dose of 1 mg/kg decreased the risk of failure to improve resistance within 30 minutes (RR 0.13, CI 0.02,0.78; RD ‐0.88, CI ‐1.16, ‐0.59) and four hours (RR 0.13, CI 0.02,0.78; RD ‐0.88, CI ‐1.16, ‐0.59). The dose of 1 mg/kg decreased the risk of failure to improve tidal volume within 30 minutes (RR 0.06, CI 0.00, 0.87; RD ‐1.00, CI ‐1.21, ‐0.79) and four hours (RR 0.25, CI 0.08, 0.83; RD ‐0.75, CI ‐1.08, ‐0.42).

Outcomes 3.4 and 3.5: Urinary calcium excretion   Administration of a 1 mg/kg dose of aerosolized furosemide did not significantly affect 24‐hour calciuria or urine calcium:creatinine ratio compared with a lower dose of furosemide.

Comparison 4: 2 mg/kg aerosolized furosemide versus lower doses:   A single studied analyzed the effects of the standard dose of 1 mg/kg with a higher dose of 2 mg/kg on pulmonary mechanics (n = 13 patients) (Prabhu 1998).

Outcome 4.1: Change in compliance   In comparison with the lower dose, the dose of 2 mg/kg of furosemide significantly increased compliance after 2 hours using a correlation coefficient of 0.4 for the cross‐over trial (WMD 0.10, CI 0.01,0.19) but not using a correlation coefficient of 0.3 (CI ‐0.07,+0.27). No significant difference was observed after four and six hours.     Outcome 4.2: Change in resistance   In comparison with the lower dose, the dose of 2 mg/kg of furosemide did not significantly affect resistance after 30 minutes or after six hours. It significantly increased resistance after four hours (WMD 37 cm/L/sec, CI 2.25, 71.75) using a correlation coefficient of 0.4 for the cross‐over trial, but not using a correlation coefficient of 0.3 (CI ‐2.77, + 76.77).

Outcome 4.3: Change in tidal volume   In comparison with the lower dose, the dose of 2 mg/kg of furosemide did not significantly affect tidal volume.

Outcome 4.4: Change in urine output   The higher dose tended to increase urine output compared with the lower dose, but this did not reach statistical significance.

Discussion

1. Limitations   1.1. Limitations of the studies included in this review:   In five of eight studies blinding was either not documented or not done. This could potentially have biased the results in favor of furosemide.

1.2. Limitations of this review:   Outcomes analyzed:   Most studies focused on pathophysiological parameters, e.g., pulmonary mechanics, and did not assess the most important outcomes defined in this review or the potential complications of diuretic therapy.

Methods used for the analysis:   We used the methods recommended by the Cochrane Neonatal Review Group. For almost all studies, we did not have access to the original data. Therefore, we used multiple transformations using formulae established by or derived from Follmann, Baird, and Armitage. Calculations using Baird and Armitage overestimate the SD of the final variable if the numerator is related to the denominator, because they assume lack of correlation between them.

For calculations using Follman's formula, we usually assumed an pretest‐posttest correlation of 0.4 and did a sensitivity analysis using a correlation coefficient of 0.3. We only used other values for r if they were available for preterm infants of similar size and age, for an identical test (e.g., compliance) performed at similar time intervals and using the same method. We have found higher values of average correlation coefficient for serial dynamic measurements of tidal volume (r = 0.72), compliance (r = 0.92) and resistance (r = 0.80) in full‐term infants over a period of 66 hours (Goyal 1995). We are unaware of similar data in very low birth weight infants. Therefore, in this review we may have overestimated the SD of long‐term change scores for pulmonary mechanics, especially compliance. Therefore, the results are likely to be conservative, i.e., confidence intervals may be wider than they should be.

Heterogeneity:   Within each subgroup, we used chi‐square analysis to test for statistical evidence of heterogeneity among studies. When heterogeneity analysis was significant, we analyzed differences (in patient selection, baseline values, bias, design and methods) among studies that could possibly explain the heterogeneity.     Heterogeneity in response did not appear to result from differences in methods used for pulmonary function tests. Dynamic measurements were obtained in three (Prabhu 1997; Rastogi 1992, Rastogi 94) of four studies showing a transient improvement of pulmonary mechanics 1 to 2 hours after a single dose of furosemide on pulmonary mechanics and in the single study showing no effect (Kugelman 1997). Static measurements were obtained in one study, which showed a transient improvement in pulmonary mechanics after furosemide (Ohki 1997). The reader is referred elsewhere (Brion 1999a) for further discussion of methods of measuring pulmonary mechanics.

