TY - JOUR

T1 - Induced hypothermia in patients with septic shock and respiratory failure (CASS)

T2 - a randomised, controlled, open-label trial

AU - Itenov, Theis Skovsgaard

AU - Johansen, Maria Egede

AU - Bestle, Morten

AU - Thormar, Katrin

AU - Hein, Lars

AU - Gyldensted, Louise

AU - Lindhardt, Anne

AU - Christensen, Henrik

AU - Estrup, Stine

AU - Pedersen, Henrik Planck

AU - Harmon, Matthew

AU - Soni, Uday Kant

AU - Perez-Protto, Silvia

AU - Wesche, Nicolai

AU - Skram, Ulrik

AU - Petersen, John Asger

AU - Mohr, Thomas

AU - Waldau, Tina

AU - Poulsen, Lone Musaeus

AU - Strange, Ditte

AU - Juffermans, Nicole P

AU - Sessler, Daniel I

AU - Tønnesen, Else

AU - Møller, Kirsten

AU - Kristensen, Dennis Karsten

AU - Cozzi-Lepri, Alessandro

AU - Lundgren, Jens D

AU - Jensen, Jens-Ulrik

AU - Cooling and Surviving Septic Shock (CASS) Trial Collaboration

AU - Hägi-Pedersen, Daniel

AU - Poulsen, Anne

AU - Nielsen, Kim G.

N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.

PY - 2018

Y1 - 2018

N2 - BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock.METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116.FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]).INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock.FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

AB - BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock.METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116.FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]).INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock.FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

KW - APACHE

KW - Aged

KW - Europe

KW - Female

KW - Humans

KW - Hypothermia, Induced/methods

KW - Intensive Care Units

KW - Male

KW - North America

KW - Respiration, Artificial/methods

KW - Respiratory Insufficiency/etiology

KW - Shock, Septic/complications

KW - Treatment Outcome

U2 - 10.1016/S2213-2600(18)30004-3

DO - 10.1016/S2213-2600(18)30004-3

M3 - Journal article

C2 - 29325753

VL - 6

SP - 183

EP - 192

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

SN - 2213-2600

IS - 3

ER -