Characteristics of participants
There were a total of 16602 patients with infection in the database according to the results of microbial cultivation, and 7918 patients with a SOFA score≥2 were diagnosed as sepsis. After screening by the exclusion criteria, a total of 4446 patients were included into the final cohort and conscious dysfunction (GCS<15) was observed in 2126 (47.8%) patients.
The baseline characteristics and the characteristics at ICU admission of all participants were exhibited in Table 1 and Table 2. Patients who died (victims) within 30-day since ICU admission were older than those who survived (survivors), with a median age of 78 [67, 86] in victims and 68 [55, 78] in survivors. Patients were predominantly male in both victims and survivors. Comorbidities showed that victims had higher proportion of cardiovascular diseases, chronic liver disease and coagulopathy. Organ failure and the state of illnesses were more severe in victims, with higher modified SOFA and SAPSII score, and higher frequency of coagulation, brain, cardiovascular and renal dysfunctions in victims than that in survivors. Victims had higher proportion of pulmonary and/or fungal infection than survivors. Besides, several vital signs and laboratory indexes were different between victims and survivors, with higher level of respiratory rate, lactate, AST, bilirubin, potassium, RDW and WBC, and lower level of arterial blood pressure, temperature, PO2 and hemoglobin in victims, respectively.
Medical interventions are described in Additional file 2:Table S1. Victims had longer ICU stay time and shorter hospital stay time than survivors. The proportion of vasopressor adoption and mechanical ventilation were higher in victims than that in survivors. Moreover, victims had higher frequency use of carbapenems, vancomycin, benzodiazepines and analgesic drugs than survivors.
Table 1. Patients’ baseline characteristics a
Variable
|
All patients n=4446
|
Survival n=3685
|
Death n=761
|
P value
|
Age, years
|
70 [56, 81]
|
68 [54, 80]
|
78 [67, 86]
|
<0.001
|
Gender, male
|
2397 (53.91)
|
1996 (54.17)
|
401 (52.69)
|
0.483
|
Ethnicity, n (%)
|
|
|
|
<0.001
|
White
|
3299 (74.20)
|
2749 (74.60)
|
550 (72.27)
|
|
Black
|
333 (7.49)
|
296 (8.03)
|
37 (4.86)
|
|
Hispanic or Latino
|
132 (2.97)
|
117 (3.18)
|
15 (1.97)
|
|
Asian
|
88 (1.98)
|
72 (1.95)
|
16 (2.10)
|
|
Others
|
594 (13.36)
|
451 (12.24)
|
143 (18.79)
|
|
Comorbidity, n (%)
|
|
|
|
|
Cardiovascular diseases
|
2512 (56.50)
|
2000 (54.27)
|
512 (67.28)
|
<0.001
|
Peripheral vascular disease
|
526 (11.83)
|
426 (11.56)
|
100 (13.14)
|
0.243
|
Other neurological Diseases
|
631 (14.19)
|
524 (14.22)
|
107 (14.06)
|
0.954
|
Hypertension
|
2226 (50.07)
|
1859 (50.45)
|
367 (48.23)
|
0.282
|
Chronic Pulmonary Disease
|
1039 (23.37)
|
830 (22.52)
|
209 (27.46)
|
0.004
|
Diabetes
|
839 (18.87)
|
693 (18.81)
|
146 (19.19)
|
0.847
|
Hypothyroidism
|