Because of the long half‐life of loop diuretics in immature infants, a prolonged washout period is required to eliminate all diuretic effect before initiating a study or between exposures in a cross‐over study. However, a prolonged washout period may not be possible or ethically acceptable for patients considered clinically to require diuretics. Several studies had a short or no washout period, thereby possibly decreasing the apparent effect of diuretic administration on short‐ and long‐term outcome. All cross‐over trials failed to provide information that would rule out a carry‐over effect (possibly yielding an underestimation of the real effect of diuretic administration) and a period effect.

All studies failed to demonstrate actual delivery of furosemide to the distal airways. None measured the percent recovery of furosemide in the expiratory tubing or serum levels of furosemide.

Sample size:   Because of small sample size in most of the subgroups, any real effects of furosemide may have remained undetected.

2. Group‐specific comments:   Studies only included intubated patients.

In infants < 3 weeks of age, available evidence (single study, pulmonary mechanics measured only after 20 minutes, abstract only) shows no benefit of a two‐day course of aerosolized furosemide.

In infants > 3 weeks of age, a single aerosolized dose of 1 mg/kg of furosemide transiently (at one to two) improves compliance compared with intravenous furosemide but does not affect resistance or tidal volume. Four of six studies have shown that a single dose of 1 mg/kg of aerosolized furosemide was more effective in transiently improving compliance than placebo, iv furosemide or a lower dose of aerosolized furosemide. The single study assessing the effect of chronic administration of a daily dose of aerosolized furosemide showed no effect on pulmonary mechanics. This study was published as an abstract only, had no documented washout period, and included only 10 patients.

Double‐blinded studies are needed (1) to analyze factors likely to affect the response to aerosolized diuretics, e.g., washout period and delivery of furosemide to distal airways, and (2) to assess the effects of chronic administration of aerosolized diuretics on O2‐ and ventilator‐dependency and long‐term outcome.

Authors' conclusions

Implications for practice.

Most studies focused on pathophysiological parameters and did not assess the most important outcomes defined in this review or the potential complications of diuretic therapy.

In infants > 3 weeks of age with CLD, a single aerosolized dose of 1 mg/kg of furosemide may transiently improve pulmonary mechanics. There is no evidence to support any benefit of aerosolized diuretic administration on need for ventilatory support, length of 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 aerosolized loop diuretics in infants with (or developing) CLD cannot be justified based on current evidence.

Implications for research.

Investigators planning randomized trials should consider (1) using double‐blinded design (2) analyzing factors likely to affect the response to aerosolized furosemide, e.g., washout period and delivery of furosemide to distal airways, and (3) assessing, in addition or instead of short‐term outcome, the effects of chronic administration of aerosolized furosemide on mortality, O2 dependency, ventilator dependency, length of hospital stay and long‐term outcome.

What's new

Date	Event	Description
10 September 2009	New search has been performed	This review updates the existing review "Aerosolized diuretics for preterm infants with (or developing) chronic lung disease" published in the Cochrane Database of Systematic Reviews, Issue 3, 2006 (Brion 2006). Updated search found no new trials. No changes to conclusions.

