Clinical trial NCT01455116: The Cooling And Surviving Septic Shock Study (CASS)
Official title: Randomized Trial to Determine Whether Mild Induced Hypothermia Can Reduce Mortality in Adult Patients With Septic Shock
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Septic Shock
Keywords: Sepsis
Multi organ dysfunction syndrome
Mild Induced Hypothermia
Lead sponsor: Danish Procalcitonin Study Group
Sponsor class: OTHER
Collaborators: name: TRYG Foundation
name: Lundbeck Foundation
First posted: 2011-10-19
Enrollment: 433
Sex: ALL
Minimum age (years): 50
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Aged \> 50 years of age.
2. Severe sepsis /septic shock = SIRS + suspected infection+hypotension Mean Arterial Blood Pressure (MAP) \<70 mmHg,
3. Admitted to the participating intensive care units (ICU)
4. Indication for intubation
5. 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.
6. 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:

1. Patients are pregnant or breast feeding
2. 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
3. Persons who are detained under the Act on the use of coercion in psychiatry

Primary outcomes:
measure: Mortality
timeFrame: 30 days
Secondary outcomes:
measure: Renal failure
timeFrame: 30 days
measure: Respiratory
timeFrame: 30 days
measure: Circulatory breakdown/Septic Shock
timeFrame: Measure on day 4
measure: Cerebral dysfunction
timeFrame: Day 1-4
measure: Hepatic Failure
timeFrame: Days 1-4
measure: Coagulatory Failure
timeFrame: Until Day 4/10
measure: Duration of clinical infection
timeFrame: Days 1-4 + 1-30
measure: Number of days Free of Organ failure
timeFrame: 30 days
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Cleveland Clinic - Outcomes Research
state: Ohio
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
state: Capital Region
city: Copenhagen
country: Denmark
facility: Jens Ulrik S. Jensen
state: Capital Region
city: Gentofte
country: Denmark
facility: Gentofte Hospital
state: Capital Region
city: Herlev
country: Denmark
facility: Herlev Hospital
state: Capital Region
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital, Hillerød
state: Capital Region
city: Aarhus
country: Denmark
facility: Aarhus University Hospital, Skejby
state: Jutland
city: Horsens
country: Denmark
facility: Horsens Hospital
state: Jutland
city: Køge
country: Denmark
facility: Køge Hospital
state: Region Sealand
city: Roskilde
country: Denmark
facility: Roskilde Hospital
state: Region Sealand
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
Study officials:
affiliation: CHIP & PERSIMUNE, Rigshospitalet, University of Copenhagen
name: Jens Ulrik S Jensen, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Itenov TS, Johansen ME, Bestle M, Thormar K, Hein L, Gyldensted L, Lindhardt A, Christensen H, Estrup S, Pedersen HP, Harmon M, Soni UK, Perez-Protto S, Wesche N, Skram U, Petersen JA, Mohr T, Waldau T, Poulsen LM, Strange D, Juffermans NP, Sessler DI, Tonnesen E, Moller K, Kristensen DK, Cozzi-Lepri A, Lundgren JD, Jensen JU; Cooling and Surviving Septic Shock (CASS) Trial Collaboration. Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial. Lancet Respir Med. 2018 Mar;6(3):183-192. doi: 10.1016/S2213-2600(18)30004-3. Epub 2018 Jan 8.
citation: Johansen ME, Jensen JU, Bestle MH, Ostrowski SR, Thormar K, Christensen H, Pedersen HP, Poulsen L, Mohr T, Kjaer J, Cozzi-Lepri A, Moller K, Tonnesen E, Lundgren JD, Johansson PI. Mild induced hypothermia: effects on sepsis-related coagulopathy--results from a randomized controlled trial. Thromb Res. 2015 Jan;135(1):175-82. doi: 10.1016/j.thromres.2014.10.028. Epub 2014 Nov 5.