519 (11.67)
|
419 (11.37)
|
100 (13.14)
|
0.186
|
Liver Disease
|
395 (8.89)
|
295 (8.01)
|
100 (13.14)
|
<0.001
|
Coagulopathy
|
742 (16.69)
|
559 (15.17)
|
183 (24.05)
|
<0.001
|
Anemias
|
1158 (26.05)
|
966 (26.21)
|
192 (25.23)
|
0.605
|
a Continuous data are presented as median (interquartile range), whereas categorical data are presented as frequency (percentage)
Table 2. Patients’ characteristics at ICU admission a
Variable
|
All patients n=4446
|
Survival n=3685
|
Death n=761
|
P value
|
First careunit,n (%)
|
|
|
|
<0.001
|
CCU
|
538 (12.10)
|
433 (11.75)
|
105 (13.80)
|
|
CSRU
|
555 (12.48)
|
510 (13.84)
|
45 (5.91)
|
|
MICU
|
2107 (47.39)
|
1654 (44.88)
|
453 (59.53)
|
|
SICU
|
675 (15.18)
|
584 (15.85)
|
91 (11.96)
|
|
TSICU
|
571 (12.84)
|
504 (13.68)
|
67 (8.80)
|
|
Severe Score b
|
|
|
|
|
Modified SOFA
|
4.58±2.88
|
4.32±2.63
|
5.90±3.60
|
<0.001
|
Modified SAPSII
|
37.42±10.79
|
35.79±10.79
|
45.34±11.95
|
<0.001
|
GCS score
|
15 [13,15]
|
15 [13,15]
|
14 [12,15]
|
<0.001
|
Organ dysfunction (SOFA>2), n(%)
|
|
|
|
|
Respiration
|
3719 (83.65)
|
3067 (83.23)
|
652 (85.68)
|
0.108
|
Coagulation
|
674 (15.16)
|
511 (13.87)
|
163 (21.42)
|
<0.001
|
Liver
|
2492 (56.05)
|
2064 (56.06)
|
428 (56.24)
|
0.934
|
CNS
|
526 (11.83)
|
404 (10.96)
|
211 (16.03)
|
<0.001
|
Cardiovascular
|
981 (22.06)
|
749 (20.33)
|
232 (30.49)
|
<0.001
|
Renal
|
742 (16.71)
|
506 (13.73)
|
237 (31.14)
|
<0.001
|
Vital signs c
|
|
|
|
|
Mean heart rate (min-1)
|
88.69±16.18
|
88.52±15.92
|
89.48±17.41
|
0.163
|
Systolic pressure (mmHg)
|
113.39±14.41
|
113.98±14.11
|
110.51±15.44
|
<0.001
|
Diastolic pressure (mmHg)
|
57.82±9.68
|
58.37±9.55
|
55.18±9.90
|
<0.001
|
Mean respiratory rate (min-1)
|
20.00±4.15
|
19.76±3.99
|
21.17±4.66
|
<0.001
|
Mean temperature (℃)
|
36.93±0.68
|
36.98±0.66
|
36.69±0.72
|
<0.001
|
Mean SpO2 (%)
|
97.3 [96.0, 98.5]
|
97.4 [96.0, 98.5]
|
97.0 [95.5, 98.3]
|
<0.001
|
Laboratory tests d
|
|
|
|
|
Lactate (mmol/L)
|
1.6 [1.1, 2.4]
|
1.5 [1.1, 2.3]
|
1.8 [1.3, 2.7]
|
<0.001
|
PCO2 (mmHg)
|
40 [35, 47]
|
40 [35,47]
|
39 [33,47]
|
0.006
|
PO2 (mmHg)
|
112 [75,199]
|
115 [76, 210]
|
98 [69,172]
|
<0.001
|
PH
|
7.368±0.096
|
7.371±0.092
|
7.358±0.110
|
0.003
|
Creatinine (K/uL)
|
1.1 [0.8, 1.7]
|
1.1 [0.8, 1.6]
|
1.4 [0.9, 2.4]
|
<0.001
|
BUN (K/uL)
|
23 [15, 37]
|
22 [15, 34]
|
31 [21, 50]
|
<0.001
|
ALT e
|
1.4 [1.2, 1.7]
|
1.4 [1.2, 1.7]
|
1.4 [1.1, 1.7]
|
0.755
|
AST f
|
1.5 [1.3, 1.8]
|
1.5 [1.3, 1.8]
|
1.6 [1.3, 1.9]
|
<0.001
|
Bilirubin (EU/dL)
|
0.6 [0.4, 1.1]
|
0.6 [0.4, 1.1]
|
0.7 [0.4, 1.6]
|
<0.001
|
Hemoglobin (g/dL)
|
11.59±2.23
|
11.71±2.24
|
11.03±2.11
|
<0.001
|
Platelet (K/uL)
|
226 [162, 302]
|
227 [167, 300]
|
220 [142, 314]
|
0.030
|
Potassium (K/uL)
|
4.2 [3.8, 4.6]
|
4.1 [3.7, 4.6]
|
4.3 [3.8, 4.8]
|
<0.001
|
Sodium (K/uL)
|
138 [135, 141]
|
138 [135, 141]
|
138 [134, 141]
|
0.087
|
PT (sec)
|
14 [12.9,16.3]
|
13.8 [12.9,15.9]
|
