The Cooling And Surviving Septic Shock Study (CASS) (CASS)

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

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.

Study Overview

• Status: Terminated
• Conditions: Septic Shock
• Intervention / Treatment: Procedure: Mild Induced Hypothermia

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.

• Study Type: Interventional
• Enrollment (Actual): 433
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Capital Region
    • Copenhagen, Capital Region, Denmark, 2400
      • Bispebjerg Hospital
    • Copenhagen, Capital Region, Denmark, DK-2200
      • Jens Ulrik S. Jensen
    • Gentofte, Capital Region, Denmark, 2900
      • Gentofte Hospital
    • Herlev, Capital Region, Denmark, 2730
      • Herlev Hospital
    • Hillerød, Capital Region, Denmark, 3400
      • Nordsjællands Hospital, Hillerød
  • Jutland
    • Aarhus, Jutland, Denmark, 8200
      • Aarhus University Hospital, Skejby
    • Horsens, Jutland, Denmark
      • Horsens Hospital
  • Region Sealand
    • Køge, Region Sealand, Denmark, 4600
      • Køge Hospital
    • Roskilde, Region Sealand, Denmark, 4000
      • Roskilde Hospital
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Center
• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic - Outcomes Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years to 118 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Danish Procalcitonin Study Group
• Collaborators: Lundbeck Foundation; TRYG Foundation
• Investigators: Study Director: Jens Ulrik S Jensen, MD, PhD, CHIP & PERSIMUNE, Rigshospitalet, University of Copenhagen

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: October 15, 2011
• First Submitted That Met QC Criteria: October 18, 2011
• First Posted (Estimate): October 19, 2011

Study Record Updates

• Last Update Posted (Estimate): November 22, 2016
• Last Update Submitted That Met QC Criteria: November 21, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Sepsis; Multi organ dysfunction syndrome; Mild Induced Hypothermia
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock
• Other Study ID Numbers: H-A-2008-086

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: The Steering Committee will share data after reviewing study propositions - this to assure quality