Date	Event	Description
3 November 2008	Amended	Converted to new review format.
3 May 2006	New citation required but conclusions have not changed	Substantive amendment
3 May 2006	New search has been performed	This review updates the previously published review in The Cochrane Library "Aerosolized diuretics for preterm infants with (or developing) chronic lung disease" (Brion 2003).     A search of MEDLINE in March 2006 and of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1, 2006) did not yield any additional eligible studies.     The methods and the results sections of the review were entirely revised according to new Cochrane guidelines for cross‐over trials.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in transcutaneous pO2 (mm Hg), patients > 3 weeks of age	1		WMD (Fixed, 95% CI)	Subtotals only
1.1 1 hour after single dose	1	18	WMD (Fixed, 95% CI)	‐3.96 [‐8.77, 0.85]
1.2 2 hours after single dose	1	18	WMD (Fixed, 95% CI)	4.75 [‐4.54, 14.04]
2 Change in blood pH, 1 hour after 1 dose, patients > 3 weeks of age	1	16	WMD (Fixed, 95% CI)	0.0 [‐0.02, 0.02]
3 Change in compliance (ml/cm H2O/kg)	4		WMD (Fixed, 95% CI)	Subtotals only
3.1 20 min after single dose, on second day, patients < 3 weeks of age	1	22	WMD (Fixed, 95% CI)	‐0.21 [‐0.38, ‐0.04]
3.2 30 min after a single dose, patients > 3 weeks of age	1	10	WMD (Fixed, 95% CI)	‐0.13 [‐0.40, 0.14]
3.3 1 hour after single dose, patients > 3 weeks of age	2	34	WMD (Fixed, 95% CI)	0.03 [‐0.01, 0.08]
3.4 2 hours after single dose, patients > 3 weeks of age	2	34	WMD (Fixed, 95% CI)	0.00 [‐0.03, 0.04]
3.5 Before therapy, on seventh day of therapy, patients > 3 weeks of age	1	10	WMD (Fixed, 95% CI)	‐0.21 [‐1.57, 1.15]
4 Change in resistance (cm/L/sec)	4		WMD (Fixed, 95% CI)	Subtotals only
4.1 20 min after a single dose, on second day, patients < 3 weeks of age	1	22	WMD (Fixed, 95% CI)	‐10.0 [‐50.59, 30.59]
4.2 30 min after single dose, patients > 3 weeks	1	10	WMD (Fixed, 95% CI)	28.32 [‐28.34, 84.98]
4.3 1 hour after single dose, patients > 3 weeks of age	2	34	WMD (Fixed, 95% CI)	‐12.15 [‐28.23, 3.94]
4.4 2 hours after single dose, patients > 3 weeks	2	34	WMD (Fixed, 95% CI)	‐3.18 [‐17.68, 11.32]
4.5 2 hours after single dose, furosemide first	1	9	WMD (Fixed, 95% CI)	11.8 [‐8.26, 31.86]
4.6 2 hours after single dose, furosemide second	1	8	WMD (Fixed, 95% CI)	‐3.25 [‐34.85, 28.35]
4.7 Before therapy, on seventh day of therapy, patients > 3 weeks	1	10	WMD (Fixed, 95% CI)	‐1.88 [‐218.27, 214.51]
5 Change in tidal volume (ml/kg)	3		WMD (Fixed, 95% CI)	Subtotals only
5.1 20 min after dose, on second day, patients < 3 weeks of age	1	22	WMD (Fixed, 95% CI)	‐0.9 [‐1.94, 0.14]
5.2 1 hour after single dose, patients > 3 weeks of age	2	34	WMD (Fixed, 95% CI)	1.86 [1.14, 2.59]
5.3 2 hours after single dose, patients > 3 weeks of age	2	34	WMD (Fixed, 95% CI)	1.11 [0.28, 1.94]
6 Change in minute ventilation (ml/kg/min) 20 min after dose, on 2nd day, > 3 weeks of age	1		WMD (Fixed, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in % inspiratory O2 2 hours after 1 dose	1		WMD (Fixed, 95% CI)	Subtotals only
2 Change in transcutaneous O2 saturation (%) 2 hours after 1 dose	1		WMD (Fixed, 95% CI)	Subtotals only
3 Change in peak inspiratory pressure (cm H2O) 2 hours after 1 dose	1		WMD (Fixed, 95% CI)	Subtotals only
4 Change in positive end expiratory pressure (cm H2O) 2 hours after 1 dose	1		WMD (Fixed, 95% CI)	Subtotals only
5 Change in ventilator rate (cycles per minute) 2 hours after 1 dose	1		WMD (Fixed, 95% CI)	Subtotals only
6 Change in compliance (ml/cm H2O/kg)	2		WMD (Fixed, 95% CI)	Subtotals only
6.1 30 min after single dose	2	48	WMD (Fixed, 95% CI)	0.07 [0.01, 0.13]
6.2 1 hour after single dose	2	48	WMD (Fixed, 95% CI)	0.15 [0.08, 0.23]
6.3 2 hours after single dose	2	48	WMD (Fixed, 95% CI)	0.18 [0.09, 0.26]
6.4 4 hours after single dose	1	10	WMD (Fixed, 95% CI)	0.23 [‐0.24, 0.70]
7 Change in resistance (cm/L/sec)	2		WMD (Fixed, 95% CI)	Subtotals only
7.1 30 min after a single dose	2	48	WMD (Fixed, 95% CI)	‐14.28 [‐29.13, 0.57]
7.2 1 hour after a single dose	2	48	WMD (Fixed, 95% CI)	‐0.10 [‐9.04, 8.84]
7.3 2 hours after a single dose	2	48	WMD (Fixed, 95% CI)	‐8.49 [‐21.90, 4.92]
7.4 4 hours after a single dose	1	10	WMD (Fixed, 95% CI)	‐19.3 [‐36.93, ‐1.67]
8 Change in tidal volume (ml/kg)	2		WMD (Fixed, 95% CI)	Subtotals only
8.1 30 min after single dose	2	48	WMD (Fixed, 95% CI)	0.79 [‐0.22, 1.81]
8.2 1 hour after single dose	2	48	WMD (Fixed, 95% CI)	1.34 [0.12, 2.57]
8.3 2 hours after single dose	2	48	WMD (Fixed, 95% CI)	1.79 [0.53, 3.05]
8.4 4 hours after single dose	1	10	WMD (Fixed, 95% CI)	3.1 [‐0.38, 6.58]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Failure to improve compliance	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.1 30 min after single dose	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.04, 0.77]
1.2 4 hours after single dose	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.10, 0.85]
2 Failure to improve resistance	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 30 min after single dose	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.04, 0.77]
2.2 4 hours after single dose	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.04, 0.77]
3 Failure to improve tidal volume	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 30 min after single dose	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.00, 0.87]
3.2 4 hours after single dose	1	16	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.10, 0.85]
4 Urinary calcium (mg/kg/day) over 24 hours	1		WMD (Fixed, 95% CI)	Subtotals only
5 Calcium:creatinine ratio (mg:mg)	1		WMD (Fixed, 95% CI)	Subtotals only

