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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in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention).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.

Fresh-frozen plasma (FFP) transfusion may be widely used in patients in septic shock, but the use is not well-described. Our aim was to describe the current use of FFP transfusion in medical patients with septic shock.This was a prospective cohort study of medical patients with septic shock (n = 60) admitted to two general intensive care units (ICUs) during a three-month period. Patients were divided into two groups, one received FFP transfusion, the other did not. Baseline characteristics, transfusions and outcome were compared between the groups. Episodes of bleeding, procedures and coagulation parameters were compared between days with and without FFP transfusion.57% of the patients received a median of six (interquartile range: 3-10) units of FFP during their ICU stay. The FFP-transfused patients had higher sequential organ failure assessment scores at admission (13 (9-15) versus 10 (7-11), p = 0.02) than the untransfused patients, but there were no differences in simplified acute physiology score II or mortality. On days of FFP transfusion, international normalized ratio levels (1.8 (1.4-2.3) versus 1.3 (1.2-1.6), p0.0001) were higher, and invasive procedures (p0.0001), episodes of bleeding (p0.0001), transfusion of red blood cells (p0.0001) and platelets (p0.0001) more frequent than on days without transfusion. Two thirds of FFP transfusions were given to patients with clinical evidence of bleeding and/or as prophylaxis before invasive procedures.The majority of medical ICU patients with septic shock received FFP transfusion. One third of the FFPs were given unrelated to invasive procedures or bleeding.not relevant.not relevant.

Background Animal models of serious infection suggest that 24 hours of induced hypothermia improves circulatory and respiratory characteristics and enhances survival, but whether therapeutic mild hypothermia in such conditions is of clinical benefit remains unknown. We, therefore, tested whether reducing core temperature to 32–34oC in critically ill patients with septic shock and ventilator-demanding respiratory failure improves survival and reduces organ dysfunction. Methods In this multi-national trial, patients with septic shock were enrolled within 6 hours of onset of septic shock and ventilator-demanding respiratory failure and randomized 1:1, stratified by site (target sample = 560), to routine thermal management or 24 hours of induced hypothermia (target 32–34°C) followed by 48 hours of normothermia. Other aspects of care were per routine in each participating center. The primary endpoint was 30-day all-cause mortality. Results At the third ordinary interim analysis, after recruitment of 432 participants, the Data and Safety Monitoring Board recommended the trial be terminated for futility; the conditional power for rejection of the null hypothesis in favor of efficacy was null. In the induced hypothermia group, target temperature was reached within median 3.2 hours [IQR: 2.2, 4.8], and maintained for 24 hours [IQR: 24, 24] (Figure 1). There was no evidence for a difference in 30-day mortality risk in patients randomized to hypothermia (96/217) vs. routine thermal management (77/215): relative risk 1.24 [95% CI: 0.98, 1.56] (Figure 2). At the end of the temperature intervention (72 hours), more patients assigned to hypothermia were in continued shock (vasoactive medication 71% vs. 58%; P = 0.01), and fewer cooled patients had inflammatory control (32% vs. 47% had CRP decline of >30%, P = 0.005). More harm from cooling was seen in patients entering the trial with normal renal function and with normal platelet count (P for interaction Conclusion Among patients with septic shock and ventilator-demanding respiratory failure, induced hypothermia did not improve survival, but adversely affected the duration of shock, and inflammatory control. Induced hypothermia should not routinely be used in patients with septic shock. Disclosures All authors: No reported disclosures.

Patients in septic shock have a 33-42% 30-day mortality, but characteristics and outcome have not been assessed in Danish intensive care units (ICUs).This is a cohort study with prospective registration over a 3-month period of all patients suffering from septic shock at six Danish ICUs. We registered admission-, disease- and treatment characteristics during the first day after the diagnosis and 30- and 90-day mortality.A total of 132 patients with a median age of 64 years (range 15-92 years) were included. Patients were primarily admitted from general wards (n = 56), operation- (31) and emergency rooms (25) and other hospitals (19). Most were diagnosed at ICU admittance. Abdominal focus of infection was most frequent (n = 47) followed by pneumonia (45), soft tissue (14), urinary tract (8), other (6) and unknown (11). Most patients were resuscitated with a combination of crystalloids and colloids (98) and noradrenalin (119), and 100 had broad-spectrum antibiotics prior to the diagnosis, while 27 received such medication 120 (2-450) mins. after diagnosis. Mortality at 30 and 90 days was 33 and 41%, respectively - and highest for patients with abdominal infection 42 and 55%, respectively.Patients in septic shock in Danish ICUs are admitted from different hospital locations, have abdominal or pulmonary foci, but the treatment is relatively uniform. The mortality is high, but at par with the best results from other countries.