14.7 [13.2,18.5]
|
<0.001
|
RDW (%)
|
14.7 [13.7, 16.2]
|
14.5 [13.6, 16.0]
|
15.7 [14.3, 17.6]
|
<0.001
|
WBC (K/uL)
|
10.8 [7.5, 15.4]
|
10.6 [7.4, 15.1]
|
11.6 [8.2, 16.6]
|
<0.001
|
Lymphocyte (%)
|
9.5 [5.7, 16.0]
|
9.8 [6.0, 16.1]
|
8.0 [4.8, 13.9]
|
<0.001
|
Neutrophil (%)
|
81.3 [72.4, 87.8]
|
81.0 [72.0, 87.4]
|
83.4 [74.9, 89.6]
|
<0.001
|
MCV (fL)
|
90 [86,95]
|
90 [86,94]
|
92 [87,97]
|
<0.001
|
Infection site, n(%)
|
|
|
|
|
Urine
|
1994 (44.85)
|
1650 (44.78)
|
344 (45.20)
|
0.860
|
Blood
|
1151 (25.89)
|
936 (25.40)
|
215 (28.25)
|
0.112
|
Lung
|
1708 (38.40)
|
1331 (36.12)
|
377 (49.54)
|
<0.001
|
Catheter
|
239 (5.38)
|
213 (5.78)
|
26 (3.42)
|
0.011
|
Gastrointestinal tract
|
268 (6.03)
|
216 (5.86)
|
52 (6.83)
|
0.346
|
Abdominal cavity
|
108 (2.43)
|
87 (2.36)
|
21 (2.76)
|
0.602
|
Skin/Soft tissue
|
758 (17.05)
|
627 (17.01)
|
131 (17.21)
|
0.936
|
Others
|
142 (3.19)
|
126 (3.42)
|
16 (2.10)
|
0.077
|
Microorganisms, n(%)
|
|
|
|
|
Gram-positive
|
2269 (51.03)
|
1872 (50.80)
|
397 (52.17)
|
0.517
|
Gram-negative
|
1770 (39.81)
|
1483 (40.24)
|
287 (37.71)
|
0.209
|
Fungus
|
1338 (30.09)
|
989 (26.84)
|
349 (45.86)
|
<0.001
|
a Normally distributed variables are presented as mean ± standard deviation (SD), non-normal variables are presented as median (interquartile ranges), whereas categorical data are presented as frequency (percentage)
b Severe score is calculated on the first day of each ICU patients' stay
c Vital signs is calculated on the first 24 hours of each ICU patients' stay
d Laboratory tests recorded the first result of each patients' ICU stay
e ALT in the table is the value after logarithmic transformation
f ALT in the table is the value after logarithmic transformation
CCU, coronary care unit; CSRU, cardiac surgical intensive care unit; MICU, medical intensive care unit; SICU, surgical intensive care unit; TSICU, trauma/surgical intensive care unit; SOFA, sequential organ failure assessment; SAPS II: the simplified acute physiology score; RDW, red blood cell distribution widths; MCV, mean corpuscular volume;
Risk factors for the 30-day mortality of sepsis
The HR (95%CI) of variables with p value<0.05 in multivariate Cox regression were exhibited in Table 3. One variable with a HR-change<10% demonstrated that the impact of it on the 30-day mortality of patients with sepsis was not significantly influenced by the other variables in the multivariate Cox regression, and can be considered as the independent risk factor for the 30-day mortality of sepsis (Additional file 3: Figure S2). Then, the relative importance of independent risk factors were visualized by the rank-hazard plot (Figure 1). Results revealed that among the risk factors which were negatively associated with the 30-day mortality of sepsis, GCS score was the most important one with the highest relative hazard at a range of 3-13 except for that of Mean SpO2 at the lower limit.
