Table 2:
Outcomes
| Routine thermal management (n=215) | Induced hypothermia (n=217) | Risk ratio (95% CI)* | Absolute difference (% [95% CI])* | p value | |
|---|---|---|---|---|---|
|
| |||||
| Primary outcome | |||||
| 30 day mortality | 77 (35.8%) | 96 (44.2%) | 1.2 (1.0 to 1.6)† | 8.4% (−0.8 to 17.6) | 0.07 |
| Secondary outcome ‡ | |||||
| 180 day mortality | 109 (50.7%) | 122 (56.2%) | 1.1 (0.9 to 1.3) | 5.5% (−3.9 to 14.9) | 0.25 |
| Days alive without respiratory support to day 30§ | 15 (0 to 26) | 3 (0 to 24) | .. | .. | 0.03 |
| Days alive without renal replacement therapy to day 30§ | 30 (0 to 30) | 20 (0 to 30) | .. | .. | 0.04 |
| Days alive without vasoactive medication to day 30§ | 23 (0 to 28) | 19 (0 to 27) | .. | .. | 0.006 |
| ICU length of stay (days)¶ | |||||
| All | 9 (3 to 17) | 8 (4 to 15) | .. | .. | 0.59 |
| Survivors | 9 (4 to 18) | 9 (6 to 19) | .. | .. | 0.12 |
| Non-survivors | 8 (2 to 15) | 7 (3 to 13) | .. | .. | 0.73 |
| Secondary outcomes and organ failure at 72 h‡ || | |||||
| SOFA score | 9 (6 to 12) | 11 (7 to 13) | .. | .. | 0.04 |
| Respiratory function | |||||
| On ventilator | 144/192 (75.0%) | 165/191 (86.4%) | 1.2 (1.0 to 1.3) | 11.4% (3.1 to 18.9) | 0.007 |
| PaO2 to FiO2 ratio | 25.4 (18.6 to 30.6) | 25.8 (18.7 to 34.3) | .. | .. | 0.52 |
| SOFA respiratory score | 2 (2 to 3) | 2 (2 to 3) | .. | .. | 0.74 |
| Circulatory function | |||||
| Mean arterial pressure (mm Hg) | 78 (70 to 86) | 75 (70 to 84) | .. | .. | 0.13 |
| Received vasoactive drugs | 102/192 (53.1%) | 132/191 (69.1%) | 1.3 (1.1 to 1.5) | 15.9% (6.8 to 26.4) | 0.002 |
| Vasoactive-inotropic score | 1 (0 to 14) | 10 (0 to 20) | .. | .. | <0.0001 |
| Accumulated vasoactive-inotropic score | 52 (27 to 104) | 74 (43 to 126) | .. | .. | <0.0001 |
| Achieved 50% reduction in vasoactive-inotropic score | 128/184 (69.6%) | 104/187 (55.6%) | 0.8 (0.7 to 0.9) | −14.0% (−23.7 to −4.2) | 0.006 |
| SOFA cardiovascular score | 3 (0 to 3) | 3 (0 to 4) | .. | .. | 0.002 |
| Renal function | |||||
| Diuresis (mL/kg per h) | 1.3 (0.6to 1.8) | 1.4 (0.6 to 2.0) | .. | .. | 0.25 |
| Creatinine concentration (μmol/L) | 83 (61 to 130) | 96 (64 to 146) | .. | .. | 0.08 |
| Renal replacement therapy | 36/192 (18.8%) | 43/191 (22.5%) | 1.2 (0.8 to 1.8) | 3.8% (−4.2 to 11.8) | 0.37 |
| Acute kidney injury (RIFLE)** | |||||
| Risk | 17/173 (9.8%) | 14/181 (7.7%) | 0.8 (0.4 to 1.6) | −2.1% (−8.0 to 3.8) | 0.49 |
| Injury | 4/173 (2.3%) | 2/181 (1.1%) | 0.5 (0.1 to 2.6) | −1.2% (−3.9 to 1.5) | 0.38 |
| Failure | 42/173 (24.3%) | 55/181 (30.4%) | 1.3 (0.9 to 1.8) | 6.1% (−3.2 to 15.4) | 0.19 |
| Any | 63/173 (36.4%) | 71/181 (39.2%) | 1.1 (0.8 to 1.4) | 2.8% (−7.3 to 12.9) | 0.59 |
| SOFA renal score | 0 (0 to 2) | 0 (0 to 2) | .. | .. | 0–08 |
| Coagulation and liver function | |||||
| INR | 1.3 (1.1 to 1.5) | 1.2 (1.1 to 1.5) | .. | .. | 0.80 |
| Bilirubin concentration (μmol/L) | 9 (6 to 16) | 11 (6 to 21) | .. | .. | 0.21 |
| Bilirubin concentration of >21 mmol/L | 33/172 (19.2%) | 45/188 (23.9%) | 1.3 (0.8 to 1.9) | 4.8% (−3.7 to 13.2) | 0.27 |
| ' SOFA liver score | 0 (0 to 0) | 0 (0 to 1) | .. | .. | 0.18 |
