Background
Methods
Study design and settings
Study population
Phenotyping variables
Exposure
Outcomes
Definitions
Statistical analysis
Analytical cohorts
Cluster derivation
Evaluation of rhTM effects in derived phenotypes
Cluster validation and evaluation of rhTM effects
Results
Patients in the derivation cohort
Overall | Cluster dA | Cluster dB | Cluster dC | Cluster dD | P* | |
---|---|---|---|---|---|---|
Variables | n = 3694 | n = 323 | n = 629 | n = 1147 | n = 1595 | |
Age*, median (IQR) | 72.0 (62.0, 81.0) | 72.0 (58.0, 80.0) | 72.0 (63.0, 81.0) | 73.0 (63.0, 81.0) | 72.0 (62.0, 80.0) | 0.25 |
Sex*, female | 1468 (39.7%) | 164 (50.8%) | 268 (42.6%) | 483 (42.1%) | 553 (34.7%) | < 0.001 |
Body weight kg, median (IQR) | 54.7 (46.6, 64.2) | 55.0 (47.5, 64.0) | 52.0 (45.0, 61.1) | 55.0 (46.8, 64.3) | 55.0 (47.0, 65.0) | < 0.001 |
Comorbidity* | ||||||
Liver | 149 (4.0%) | 28 (8.7%) | 73 (11.6%) | 30 (2.6%) | 18 (1.1%) | < 0.001 |
Respiratory | 141 (3.8%) | 8 (2.5%) | 23 (3.7%) | 43 (3.7%) | 67 (4.2%) | 0.52 |
Cardiovascular | 316 (8.6%) | 20 (6.2%) | 49 (7.8%) | 97 (8.5%) | 150 (9.4%) | 0.23 |
Renal | 306 (8.3%) | 24 (7.4%) | 50 (7.9%) | 111 (9.7%) | 121 (7.6%) | 0.23 |
Immunodeficiency | 709 (19.2%) | 62 (19.2%) | 119 (18.9%) | 233 (20.3%) | 295 (18.5%) | 0.69 |
Infection site | < 0.001 | |||||
Unknown | 218 (6.8%) | 32 (11.0%) | 49 (8.4%) | 64 (6.4%) | 73 (5.5%) | |
Catheter-related | 44 (1.4%) | 1 (0.3%) | 6 (1.0%) | 19 (1.9%) | 18 (1.4%) | |
Bone/soft tissue | 374 (11.7%) | 20 (6.9%) | 60 (10.3%) | 108 (10.9%) | 186 (14.0%) | |
Cardiovascular | 68 (2.1%) | 13 (4.5%) | 4 (0.7%) | 26 (2.6%) | 25 (1.9%) | |
Central nervous system | 63 (2.0%) | 14 (4.8%) | 1 (0.2%) | 26 (2.6%) | 22 (1.7%) | |
Urinary tract | 509 (15.9%) | 71 (24.5%) | 40 (6.8%) | 210 (21.1%) | 188 (14.2%) | |
Lung/thoracic | 827 (25.9%) | 38 (13.1%) | 117 (20.0%) | 243 (24.4%) | 429 (32.3%) | |
Abdomen | 1032 (32.3%) | 94 (32.4%) | 294 (50.3%) | 279 (28.1%) | 365 (27.5%) | |
Other | 60 (1.9%) | 7 (2.4%) | 13 (2.2%) | 19 (1.9%) | 21 (1.6%) | |
APACHE II, median (IQR) | 22.0 (17.0, 28.0) | 26.0 (20.0, 33.0) | 26.0 (19.0, 32.0) | 23.0 (17.0, 29.0) | 20.0 (15.0, 26.0) | < 0.001 |
SIRS score, median (IQR) | 3.0 (2.0, 4.0) | 3.0 (3.0, 4.0) | 3.0 (2.0, 4.0) | 3.0 (2.0, 4.0) | 3.0 (2.0, 4.0) | < 0.001 |
SOFA scores* | 9.0 (6.0, 12.0) | 13.0 (10.0, 16.0) | 11.0 (9.0, 14.0) | 10.0 (7.0, 12.0) | 7.0 (5.0, 10.0) | < 0.001 |
Lab data | ||||||