Table 3. Cox proportional hazard regression to identify variables independently associated with 30-day mortality of patients with sepsis.
Variables
|
|
Univariate Cox Regression
|
|
Multivariate Cox Regression
|
|
HR change(%)
|
|
HR
|
95%CI
|
P value
|
|
HR
|
95%CI
|
P value
|
|
Age, years
|
|
1.03
|
1.03
|
1.04
|
<0.001
|
|
1.04
|
1.03
|
1.04
|
<0.001
|
|
1.0
|
GCS score
|
|
0.95
|
0.93
|
0.97
|
<0.001
|
|
0.93
|
0.90
|
0.95
|
<0.001
|
|
2.1
|
Liver diseases
|
|
1.65
|
1.34
|
2.04
|
<0.001
|
|
1.62
|
1.25
|
2.09
|
<0.001
|
|
1.8
|
Solid tumor
|
|
1.57
|
1.23
|
2.01
|
<0.001
|
|
1.38
|
1.08
|
1.78
|
0.011
|
|
12.1
|
Lactate (mmol/L)
|
|
1.19
|
1.15
|
1.23
|
<0.001
|
|
1.08
|
1.04
|
1.12
|
<0.001
|
|
9.2
|
BUN (K/uL)
|
|
1.01
|
1.01
|
1.02
|
<0.001
|
|
1.00
|
1.00
|
1.01
|
0.018
|
|
1.0
|
AST a
|
|
1.45
|
1.26
|
1.68
|
<0.001
|
|
1.44
|
1.03
|
2.03
|
0.034
|
|
0.7
|
Bilirubin (EU/dL)
|
|
1.05
|
1.04
|
1.06
|
<0.001
|
|
1.02
|
1.01
|
1.04
|
0.005
|
|
2.9
|
RDW (%)
|
|
1.18
|
1.15
|
1.21
|
<0.001
|
|
1.13
|
1.09
|
1.17
|
<0.001
|
|
4.2
|
MCV (fL)
|
|
1.03
|
1.03
|
1.04
|
<0.001
|
|
1.02
|
1.01
|
1.03
|
<0.001
|
|
1.0
|
Heartrate (min-1)
|
|
1.00
|
1.00
|
1.01
|
0.074
|
|
1.01
|
1.00
|
1.01
|
0.005
|
|
1.0
|
Diastolic pressure (mmHg)
|
|
0.97
|
0.96
|
0.97
|
<0.001
|
|
0.99
|
0.98
|
1.00
|
0.017
|
|
2.1
|
Respiratory rate (min-1)
|
|
1.07
|
1.06
|
1.09
|
<0.001
|
|
1.06
|
1.04
|
1.08
|
<0.001
|
|
0.9
|
Temperature (℃)
|
|
0.56
|
0.51
|
0.62
|
<0.001
|
|
0.70
|
0.62
|
0.79
|
<0.001
|
|
25.0
|
Mean SpO2 (%)
|
|
0.92
|
0.90
|
0.95
|
<0.001
|
|
0.97
|
0.94
|
1.00
|
0.033
|
|
5.4
|
Mechanical ventilation
|
|
1.38
|
1.11
|
1.72
|
0.004
|
|
1.43
|
1.13
|
1.80
|
0.002
|
|
3.6
|
Vasopressor
|
|
2.17
|
1.88
|
2.50
|
<0.001
|
|
1.60
|
1.36
|
1.87
|
<0.001
|
|
26.3
|
Lung infection
|
|
1.62
|
1.40
|
1.86
|
<0.001
|
|
1.41
|
1.18
|
1.67
|
<0.001
|
|
13.0
|
Catheter-related infection
|
|
0.59
|
0.40
|
0.87
|
0.008
|
|
0.50
|
0.33
|
0.75
|
<0.001
|
|
15.3
|
Other infections
|
|
0.62
|
0.38
|
1.01
|
0.056
|
|
0.51
|
0.31
|
0.84
|
0.009
|
|
17.7
|
Fungal infection
|
|
2.06
|
1.79
|
2.38
|
<0.001
|
|
1.19
|
1.00
|
1.41
|
0.047
|
|
42.2
|
a AST in the table is the value after logarithmic transformation.