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in compliance (ml/cm H2O/kg)	1		WMD (Fixed, 95% CI)	Subtotals only
1.1 2 hours after single dose	1	26	WMD (Fixed, 95% CI)	0.1 [0.01, 0.19]
1.2 4 hours after single dose	1	26	WMD (Fixed, 95% CI)	0.0 [‐0.17, 0.17]
1.3 6 hours after single dose	1	26	WMD (Fixed, 95% CI)	0.0 [‐0.17, 0.17]
2 Change in resistance (cm/L/sec)	1		WMD (Fixed, 95% CI)	Subtotals only
2.1 2 hours after single dose	1	26	WMD (Fixed, 95% CI)	‐4.0 [‐29.63, 21.63]
2.2 4 hours after single dose	1	26	WMD (Fixed, 95% CI)	37.0 [2.25, 71.75]
2.3 6 hours after single dose	1	26	WMD (Fixed, 95% CI)	28.0 [‐3.77, 59.77]
3 Change in tidal volume (ml/kg)	1		WMD (Fixed, 95% CI)	Subtotals only
3.1 2 hours after single dose	1	26	WMD (Fixed, 95% CI)	0.6 [‐1.05, 2.25]
3.2 4 hours after single dose	1	26	WMD (Fixed, 95% CI)	‐0.7 [‐2.96, 1.56]
3.3 6 hours after single dose	1	26	WMD (Fixed, 95% CI)	‐0.9 [‐3.29, 1.49]
4 Change in urine output	1		WMD (Fixed, 95% CI)	Subtotals only

