The Cooling And Surviving Septic Shock Study (CASS)

Study Overview
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Brief Summary
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Septic shock is in critically ill patients is a condition associated with a high rate of organ failure and hereto attributable mortality  45-55% Hypothesis: Mild Induced Hypothermia reduces the mortality of critically ill patients with septic shock by reducing organ metabolism, counteracting on microcirculatory thrombosis, genetically downregulating tissue apoptosis and by reducing bacterial growth rate and toxin production.

Detailed Description
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Septic shock is an acute life-threatening condition, with great organ damage for every hour. The patients have a high risk of dying and therefore rapid treatment is of crucial importance for survival of the patients. Septic shock is mainly due to a collapse in the blood circulation (the capillary system) due to blockage by blood cells - a process initiated by substances from the cells of the immune system via activation of coagulation. The normal function of the smallest blood vessels is to transport oxygen, nutrients and drugs to organs and tissues, and lead waste products away. While the offer of oxygen and nutrients to the organs decreases, the consumption of oxygen and nutrients increases due to fever and immune reactions. When the capillary system collapses, the organs and tissues suffer, and various forms of cell death in the organs begins including programmed cell death (apoptosis). This leads to organ damage, for example brain damage or kidney damage and ultimately to multiple organ dysfunction which is the direct cause of the patient dies. Mild induced hypothermia (cooling to 32 0C-34 0C) affects at least 5 core areas in the pathophysiology of septic shock: 1) inhibition of inflammation 2) inhibition of apoptosis (programmed cell death), 3) antithrombotic, 4) decreases the metabolism and 5) inhibits bacterial growth and production of toxins.

Official Title
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Randomized Trial to Determine Whether Mild Induced Hypothermia Can Reduce Mortality in Adult Patients With Septic Shock

Conditions
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Septic Shock

Intervention / Treatment
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* Procedure: Mild Induced Hypothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged > 50 years of age. Severe sepsis /septic shock = SIRS + suspected infection+hypotension Mean Arterial Blood Pressure (MAP) <70 mmHg, Admitted to the participating intensive care units (ICU) Indication for intubation Possibility of inclusion within 6 hours after septic shock/severe sepsis is diagnosed in the ICU. Patients admitted with septic shock/severe sepsis should be included within 6 hours after admission. If a patient is not included within this period, that patient cannot be included within the same hospitalization. The patient must have an expected stay in the ICU of more than 24 hours. Anticipated death within 24 hours after admission to the ICU does not exclude participation; however no decision of reduction of treatment level must have been taken. During this time period, probability that the patient is discharged to a floor department must not be likely (<10% probability). Exclusion Criteria: Patients are pregnant or breast feeding The findings of the initial screening, shows that the patient has a bleeding disorder and/or the patient has an uncontrollable bleeding and /or surgery within the last 24 hours Persons who are detained under the Act on the use of coercion in psychiatry

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mild induced hypothermia<br>Induced hypothermia to 32-34 degrees Celsius (90 - 93 degrees Fahrenheit) | Procedure: Mild Induced Hypothermia<br>* Induction of hypothermia to a target temperature of 32 - 34 degrees Celsius (90 - 93 degrees Fahrenheit<br>* Other names: Cooling;|
| No Intervention: Fever Respect<br>Standard of care septic shock therapy according to Surviving Sepsis Campaign guidelines | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | All cause | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal failure | RIFLE criteria (R+I+F) eGFR decrease (ml/min/1.73 m2) eGFR decrease to <60 ml/min/1,73) + derivatives of the above | 30 days | 
| Respiratory | Use of Mechanical Ventilation on day 4 No. of days where Mechanical Ventilation is used Delta PaO2/FiO2 ratio until day 4 +Derivatives of the above | 30 days | 
| Circulatory breakdown/Septic Shock | Delta MAP days 1-4 Inotropic Score day 1-4 Achieved discontinuation of inotropics on day 4 | Measure on day 4 | 
| Cerebral dysfunction | Delta RASS 1-4 CAM-ICU: Days with positive CAM-ICU within 72 h after awakening MiniMentalState Examination (MMSE) | Day 1-4 | 
| Hepatic Failure | Delta Bilirubin 1-4 Fraction of subjects with Bilirubin level >21 micromoles/L on day 4 | Days 1-4 | 
| Coagulatory Failure | Delta Platelets day 1-4 Delta INR days 1-4 (and factor 2/7/10) Delta APTT (days 1-4) Total consumption of SAG-M on days 1-10 Occurrence of Severe bleeding (surgery demanding or CT-verified, fresh upper or lower G-I bleeding) Thromboelastography | Until Day 4/10 | 
| Duration of clinical infection | Delta C-reactive protein day 1-4 Achieved decrease in CRP >30 % from day 1-4 PCT decrease (Quantitative) day 1-10 | Days 1-4 + 1-30 | 
| Number of days Free of Organ failure | Number of days Free of Organ failure until day 30: Need for Mechanical ventilation, need for inotropic, RIFLE criteria positive, positive CAM-ICU days. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Multi organ dysfunction syndrome, Mild Induced Hypothermia