GCS, Glasgow coma score; RDW, red blood cell distribution width; MCV, mean corpuscular volume.
C-index = 0.76
Survival analysis of patients with sepsis according to the GCS score
As GCS has been demonstrated to be an independent risk factor for the 30-day mortality of sepsis, Kaplan-Meier’s survival analysis was then conducted to visualize the 30-day survival according to different GCS score of participants (Figure 2). Results showed that the 30-day survival had no difference between septic patients with normal consciousness (GCS=15) and those with mild impairment of consciousness (GCS 13-14) (log-rank p=0.28), whereas septic patients with moderate impairment of consciousness (GCS 9-12) or coma (GCS 3-8) had higher 30-day mortality than both of them (log-rank p<0.0001). Besides, the 30-day survival had no difference between septic patients with moderate impairment of consciousness and those with coma (log-rank p=0.48). These results indicated that it was GCS 3-12 that contribute to the increased 30-day mortality of patients with sepsis and was the independent risk factor for it.
Risk factors for sepsis-associated moderate impairment of consciousness and coma
The OR (95%CI) of variables with p value<0.05 in multivariate logistic regression were exhibited in Table 4. One variable with a OR-change<10% demonstrated that its effect on the incidence of GCS≤12 in patients with sepsis was not significantly influenced by the other variables in the multivariate logistic regression, and can be considered as the independent risk factor contributing to the moderate impairment of consciousness and coma in sepsis (Figure 3). Sensitivity analysis was conducted in patients without a history of neurological diseases and the results were exhibited in Additional file 4: Figure S3. Then, we divided the continuous variables of the independent risk factors into three groups based on their reference range and the proportion of patients with GCS≤12 in each group were calculated and visualized in Figure 4.
Table 4. Logistic regression to identify variables independently associated with sepsis-associated moderate impairment of consciousness and coma
Variables
|
|
Univariate Logistic Regression
|
|
Multivariate Logistic Regression
|
|
OR change(%)
|
|
OR
|
95%CI
|
P value
|
|
OR
|
95%CI
|
P value
|
|
Respiration(SOFA>2)
|
|
0.59
|
0.50
|
0.71
|
<0.001
|
|
0.70
|
0.57
|
0.85
|
<0.001
|
|
18.6
|
Cardiovascular diseases
|
|
0.73
|
0.64
|
0.84
|
<0.001
|
|
0.81
|
0.69
|
0.95
|
0.009
|
|
23.3
|
Neurodegenerative disorders
|
|
3.56
|
2.98
|
4.25
|
<0.001
|
|
2.94
|
2.44
|
3.54
|
<0.001
|
|
16.3
|
Hemoglobin (g/dL)
|
|
1.06
|
1.03
|
1.10
|
<0.001
|
|
1.05
|
1.01
|
1.09
|
0.019
|
|
0.9
|
Sodium (K/uL)
|
|
1.04
|
1.02
|
1.05
|
<0.001
|
|
1.02
|
1.00
|
1.03
|
0.018
|
|
1.9
|
Neutrophil (%)
|
|
1.01
|
1.00
|
1.01
|
0.004
|
|
1.01
|
1.00
|
1.02
|
0.004
|
|
0.0
|
Systolic pressure (mmHg)
|
|
1.04
|
1.03
|
1.04
|
<0.001
|
|
1.03
|
1.02
|
1.04
|
<0.001
|
|
1.0
|
Urinary infection
|
|
1.20
|
1.04
|
1.38
|
0.011
|
|
1.17
|
1.00
|
1.37
|
0.045
|
|
1.7
|
Cephalosporin
|
|
1.31
|
1.13
|
1.52
|
<0.001
|
|
1.36
|
1.16
|
1.60
|
<0.001
|
|
3.1
|
SOFA, sequential organ failure assessment;
AUC = 0.67; Hosmer and Lemeshow test: P=0.12.