Methods	Blinding of randomization: yes   Blinding of intervention: yes   Complete follow up: yes   Blinding of outcome: yes   Randomized clinical trial, cross‐over design with pooled data   Washout period (thiazides, spironolactone, furosemide, albuterol, aminophylline): 6 hr before the study; 24 hours at cross‐over
Participants	Number of patients entered into the study: n=9   Mechanical ventilation   Entry criteria: birth weight 500‐2500 g, gestational age maximum 32 weeks, persistent respiratory failure requiring mechanical ventilation and > 30% O2 at 21 days of life, radiographic changes consistent with BPD.   Exclusion criteria: proven sepsis, cardiac disease (except patent ductus arteriosus), unstable clinical status.   Average birth weight was 1.1±0.3 kg, gestational age 29±3 weeks, postnatal age 47±18 days, postconceptional age 35.7±4.0 weeks and study weight 1.8±0.6 kg. Serum electrolyte concentrations were normal.   Six patients were receiving albuterol aerosols and one was receiving aminophylline. Seven were being treated with iv furosemide, one of whom was also receiving thiazide and spironolactone. All these medications were stopped at least 6 hours before the study. No patients received dexamethasone for prevention or treatment of BPD.   Ventilatory settings were similar on each day of the study: FiO2 0.35±0.06 vs 0.36±0.09, on day of furosemide administration and on the day of placebo administration, respectively. Peak inspiratory pressure was 22.8±2.4 and 22.4±2.4 cm H2O, positive end expiratory pressure 3.8±0.6 cm H2O in both groups, and ventilator rate 19.7±10.5 and 19.3±11.7 breaths per minute.
Interventions	Aerosolized furosemide vs placebo   Diuretics and bronchodilators were held for 6 hours before the study. Patients were randomly allocated to receive either 1 dose of aerosolized furosemide 1 mg/kg in 2 ml of normal saline followed by placebo within 24 hours, or vice versa.
Outcomes	Main outcome: Pulmonary mechanics   Other variables mentioned in the text: transcutaneous pO2 and pCO2, pulse oximetry, ventilator settings, vital signs, urinary output   Measurements of compliance, resistance, pO2 and pCO2 obtained after furosemide were not statistically significant from those after placebo.
Notes	Nebulization was done using a neonatal nebulizer (Adaptor Kit, Hudson RCI, Temecula, CA) (providing 1‐2.1 µm‐droplets) placed 10‐12 cm from the endotracheal tube on the inspiratory limb of the ventilator, using a side flow of 5‐6 L/min. Ventilator conditions were kept constant during treatment.   Pulmonary mechanics were assessed at baseline, and 1 hour and 2 hours after the aerosol. The authors measured dynamic compliance and resistance using the two‐factor least mean square analysis, without an esophageal balloon.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Blinding of randomization: yes
Allocation concealment?	Low risk	Blinding of randomization: yes
Blinding?   All outcomes	Low risk	Blinding of intervention: yes     Blinding of outcome: yes
Incomplete outcome data addressed?   All outcomes	Low risk	Complete follow‐up: yes
Free of selective reporting?	Unclear risk	Incomplete or no data provided for pulse oximetry, vital signs, urine output
Free of other bias?	Unclear risk	Randomized clinical trial, cross‐over design with pooled data   Washout period (thiazides, spironolactone, furosemide, albuterol, aminophylline): 6 hr before the study; 24 hours at cross‐over

Methods	Blinding of randomization: no   Blinding of intervention: no   Complete follow up: yes   Blinding of outcome: no   Randomized clinical trial, cross‐over design with pooled data   Washout period: bronchodilators 4 hr before study; no diuretics used before study
Participants	Number of patients entered into the study: n=19   Mechanical ventilation.   Entry criteria: (1) neonate ventilated and O2‐dependent for 14 or more days since birth for primary lung disease, (2) decision by physician caring for the infant to initiate diuretic treatment with furosemide.   Exclusion criteria: glucocorticosteroids or diuretics before or during the study.   Nineteen patients were randomized, including 6 girls and 13 boys. Eleven were randomized to receive iv furosemide first. Average birth weight was 800±170 g, gestational age 26.2±2.1 weeks, postnatal age 27±11 days, postconceptional age 30.0±2.4 weeks and weight at the time of the study 910±180 g.   FiO2 before aerosolized furosemide was 0.45±0.13 vs 0.37±0.13 before intravenous furosemide. Peak pressure was 17.7±2.5 and 17.8±2.7 cm H2O, respectively, PEEP was 5.0±0.7 cm for both, and rate of mechanical ventilation was 26±13 and 29±17 breaths/ min.
Interventions	Aerosolized furosemide vs iv furosemide   Patients were randomized to receive either 1 dose of aerosolized furosemide 1 mg/kg followed within 24 hours by 1 dose of intravenous furosemide 1 mg/kg, or vice versa. Nebulized bronchodilator (adrenergic) therapy was withheld for 4 hours before and during the 2 hours after furosemide administration. Infants who were receiving theophylline continued to receive it during the study. However, no infant was started on theophylline during the study.
Outcomes	Main outcome: pulmonary function, fluid and electrolyte balance.   Administration of aerosolized furosemide did not affect ventilatory settings or FiO2 compared to intravenous administration, but significantly reduced urine output (p<0.01) and excretion of Na (p<0.01) and Cl (p<0.01).   Repeated measures analysis of variance showed significant increase in tidal volume and in compliance but no change in resistance in after nebulized furosemide; no significant change from baseline was observed after intravenous furosemide. The % change in tidal volume from baseline was higher after aerosolized furosemide than after intravenous administration, both at 30 min (p<0.05) and at 120 min (p<0.01) but not at 60 min. Compliance was higher after aerosolized furosemide than after intravenous administration at 60 min (p<0.05) and 120 min (p<0.01) but not at 30 min.
Notes	Furosemide was provided by using a commercial nebulizer connected to the inspiratory limb of ventilatory circuit. The entire dose was administered at a flow of 2 l/min over 5‐10 min.   Pulmonary function tests were obtained at baseline and at 30 min, 1hr and 2 hr after furosemide administration, whereas the other variables were obtained at baseline and 2 hours after furosemide administration. Pulmonary mechanics were measured using the two‐factor, least mean square technique without an esophageal balloon.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Blinding of randomization: no
Allocation concealment?	High risk	Blinding of randomization: no
Blinding?   All outcomes	High risk	Blinding of intervention: no     Blinding of outcome: no
Incomplete outcome data addressed?   All outcomes	Low risk	Complete follow‐up: yes
Free of selective reporting?	Low risk

