Outcome | Hypothesis | Outcome measure | Covariates | Methods of analysis |
---|---|---|---|---|
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 ventilator-free days in treatment group | Number of ventilator-free 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 | Chi-squared 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 | All-cause mortality (binary) | APACHE-2 and SOFA scores at randomization | Kaplan-Meyer survival curve (time to death) |
30-day mortality | Decreased 30-day mortality in treatment group | All-cause mortality (binary) | APACHE-2 and SOFA scores at randomization | Kaplan-Meyer survival curve (time to death) |
Physiologic outcomes | ||||
Change in oxygenation | Greater increase PaO2/FiO2 ratio in treatment group at day 3 and day 5 | Change in PaO2/FiO2 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/cmH2O) | 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 | Â | None | Regression methods with appropriate interaction term |
Severity of disease | Improved hemodynamic stability in patients with severe disease | Â | 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 | ||||
Per-protocol analysis | Â | All outcomes | None | Â |
Adjusting for baseline covariates | Â | 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 |