Septic Shock
Conditions
Keywords
septic shock, coagulation, immunomodulation, survival
Brief summary
This study aims at comparing the efficacy and safety of recombinant human activated protein C to that of low dose of corticosteroids and at investigating the interaction between these drugs in the management of septic shock
Detailed description
Septic shock still places a burden in the healthcare system round around the world. In the early 20ties, clinical trials suggested potential benefits from activated protein C in severe sepsis and of corticosteroids when given to adults with refractory shock. More recent studies suggested that patients with moderate sepsis or septic shock may not benefit from either activated protein C or corticosteroids. Therefore, current international guidelines suggest that physicians may consider using these drugs in the more severe cases of sepsis. The main risk associated with the use of activated protein C is bleeding and the main risk associated with the use of steroids is superinfection. It is paramount that a new adequately powered trial explores the benefit/risk ratio of these two drugs and of their combination in a population of adult patients with septic shock. After the withdrawal of Xigris in October 2011, the study was suspended and restarted in June 2012 to investigate the benefit to risk ratio of corticosteroids.
Interventions
DRUGplacebos
placebo of hydrocortisone as an iv bolus every 6 hours for seven days plus placebo of fludrocortisone given through the nasogastric tube once a day for seven days plus placebo of activated protein C given as a continuous infusion for 96 hours
DRUGhydrocortisone and fludrocortisone and placebo
hydrocortisone will be given as 50mg iv bolus every 6 hours for seven days and a tablet of 50µg of fludrocortisone will be given once a day via the nasogastric tube for seven days and a placebo of activated protein C will be given as a continuous infusion for 96 hours
DRUGrecombinant human activated protein C and placebos
activated protein C will be given as a continuous infusion at a dose of 24 µg/kg/h four 96 hours and hydrocortisone placebo as an iv bolus every 6 hours and fludrocortisone placebo once a day through the gastric tube will be given for seven days
DRUGrecombinant human activated protein C and hydrocortisone and fludrocortisone
96 hours continuous infusion of 24µg/kg/h of activated protein C plus seven day treatment with 50mg iv bolus of hydrocortisone every 6 hours and 50µg of fludrocortisone via the nasogastric tube once a day
Sponsors
Assistance Publique - Hôpitaux de Paris
Ministry of Health, France
University of Versailles
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* hospitalized in intensive care unit for less than 7 days * septic shock for less than 24 hours * at least one proven site of infection * at least 2 organ dysfunction as defined by a SOFA score =or\> to 3 for at least 6 consecutive hours * need for vasopressor (dopamine =or\>15µg/kg/min or epinephrine/norepinephrine at =or\>0,25 µg/kg/min for at least 6 consecutive hours, to maintain systolic arterial pressure at 90 mmHg or more OR mean arterial pressure at 6( mmHg or more * informed consent
Exclusion criteria
* pregnancy or breath feeding * decision not to resuscitate * underlying disease with an estimated life expectancy of less than 1 month * formal indication for corticosteroids * recent surgery (ie within the past 72 hours) or a surgery at high risk of bleeding * gastro-intestinal bleeding within the past 6 weeks * chronic liver disease (Child C) * recent trauma (ie within the past 72 hours) * intracranial process * history of stroke, CNS bleeding or traumatic brain injury within the past 3 months * platelet counts of less than 30000 per cubic millimeter * formal indication for curative anticoagulant; prophylactic use of heparin is allowed * any condition of high risk of bleeding as per patient's primary physicians * hypersensitivity of activated drotrecogin alpha or any other component of the drug * no affiliation to a social security Amendments to eligibility criteria were: On 27/03/2008: Changes in following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 90-day mortality | 90 day |
Secondary
| Measure | Time frame |
|---|---|
| mortality at ICU discharge | ICU discharge |
| mortality at hospital discharge | hospital discharge |
| mortality at 6 months | 6 months |
| decision to withhold or withdraw active treatments | up to 90 days |
| Time to wean vasopressor therapy | up to 90 days |
| number of days alive and free of vasopressor therapy | up to 90 days |
| time to achieve an SOFA score of less than 6 | up to 90 days |
| number of days alive with a SOFA score < 6 points | up to 90 days |
| mortality at 28 day | 28-day |
| number of days alive and free of mechanical ventilation | up to 90 days |
| Length of intensive care unit and hospital stay | up to hospital discharge |
| acquisition of new infection | up to 180 days |
| new episode of sepsis | up to 90 days |
| new episode of septic shock | up to 90 days |
| bleeding events | up to 90 days |
| neurological sequels at intensive care unit and at hospital discharge and at 90 and 180 days | up to 6 months |
| time to wean mechanical ventilation | up to 90 days |
Countries
France
Outcome results
None listed