Methods	Blinding of randomization: not documented   Blinding of intervention: not documented   Complete follow up: yes   Blinding of outcome: not documented   Randomized clinical trial, cross‐over design with pooled data   Washout period: bronchodilators 4 hr before study; no diuretics or glucocorticosteroids used before study in any patient
Participants	Number of patients entered into the study: n=13   Mechanical ventilation   Entry criteria: Prematurity, requirement of oxygen and mechanical ventilation for primary lung disease for at least 14 days   Exclusion criteria: major congenital anomalies   Mean birth weight was 713±132 g, gestational age 25.4±1.5 weeks, postnatal age 24±9.5 days and postconceptional age 28.8±2.0 weeks. Baseline values of compliance, tidal volume, resistance and urine output before the 2 mg/kg dose were similar to those before the 1 mg/kg dose.
Interventions	Aerosolized furosemide 2 mg/kg vs 1 mg/kg   Patients were randomized to receive either aerosolized furosemide 1 mg/kg once, followed by a 2 mg/kg dose after 24 hours, or vice versa.
Outcomes	Main outcome: magnitude and duration (beyond 2 hours) of the effects of furosemide on pulmonary mechanics.   Secondary outcome:urine output and urinary excretion of electrolytes.   Repeated measures ANOVA showed that both doses significantly increased compliance and tidal volume for up to 6 hours. The 2 doses of furosemide yielded non significantly different values of compliance and tidal volume at 2, 4 and 6 hours.   Furosemide administration was not followed by any significant change in urinary output or urinary electrolyte excretion after either dose of furosemide.
Notes	Furosemide was nebulized via the inspiratory limb of the ventilator circuit, using a flow of 2 L/min and a nebulizer (MiniHeart, Vortran Medical Technology).   Pulmonary function tests were obtained at baseline and at 2,4 and 6 hours after administration of the aerosol. Pulmonary mechanics were measured using the two‐factor, least mean square technique without an esophageal balloon. Urine was collected for six hours before and six hours after aerosol administration.   Theophylline was continued in those infants already on this medication before the study; no infant was started on theophylline during the 2‐day study period.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Unclear risk	Blinding of randomization: not documented
Allocation concealment?	Unclear risk	Blinding of randomization: not documented
Blinding?   All outcomes	Unclear risk	Blinding of intervention: not documented   Blinding of outcome: not documented
Incomplete outcome data addressed?   All outcomes	Low risk	Complete follow‐up: yes
Free of selective reporting?	Low risk
Free of other bias?	Unclear risk	Randomized clinical trial, cross‐over design with pooled data   Washout period: bronchodilators 4 hr before study; no diuretics or glucocorticosteroids used before study in any patient