White blood cell (103/μL), median (IQR) | 11.3 (4.8, 17.8) | 12.2 (4.6, 19.7) | 7.8 (2.2, 15.5) | 11.7 (6.0, 18.6) | 11.6 (6.0, 17.5) | < 0.001 |
Platelet (103/μL), median (IQR) | 122.0 (65.0, 194.0) | 59.5 (32.0, 92.0) | 78.0 (46.5, 128.0) | 103.0 (54.0, 162.0) | 178.0 (121.0, 252.0) | < 0.001 |
PT-INR, median (IQR) | 1.3 (1.2, 1.6) | 1.6 (1.4, 2.1) | 1.7 (1.5, 2.2) | 1.3 (1.2, 1.5) | 1.2 (1.1, 1.4) | < 0.001 |
Fibrinogen (mg/mL), median (IQR) | 421.0 (296.0, 528.9) | 231.0 (151.0, 311.0) | 245.3 (157.0, 350.0) | 452.0 (367.0, 563.0) | 476.9 (395.3, 576.0) | < 0.001 |
FDP (μg/mL), median (IQR) | 17.6 (10.1, 36.2) | 120.2 (79.2, 266.0) | 16.0 (10.4, 24.0) | 34.3 (22.8, 55.1) | 10.0 (7.6, 13.8) | < 0.001 |
D-dimer (μg/mL), median (IQR) | 7.8 (3.9, 17.2) | 51.9 (35.2, 113.0) | 7.7 (4.8, 11.7) | 15.4 (10.5, 25.0) | 3.8 (2.7, 5.6) | < 0.001 |
Antithrombin (%), median (IQR) | 60.0 (50.8, 69.0) | 52.0 (42.4, 60.5) | 42.6 (33.0, 50.4) | 60.1 (54.0, 68.0) | 66.0 (59.0, 73.7) | < 0.001 |
Lactate (mmol/L), median (IQR) | 2.9 (1.7, 5.7) | 5.3 (2.9, 10.1) | 4.3 (2.3, 8.0) | 2.7 (1.5, 5.4) | 2.3 (1.4, 4.1) | < 0.001 |
ISTH DIC score | < 0.001 | |||||
0 | 685 (18.7%) | 0 (0.0%) | 15 (2.4%) | 25 (2.2%) | 645 (41.1%) | |
1 | 239 (6.5%) | 2 (0.6%) | 17 (2.7%) | 15 (1.3%) | 205 (13.0%) | |
2 | 701 (19.2%) | 3 (0.9%) | 104 (16.6%) | 116 (10.2%) | 478 (30.4%) | |
3 | 592 (16.2%) | 25 (7.8%) | 99 (15.8%) | 327 (28.8%) | 141 (9.0%) | |
4 | 530 (14.5%) | 42 (13.0%) | 143 (22.8%) | 261 (23.0%) | 84 (5.3%) | |
5 | 441 (12.1%) | 79 (24.5%) | 105 (16.7%) | 240 (21.1%) | 17 (1.1%) | |
6 | 250 (6.8%) | 78 (24.2%) | 83 (13.2%) | 88 (7.7%) | 1 (0.1%) | |
7 | 169 (4.6%) | 72 (22.4%) | 38 (6.1%) | 59 (5.2%) | 0 (0.0%) | |
8 | 40 (1.1%) | 20 (6.2%) | 15 (2.4%) | 5 (0.4%) | 0 (0.0%) | |
ISTH DIC score ≥ 5 | 1430 (39.2%) | 291 (90.7%) | 384 (62.0%) | 653 (57.5%) | 102 (6.5%) | |
Managements | ||||||
rhTM | 969 (29.3%) | 128 (44.1%) | 184 (31.5%) | 334 (33.6%) | 210 (15.8%) | < 0.001 |
Vasopressor use | 2789 (75.5%) | 289 (89.5%) | 558 (88.7%) | 882 (76.9%) | 1060 (66.5%) | < 0.001 |
Renal replacement therapy | 971 (26.3%) | 135 (41.8%) | 220 (35.0%) | 339 (29.6%) | 277 (17.4%) | < 0.001 |
Steroids | 894 (24.2%) | 112 (34.7%) | 214 (34.1%) | 285 (24.8%) | 283 (17.7%) | < 0.001 |
Intravenous immunoglobulin | 1088 (29.5%) | 116 (35.9%) | 239 (38.0%) | 362 (31.6%) | 371 (23.3%) | < 0.001 |
Antithrombin | 1092 (29.6%) | 161 (49.8%) | 296 (47.1%) | 367 (32.0%) | 268 (16.8%) | < 0.001 |
Outcomes | ||||||
