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.

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.

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.

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

Types of studies

Types of participants

Types of interventions

Types of outcome measures

See: Collaborative Review Group search strategy

Electronic searches

Searching other resources

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

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

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.

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.

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.

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.

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.

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table

Risk of bias table