1. Demographics and clinical outcome data
The demographics and clinical characteristics of the severely burned patients included are shown in Table 1. The bacteremia rate and 90-day mortality rate were 33.1% (56/169) and 21.3% (36/169), respectively. Compared to the patients without bacteremia, the Bac group had a larger TBSAB (P<0.001) and longer operation duration (P<0.001) but a shorter interval between admission and the 1st surgery (P=0.02). As shown in Table 2, the ICU stay time and 30-day and 90-day mortality rates in the Bac group were significantly higher than those in the Con group. The positive rate of blood culture within 14 days of burn was 37.5% (21/56), with a mortality rate of 47.6% (10/21), which was significantly higher than that in the Con group (P< 0.01). With increasing operation duration, the mortality rate also increased (28.9%, 37.2% and 41.1% for 2, 3 and 4 hours, respectively). Kaplan–Meier curve analysis (Figure 1) showed significantly shorter survival times in the Bac group than in the Con group (P<0.001).
Table 1. Demographics and clinical characteristics of included patients
Variables
|
All
(n= 169)
|
Bac
(n=56)
|
Con
(n=113)
|
P1
|
Deceased
(n=36)
|
Survival
(n=133)
|
P2
|
Age, y (mean±SD)
|
38.6±14.5
|
41.2±13.3
|
37.3±15.0
|
0.10
|
41.8±12.9
|
37.7±14.9
|
0.13
|
Male (n,%)
|
137 (81.1%)
|
49 (87.5)
|
88 (77.9)
|
0.15
|
32 (88.8%)
|
105 (78.9%)
|
0.15
|
Types of burn
|
|
|
|
0.36
|
|
|
0.92
|
Heat (n,%)
|
111 (65.7%)
|
34 (60.7)
|
77 (68.1)
|
|
24 (66.%)
|
87 (65.3%)
|
|
Electrical (n,%)
|
12 (7.1%)
|
3 (5.4)
|
9 (8.0)
|
|
10 (27.7%)
|
36 (27.0%)
|
|
Chemical (n,%)
|
46 (27.2%)
|
19 (33.9)
|
27 (23.9)
|
|
2 (5.5%)
|
10 (7.5%)
|
|
Burn location and severity
|
Inhalation (n,%)
|
81 (47.9%)
|
42 (75.0)
|
39 (34.1)
|
<0.001
|
30 (83.3%)
|
51 (38.3%)
|
<0.001
|
Face & neck (n,%)
|
129 (76.3%)
|
53 (94.6)
|
76 (67.3)
|
<0.001
|
33 (91.6%)
|
96 (72.1%)
|
0.01
|
TBSAB (M, IQR)
|
60.0
(36.0, 81.0)
|
84.0
(71.3, 90.0)
|
45.0
(35.0, 64.0)
|
<0.001
|
85.0
(75.0, 91.5)
|
50.0
(33.0, 70.0)
|
<0.001
|
Full-thickness TBSAB (M, IQR)
|
20.0
(2.0, 47.4)
|
45.0
(28.0, 70.0)
|
10.0
(0.0, 30.0)
|
<0.001
|
50.0
(34.3, 80.0)
|
13.0
(0.0, 35.0)
|
<0.001
|
SOFA0 (M, IQR)
|
2.0
(1.0, 5.0)
|
4.0
(3.0, 6.0)
|
2.0
(0.0, 4.0)
|
<0.001
|
5.0
(2.3, 6.8)
|
2.0
(1.0, 4.0)
|
<0.001
|
Operation duration, min (M, IQR)
|
105.0 (60.0, 180.0)
|
145.0 (70.0, 222.5)
|
85.0 (45.0, 145.0)
|
0.001
|
155.0 (63.8, 231.3)
|
100.0 (60.0, 158.8)
|
0.02
|
Interval from burn to 1st operation, d (M, IQR)
|
3.0
(2.0, 7.0)
|
2.0
(1.0, 5.0)
|
4.0
(2.0, 7.3)
|
0.02
|
2.0
(1.0, 3.0)
|
4.0
(2.0, 8.0)
|
0.006
|
Legend: All, all the severely burned patients included, Bac, severely burned with bacteremia, Con, severely burned without bacteremia, TBSAB, total body surface area of burned, SOFA0, sequential organ failure assessment score on admission, M, median, IQR,interquartile range.