Methods	Blinding of randomization: no. Randomization was obtained using a table of random numbers.   Blinding of intervention: no   Complete follow‐up: yes. Of 11 eligible infants, informed consent was denied in 3. All of 8 enrolled infants were followed throughout the study.   Blinding of outcome: no   Randomized clinical trial, cross‐over design with pooled data.   Washout: 72 hr before delivery; 24 hr at cross‐over
Participants	Number of patients entered into the study: n=8   Mechanical ventilation   Entry criteria: history of RDS requiring mechanical ventilation at birth, postnatal age > 14 days, persistence of respiratory failure and dependence on O2 and mechanical ventilation, radiographic evidence of chronic pulmonary parenchymal disease, no drug therapy other than vitamins for at least 72 hours before the start of the study   Exclusion criteria: evidence of congenital malformations, infection, congenital heart defect, or congenital heart disease.   Mean birth weight was 815±297 g and mean gestational age was 27.4±1.6 weeks. At the time of the study, postnatal age was 33±13 days, postconceptional age 32.1±2.5 weeks and weight 1013±331 g. Mean peak inspiratory pressure was 19.3±1.0 cm H2O, mean airway pressure 7.9±1.5 cm, FiO2 0.45±0.17, and ventilatory rate 30±12 per minute. Blood pH was 7.33±0.07 and pCO2 was 44±8 mm Hg.
Interventions	Aerosolized furosemide 0.1 vs 0.25, 0.5 ,1 mg/kg   Patients successively received in random order four different doses of aerosolized furosemide: 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg. Furosemide was made up to a final volume of 2 ml with 0.9% NaCl.
Outcomes	Compliance improved in 0/8 patients after a low dose of furosemide, compared to 7/8 at 30 minutes and 6/8 at 4 hours after a dose of 1 mg/kg. Resistance decreased in 0/8 patients after a low dose of furosemide, compared to 7/8 at 30 minutes and at 4 hours after a dose of 1 mg/kg. Tidal volume increased in 0/8 patients after a low dose of furosemide, compared to 8/8 at 30 minutes and 6/8 at 4 hours after a dose of 1 mg/kg. Urine output, urinary calcium, calcium/creatinine ratio, fractional excretion of sodium and creatinine clearance were similar after each of the 4 doses of furosemide, suggesting that aerosolized furosemide had no effect on the kidney.
Notes	There is no information about efficacy of the method of nebulization, so that the exact amount of drug reaching the distal airways is not sure.   Pulmonary function was measured at baseline, then at 30 min, 1,2 and 4 hours after aerosol administration. Pulmonary mechanics were measured using the least mean square method. The FiO2 was adjusted during measurement of pulmonary mechanics to maintain hemoglobin saturation >94 %. Patients did not receive sedation; most were in quiet but active sleep state during testing. Urine was collected for 24 hours after each dose of diuretic.   The authors state that doses of 0.1‐0.5 mg/kg had no effect on pulmonary function; however, no data are provided, so this information cannot be used for meta‐analysis. Furthermore, no data are provided to support that a dose of furosemide of 0.1 mg/kg had no effect on urine output. For this meta‐analysis, we assumed that 0.1 mg/kg of furosemide had no significant effect on any of the variables and thus can be considered as a placebo.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Adequate sequence generation?	Low risk	Randomization was obtained using a table of random numbers
Allocation concealment?	High risk	Blinding of randomization: no
Blinding?   All outcomes	Unclear risk	Blinding of intervention: no   Blinding of outcome: no
Incomplete outcome data addressed?   All outcomes	Unclear risk	Complete follow‐up: yes   Of 11 eligible infants, informed consent was denied in 3. All of 8 enrolled infants were followed throughout the study.
Free of selective reporting?	Low risk
Free of other bias?	Unclear risk	Randomized clinical trial, cross‐over design with pooled data.   Washout: 72 hr before delivery; 24 hr at cross‐over

PERMALINK

Aerosolized diuretics for preterm infants with (or developing) chronic lung disease

Luc P Brion

R A Primhak

W Yong

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

Results

Description of studies

Risk of bias in included studies

Effects of interventions

Discussion

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Acknowledgements

Data and analyses

Comparison 1. Aerosolized furosemide vs. control.

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

Comparison 2. Aerosolized furosemide vs. intravenous furosemide.

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

2.5. Analysis.

2.6. Analysis.

2.7. Analysis.

2.8. Analysis.

Comparison 3. 1 mg/kg aerosolized furosemide (Treatment) vs. lower dose (Control).

3.1. Analysis.

3.2. Analysis.

3.3. Analysis.

3.4. Analysis.

3.5. Analysis.

Comparison 4. 2 mg/kg aerosolized furosemide (Treatment) with 1 mg/kg (Control).

4.1. Analysis.

4.2. Analysis.

4.3. Analysis.

4.4. Analysis.

Characteristics of studies

Characteristics of included studies [ordered by study ID]