Preventive Versus Curative Treatment of Fluid Overload

Fluid overload is associated with a poor prognosis in critically ill patients, especially during weaning from mechanical ventilation as it may promote weaning induced pulmonary edema. Previous data suggest that early administration of diuretics ("preventive depletion") could shorten the duration of mechanical ventilation. However, this strategy may expose patients to a risk of metabolic complications. On the other hand, initiating fluid removal only in case of weaning induced pulmonary edema (curative depletion) may reduce the risk of metabolic complications, but prolong the duration of mechanical ventilation. Currently, there is no recommendation for a preventive or curative use of diuretics during weaning. There is therefore an equipoise on the timing of initiation of diuretics during weaning from mechanical ventilation.

Mechanical ventilation is a cornerstone treatment for critically ill patients that is however associated with complications that may alter the prognosis. A major objective is therefore to separate patients from the ventilator as quickly as possible, but without exposing them to the risk of extubation failure. Pulmonary edema is a frequent cause of extubation failure (up to 60% in recent series) and a positive fluid balance has been identified as an important risk factor for extubation failure.

Studies have tested the effect of a conservative strategy regarding the administration of fluids in patients with acute respiratory distress syndrome. This strategy is associated with an improvement in hemodynamic parameters despite an increase in urine output with a negative fluid balance and a significant weight loss as compared to a liberal strategy. The conservative approach also shows a significant improvement in oxygenation with a nonsignificant trend towards a shorter duration of artificial ventilation and ICU stay. During the specific phase of weaning from mechanical ventilation, a randomized trial (BMW trial) demonstrated that a strategy of fluid removal guided by measurement of the plasmatic B-type natriuretic peptide significantly reduced the duration of weaning. Likewise, the interest of obtaining a negative fluid balance through the administration of diuretics in weaning induced pulmonary edema has been established for decades ("curative depletion").

In this context, the hypothesis of the present study is that a preventive and systematic strategy of fluid removal through the use of diuretics initiated just before the weaning phase, as soon as the patients is stabilized would shorten the duration of weaning from mechanical ventilation as compared to a curative strategy of fluid removal, only initiated after a failure of the spontaneous breathing trial associated with weaning induced pulmonary edema.

The design of the study will be a randomized (1:1) controlled trial, open label, with 2 arms, to evaluate the superiority of the preventive strategy.

The weaning process will be protocolized and similar for the two groups.

Eligibility Criteria:
Inclusion Criteria:

1. age\>18
2. intubation and mechanical ventilation \>= 24 hours
3. cumulative fluid balance judged positive or increase in body weight since admission
4. clinical stability as defined by: 4.1. stable oxygenation (SpO2 ≥ 90 % with FiO2 ≤ 50 % and positive end-expiratory pressure (PEEP) ≤ 8 cm H2O) 4.2. stable hemodynamics (no pressors, no fluid expansion within the last 12 hours) 4.3. stopped or decreased sedation within the last 48 hours and stable neurologic state.

   4.4. temperature \>36,0 ◦C and \< 39◦C
5. consent signed by the patient or next of kin or emergency procedure

Exclusion Criteria:

1. extracorporal membrane oxygenation
2. pregnancy or breastfeeding
3. allergy to furosemide, sulfamides or spironolactone
4. tracheotomy
5. hydrocephaly
6. acute right ventricle failure
7. cardiac arrest with estimated poor prognosis
8. already enrolled in an interventional study on weaning from mechanical ventilation
9. Guillain Barre, myasthenia crisis
10. planned extubation on the day
11. criteria of clinical stability (as described above) present since more than 24 hours
12. natremia \> 150 mEq/L, kaliemia \< 3.5 mEq/L, metabolic alkalosis with pH\>7.5
13. administration of iodinated contrast within the last 6 hours
14. ongoing or planned use of artificial kidney within the next 48 hours
15. no affiliation to the health insurance system
16. patient under curatorship
17. imprisoned patient