Table 2. Clinical outcome data of included patients
Variables
|
All (n= 169)
|
Bac (n=56)
|
Con (n=113)
|
P
|
ICU stay (d) (M, IQR)
|
0.0 (0.0, 1.0)
|
0.0 (0.0, 1.0)
|
0.0 (0.0, 0.0)
|
<0.001
|
LHS (d) (M, IQR)
|
36.0 (21.0, 55.0)
|
34.0(19, 54.0)
|
37.5(21.8, 58.5)
|
0.52
|
30-day all-cause mortality (n,%)
|
18 (10.7)
|
13.0 (23.2)
|
5.0 (4.4)
|
<0.001
|
90-day all-cause mortality (n,%)
|
36 (21.3)
|
24.0 (42.8)
|
12.0 (10.6)
|
<0.001
|
Legend: All, all the severely burned patients included, Bac, severely burned with bacteremia, Con, severely burned without bacteremia, ICU, intensive care unit, LHS, length of hospital stay, M, median, IQR, interquartile range.
2. Spectrum of pathogens in blood culture
As presented in Appended Table 1, the most commonly identified pathogenic bacteria and fungi in blood culture were Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. Infection by two or more pathogens was noted in 37.5% (21/56) of cases. The three pathogens associated with the highest mortality rate following infections were Escherichia coli, Stenotrophomonas maltophilia and Aspergillus. The most common pathogens identified in patients who died of infections were Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli.
3. Blood cell changes in severe burn patients with bacteremia during the perioperative period
As presented in the Table 3 and Appended Figure, monocytes, which increased transiently shortly after severe bun in the Bac group, decreased significantly with time. Compared with the Con group, the M0, WPR0 and NLR0 in the Bac group were significantly increased (P<0.05), whereas the M1, L1, M3 and L3 decreased significantly (P<0.05). The NLR3, T3-37 and ∆M (M0-M3) in the Bac group were significantly higher than those in the Con group (P<0.05).
Table 3. Perioperative laboratory results of included patients
Variables
|
All
(n= 169)
|
Bac
(n=56)
|
Con
(n=113)
|
P1
|
Deceased (n=36)
|
Survived (n=133)
|
P2
|
Preoperative laboratory results
|
M0 (M, IQR)
|
1.0 (0.7, 1.4)
|
1.1 (0.8, 1.6)
|
1.0 (0.6, 1.3)
|
0.03
|
1.3 (0.8, 1.9)
|
1.0 (0.6, 1.3)
|
0.002
|
L0 (M, IQR)
|
1.3 (0.9, 1.8)
|
1.4 (0.7, 2.0)
|
1.2 (0.9, 1.7)
|
0.63
|
1.3 (0.8, 1.9)
|
1.3 (0.9, 1.7)
|
0.70
|
WPR0 (×100)
(M, IQR)
|
8.5 (5.5, 13.8)
|
13.1 (6.7, 19.8)
|
7.2 (5.2, 11.5)
|
<0.001
|
13.1 (8.7, 18.3)
|
7.4 (5.0, 12.2)
|
<0.001
|
NLR0 (M, IQR)
|
9.1(6.3, 14.6)
|
11.2 (7.3, 17.7)
|
8.7 (6.1,12.7)
|
0.01
|
12.0 (8.3, 20.9)
|
8.7 (6.1, 13.3)
|
0.001
|
T0-37 (M, IQR)
|
1.2 (0.7, 1.9)
|
1.6±1.0
|
1.3±0.8
|
0.41
|
1.0 (0.6, 1.9)
|
1.2 (0.8, 1.9)
|
0.42
|
Laboratory results at postoperative day 1
|
M1(M, IQR)
|
0.7 (0.4, 1.0)
|
0.6 (0.3, 0.9)
|
0.7 (0.5, 1.1)
|
0.02
|
0.6 (0.3, 1.2)
|
0.7 (0.4, 1.0)
|
0.7194
|
L1 (M, IQR)
|
0.9 (0.6, 1.3)
|
0.7 (0.6, 1.1)
|
1.0 (0.7, 1.3)
|
0.005
|
0.8 (0.6, 1.3)
|
0.9 (0.6, 1.2)
|
0.3452
|
WPR1 (×100) (M, IQR)
|
2.4 (1.1, 9.3)
|
13.1 (5.4, 22.4)
|
1.3 (0.9, 2.5)
|
<0.001
|
8.5 (4.7, 19.3)
|
1.4 (0.7, 3.4)
|
<0.001
|
NLR1 (M, IQR)
|
8.6 (6.1, 12.8)
|
9.0 (6.2, 13.1)
|
8.6 (6.1, 12.8)
|
0.70
|
8.6 (6.8, 11.5)
|
8.7 (6.1, 13.1)
|
0.971
|
T1-37 (M, IQR)
|
1.8 (1.0, 2.2)
|
2.0 (1.3, 2.3)
|
1.7 (0.9, 2.2)
|
0.13
|
1.8 (1.0, 2.0)
|
1.8 (1.0, 2.3)
|
0.8724
|
Laboratory results at postoperative day 3
|
M3 (M, IQR)
|
0.7 (0.4, 1.0)
|
0.5 (0.3, 0.8)
|
0.8 (0.6, 1.2)
|
<0.001
|
0.5 (0.3, 0.8)
|
0.8 (0.5, 1.1)
|
0.0055
|
L3 (M, IQR)
|
0.9 (0.6, 1.4)
|
0.7 (0.5, 1.0)
|
1.1 (0.8, 1.6)
|
<0.001
|
0.6 (0.5, 1.0)
|