28-day death | 753 (20.4%) | 117 (36.2%) | 198 (31.5%) | 200 (17.4%) | 238 (14.9%) | < 0.001 |
In-hospital death | 1186 (32.1%) | 151 (46.8%) | 301 (47.9%) | 358 (31.0%) | 376 (23.6%) | < 0.001 |
Derivation of clinical sepsis phenotypes
Variables | JSEPTIC-DIC (n = 3195) | Tohoku sepsis registry (n = 499) | FORECAST (n = 1184) |
---|---|---|---|
n (%) | n (%) | n (%) | |
Platelets | 10 (0.3%) | 74 (14.8%) | 6 (0.5%) |
PT-INR | 187 (5.9%) | 155 (31.1%) | 38 (3.2%) |
Fibrinogen | 753 (23.6%) | 269 (53.9%) | 226 (19.1%) |
FDP | 1101 (34.5%) | 243 (48.7%) | 376 (31.8%) |
D-dimer | 839 (26.3%) | 220 (44.1%) | 301 (25.4%) |
Antithrombin activity | 1550 (48.5%) | 346 (69.3%) | 542 (45.8%) |
Evaluation of rhTM effects in the derivation cohort
Outcomes | Cluster dA | p value | Cluster dB | p value | Cluster dC | p value | Cluster dD | p value |
---|---|---|---|---|---|---|---|---|
Associations in the derivation cohorts, risk difference, % (95%CI) | ||||||||
Unadjusted association (vs. non rhTM use) | ||||||||
28-Day death | − 10.8 (− 21.5 to − 0.1) | 0.047 | 3.5 (− 4.6 to 11.5) | 0.40 | − 1.9 (− 6.9 to 3.2) | 0.47 | 2.2 (− 2.8 to 7.1) | 0.39 |
In-hospital death | − 10.9 (− 20.8 to − 1.1) | 0.03 | 1.6 (− 7.2 to 10.3) | 0.73 | − 8.0 (− 13.8 to − 2.3) | 0.01 | 0.8 (− 5.2 to 6.8) | 0.78 |
Adjusted association (vs. non rhTM use) | ||||||||
28-Day death | − 17.8 (− 28.7 to − 6.9) | 0.001 | 0.7 (− 7.1 to 8.6) | 0.85 | − 3.1 (− 8.3 to 2.1) | 0.24 | − 0.7 (− 4.5 to 6.0) | 0.79 |
In-hospital death | − 17.7 (− 27.6 to − 7.8) | < 0.001 | 0.2 (− 7.9 to 8.3) | 0.97 | − 10.2 (− 15.9 to − 4.6) | < 0.001 | − 1.3 (− 7.6 to 4.9) | 0.67 |
Cluster vA | p value | Cluster vB | p value | Cluster vC | p value | Cluster vD | p value | |
---|---|---|---|---|---|---|---|---|
Associations in the validation cohorts, risk difference, % (95%CI) | ||||||||
Unadjusted association (vs. non-rhTM use) | ||||||||
28-Day death | − 15.0 (− 32.2 to 2.2) | 0.09 | 3.2 (− 12.5 to 18.9) | 0.69 | 4.4 (− 5 to 13.8) | 0.36 | 7.1 (− 2.4 to 16.6) | 0.14 |
In-hospital death | − 22.2 (− 39.6 to − 4.9) | 0.01 | 8.8 (− 7.3 to 24.8) | 0.29 | 5.7 (− 4.9 to 16.2) | 0.3 | 14.2 (3.8 to 24.7) | 0.008 |
Adjusted association (vs. non rhTM use) | ||||||||
28-Day death | − 24.9 (− 49.1 to − 0.7) | 0.04 | − 5.7 (− 29.9 to 18.5) | 0.64 | 1.4 (− 12.8 to 15.7) | 0.84 | − 6.7 (− 19.4 to 6.0) | 0.3 |
In-hospital death | − 30.9 (− 55.3 to − 6.6) | 0.01 | − 3.7(− 27.9 to 20.5) | 0.77 | − 0.5 (− 16.1 to 15.1) | 0.95 | 0.7 (− 13.0 to 14.5) | 0.92 |