The purpose of this study, in mechanically ventilated septic shock patients, is to determine whether a fluid loading strategy based on parameters derived from the transpulmonary thermodilution technique may lead to more ventilator free days compared to a fluid loading strategy based on the surviving sepsis guidelines.

Rationale: Fluid loading is an important intervention in patients with severe sepsis and septic shock in order to prevent development of multi organ failure and mortality. The Surviving Sepsis Guidelines recommend during the first 6 hours of resuscitation a central venous pressure (CVP) based fluid loading approach, targeting to 12-15 mmHg in mechanically ventilated patients. CVP however has proven to be a poor indicator for preload and preload dependency, while dynamic parameters as stroke volume variation (SVV) derived from the transpulmonary thermodilution technique (TPTD) are superior. Together with the ability to measure the extravascular lung water (EVLW), the TPTD technique may guide fluid management more accurately and may prevent deleterious fluid overloading.

Objective: The risk of fluid overloading in mechanically ventilated patients with septic shock is less when fluid administration is based on a fluid loading protocol using SVV together with EVLW measurements than applying the Surviving Sepsis Guidelines targeting CVP to 12-15 mmHg, in at least the first 6 hours of resuscitation, translating in more ventilator free days (VFDs) Study design: This is a prospective, randomized, non-blinded, single-center, controlled clinical trial comparing two different fluid resuscitation strategies in patients with septic shock. Patients will be randomized for fluid management based on the Surviving Sepsis Guidelines (SSG) or based transpulmonary thermodilution (TPTD) derived SVV and EVLW in at least the first 6 hours of resuscitation.

Study population: All patients of ≥18 years admitted to the ICU because of septic shock together with the need for mechanical ventilation are eligible for randomization Intervention: During at least the first 6 hours of resuscitation, the standard group (SSG guided therapy) follows a fluid resuscitation protocol based on the Surviving Sepsis Campaign recommendations. Initial trigger for fluid loading when circulatory insufficiency is present will be the CVP (target ≥12 mmHg). The intervention group (TPTD guided therapy) follows a fluid resuscitation protocol based on SVV and EVLW. Initial trigger for fluid loading when circulatory insufficiency is present will be SVV. The study protocol will be applied up to a maximum of 72 hours.

Main study parameters/endpoints: VFDs on day 28. Benefit and risks associated with participation: Since inclusion criteria include a TPTD (5F fiber optic, femoral artery) catheter, the inconvenience as compared to standard treatment is minimal. Current routine hospital policy involves TPTD catheter insertion in most of the patients meeting the inclusion criteria specified above.

Inclusion Criteria:

1. Age > 18 years

2. Clinical evidence of sepsis (microbiology confirmation, radiological or direct view (pus in biological fluid) or direct surgical view).

3. ≥ 2 SIRS criteria:

   1. Temperature < 36.0°C or > 38.0°C
   2. Heart rate > 90 bpm
   3. Respiratory rate > 20 rpm or PaCO2 < 4.2 kPa or need of mechanical ventilation.
   4. Leukocytes > 12.0 x109/L or < 4.0 x109/L or >10% bands

4. Circulatory shock defined as sustained systemic hypotension (systolic arterial pressure <90 mmHg or MAP <65 mmHg (<75 mmHg in a hypertensive patient) despite a 1,000 ml IV fluid challenge over 30 min (including IV fluids administered pre-ICU) or the need for vasopressor therapy. Hypertensive patients are patients with a history of confirmed hypertension treated with antihypertensive agents.

5. Mechanical ventilation by endotracheal tube (any form)

Exclusion Criteria:

1. Pregnancy
2. Pre-terminal illness with life expectancy <28 days
3. Duration of circulatory shock >6 hours
4. Severe peripheral arterial vascular occlusion disease (Fontaine level III-IV)
5. Inability for femoral artery canulation
6. No informed consent