| Platelet count (× 109 per L) | 194 (115 to 282) | 156 (81 to 245) | .. | .. | 0.01 |
| Platelet count of <150 × 109 per L | 61/178 (34.3%) | 89/189 (47.1%) | 1.4 (1.1 to 1.8) | 12.8% (2.7 to 22.8) | 0.01 |
| Platelet count decrease of >25% from baseline | 60/168 (35.7%) | 79/177 (44.6%) | 1.3 (1.0 to 1.6) | 8.9% (−1.4 to 19.2) | 0.09 |
| SOFA coagulation score | 0 (0 to 1) | 0 (0 to 2) | .. | .. | 0.01 |
| C-reactive protein | |||||
| C-reactive protein concentration (mg/L) | 106 (59 to 191) | 153 (96 to 236) | .. | .. | 0.0001 |
| C-reactive protein concentration decrease of >30% from baseline | 88/175 (50.3%) | 60/180 (33.3%) | 0.7 (0.5 to 0.9) | −17.0% (−27.1 to −6.8) | 0.001 |
| Cerebral function | |||||
| Received sedatives | 130/192 (67.7%) | 150/191 (78.5%) | 1.2 (1.0 to 1.3) | 10.8% (2.0 to 19.6) | 0.02 |
| Richmond Agitation-Sedation Scale | −3 (−4 to 0) | −3 (−4 to −2) | .. | .. | 0.008 |
| Delirium†† | 16/84 (19.0%) | 19/71 (26.8%) | 1.4 (0.8 to 2.5) | 7.7% (−5.6 to 21.0) | 0.25 |
| SOFA CNS score‡‡ | 2 (0 to 4) | 3 (2 to 4) | .. | .. | 0.0004 |
Data are n (%), median (IQR), or n/N (%), unless otherwise indicated. Correction for multiple comparisons was not implemented according to the latest European Medicines Agency guidelines38 since the trial had one primary hypothesis and one primary outcome and all other endpoints were considered supportive. ICU=intensive care unit. SOFA=Sequential Organ Failure Assessment. PaO2=partial pressure of arterial oxygen. FiO2=fraction of inspired oxygen. RIFLE=Risk, Injury, Failure, Loss of Kidney Function, and End-stage Kidney Disease. INR=International Normalized Ratio.
We only report risk ratios and differences for binary outcomes.
The hazard ratio for the primary endpoint adjusted for stratifying variables (Cox regression with randomisation, site, age ≥65 years, and Acute Physiology and Chronic Health Evaluation II score of ≥25) was 1.31 (95% CI 0.97-1.77).
383 patients could be included in the analysis of secondary outcome at the end of the intervention (191 [50%] in the induced hypothermia group and 192 [50%] in the routine thermal management group). In one (<1%) patient the next of kin declined further data collection (in the induced hypothermia group) and 23 (11%) patients died in the routine thermal management group compared with 25 (12%) in the induced hypothermia group).
Days alive without organ failure to day 30 was for all assessments done according to Schoenfeld and colleagues39 and, accordingly, the score “0" was given to all patients who died before day 30.
Censored on day 30.
Secondary outcomes were evaluated 72 h after initiation of the intervention.
The maximum RIFLE class reached during 72 h was used. In RIFLE “F", patients in renal replacement therapy were included.
Delirium status could be established in 155 (84 [54%] in the routine thermal management group and 71 [46%] in the induced hypothermia group) patients for whom the Richmond Agitation-Sedation Scale was less than −4.
Calculated on the basis of the Richmond Agitation-Sedation Scale according to Vasilevskis and colleagues.40