Feasibility outcomes

Adherence to treatment

>85% adherence

Proportion receiving first dose of study treatment within 2 hours of furosemide

None

95% confidence interval of a proportion

Completion of treatment

>80% completion

Proportion receiving all six doses of study treatment

None

95% confidence interval of a proportion

Absence of hyperoncotic albumin in control arm

>85% in control group without 25% albumin

Proportion of patients assigned to control receiving no 25% albumin

None

95% confidence interval of a proportion

Randomization rate of eligible patients

>50% of eligible patients recruited

Proportion of eligible patients randomized

None

95% confidence interval of a proportion

Randomization rate of patients by clinical site

Average recruitment of one patient per site per week

Rate of recruitment per week

None

Average rate of recruitment

Clinical outcomes

Primary outcome

Duration of mechanical ventilation

Increased number of ventilatorfree days in treatment group

Number of ventilatorfree days

Duration of ventilation at time of randomization

t test, linear regression

Secondary outcomes

Duration of mechanical ventilation

Decreased duration of mechanical ventilation in treatment group

Duration of mechanical ventilation (days)

Duration of ventilation at time of randomization

t test, linear regression

Episodes interrupting treatment with furosemide

Fewer episodes of interruption in treatment group

Number of episodes

None

t test

Need for dialysis

Smaller proportion of patients requiring dialysis in treatment group during ICU stay

Proportion of patients requiring dialysis during 30 days

None

Chisquared or Fisher’s exact statistic

Length of ICU stay

Shorter length of stay in treatment group

Duration of ICU stay

Duration of ICU stay at time of randomization

t test, linear regression

ICU mortality

Decreased ICU mortality in treatment group during ICU stay

Allcause mortality (binary)

APACHE2 and SOFA scores at randomization

KaplanMeyer survival curve (time to death)

30day mortality

Decreased 30day mortality in treatment group

Allcause mortality (binary)

APACHE2 and SOFA scores at randomization

KaplanMeyer survival curve (time to death)

Physiologic outcomes

Change in oxygenation

Greater increase PaO_{2}/FiO_{2} ratio in treatment group at day 3 and day 5

Change in PaO_{2}/FiO_{2} ratio

None

t test


Greater decrease in oxygenation index in treatment group at day 3 and day 5

Change in oxygenation index

None

t test

Change in lung compliance

Greater increase in dynamic compliance in treatment group at day 3 and day 5

Change in dynamic compliance during study treatment (ml/cmH_{2}O)

None

t test

Change in fluid balance

Greater net decrease in fluid balance in treatment group at day 3 and day 5

Change in net fluid balance (ml)

Net fluid balance at time of randomization

t test, linear regression

Change in body weight

Greater decrease in body weight in treatment group at day 3 and day 5

Change in body weight (kg)

Baseline weight

t test, linear regression

Urine output

Greater net urine output in treatment group at day 3 and day 5

Urine output during 3 days of study treatment (ml)

Net fluid balance at time of randomization

t test, linear regression

Dose of furosemide

Lower total amount of furosemide used in treatment group at day 3

Dose of furosemide during 3 days of study treatment (mg)

None

t test

Changes in serum albumin

Greater increase in serum albumin level in treatment group at day 3 and day 5

Change in serum albumin (g/l)

None

t test

Changes in colloid osmotic pressure

Greater increase in colloid osmotic pressure in treatment group at day 3 and day 5

Change in colloid osmotic pressure (mmHg)

None

t test

Changes in serum total protein

Greater increase in total protein in treatment group at day 3 and day 5

Change in total protein (g/l)

None

t test

Change in electrolytes

No difference between study groups for major electrolytes (sodium, potassium) at day 3 and day 5

Change in electrolytes between beginning and end of study treatment (mEq/l)

None

t test

Subgroup analyses

ARDS

Improved oxygenation in patients with ARDS
 
None

Regression methods with appropriate interaction term

Severity of disease

Improved hemodynamic stability in patients with severe disease
 
None

Regression methods with appropriate interaction term

Time since recovery of hemodynamic stability

Improved hemodynamic stability in patients with recent hemodynamic instability

>48 hours versus <48 hours of hemodynamic stability (as defined by study eligibility criteria)

None

Regression methods with appropriate interaction term

Sensitivity analyses

Perprotocol analysis
 
All outcomes

None
 
Adjusting for baseline covariates
 
All outcomes

As described

Multivariable regression

Adjusted for dose of furosemide

Treatment with albumin results in improvement beyond that explained by dose of furosemide

All outcomes

Dose of furosemide

Multivariable regression