1.0 (0.8, 1.4)
|
0.0006
|
WPR3 (×100)(M, IQR)
|
6.2 (3.7, 12.0)
|
5.0 (3.4, 12.6)
|
6.4 (3.8,12.0)
|
0.64
|
4.3 (2.7, 9.9)
|
5.1 (2.6, 11.2)
|
0.8192
|
NLR3 (M, IQR)
|
8.5 (6.3, 12.8)
|
9.2 (7.3, 15.8)
|
7.9 (6.1, 11.4)
|
0.006
|
8.6 (6.6, 13.8)
|
8.4 (6.3, 12.6)
|
0.5885
|
T3-37 (M, IQR)
|
1.6 (0.8, 2.2)
|
2.1 (1.6, 2.4)
|
1.2 (0.4, 2.1)
|
<0.001
|
2.1 (1.6, 2.7)
|
1.4, (0.6, 2.1)
|
<0.001
|
∆M (M, IQR)
|
0.37 (-0.04, 0.86)
|
0.58 (0.25, 0.58)
|
0.26 (-0.25, 0.26)
|
<0.05
|
0.76 (0.3, 1.19)
|
0.27 (-0.17, 0.72)
|
<0.001
|
Legend: All, all the severe burned patients included, Bac, severe burned with bacteremia, Con, severe burned without bacteremia, M0/1/3, monocyte counts at the day before the first surgery/1 day after the first surgery/3 days after the first surgery, L0/1/3, lymphocyte counts at the day before the first surgery/1 day after the first surgery/3 days after the first surgery, WPR0/1/3, white blood cell-to-platelets ratios at the day before the first surgery/1 day after the first surgery/3 days after the first surgery, NLR0/1/3, neutrophil-to-lymphocyte ratios at the day before the first surgery/1 day after the first surgery/3 days after the first surgery, T0-37/T1-37/T3-37, deviation of temperature from 37 degrees Celsius at the day before the first surgery/1 day after the first surgery/3 days after the first surgery, ∆M, value of M0 minus M3, M, median, IQR, Interquartile range.
4. M3 and WPR0 were independently associated with bacteremia in patients with severe burns
Univariate analysis was performed with the development of bacteremia as the dependent variable, and variables that were significant at P<0.001 were further analyzed with multivariate regression analysis (Appended Table 1 and Table 3). As shown in Appended Table 2, SOFA0, WPR0, T3-37 and M3 were independent risk factors for the development of bacteremia in patients with severe burns. The model of risk of developing bacteremia after severe burn, which we termed Xbac, was as follows: Xbac = 0.181 × SOFA0 + 6.532 × WPR0-1.171 × M3 + 0.699 × ⎮T3-37⎮- 2.297. The goodness of fit (R2) for Xbac was 0.779 (P < 0.001). The ROC curve indicated that the AUC, specificity, sensitivity and Youden index for this model were 0.809 (95% CI 0.735-0.882), 83.3%, 64.1% and 47.4, respectively (Figure 2).
5. ∆M (M0-M3) is independently associated with 90-day mortality
As presented in Appended Table 3, TBSAB, SOFA0 and ∆M (M0-M3) were independently associated with 90-day mortality. The model for predicting 90-day mortality, which we termed X90d-m, was X90d-m= 0.055 × TBSAB + 0.301 × SOFA0 + 1.508 × ∆M - 7.196. The goodness of fit (R2) for X90d-m was 0.975 (P < 0.001). Under the optimal cutoff of 0.45, the AUC, specificity, sensitivity and Youden index were 0.882 (95% CI, 0.831-0.933), 86.7%, 65.4% and 52.1, respectively (Figure 3).
6. External validation of Xbac and X90d-m
No significant differences with regard to demographics and clinical data were observed between the training cohort and the validation cohort. The validation cohort was divided into the high-risk (p-H-Bac) and the low-risk (p-L-Bac) groups for bacteremia as determined by the Xbac model or the high-risk (p-H-D) and the low-risk (p-L-D) groups for 90-day mortality based upon the X90d-m model. As shown in Table 4, risk factors for bacteremia and 90-day mortality identified in the training cohort were also noted to be statistically significant between the P-H-Bac group and P-L-Bac group. TBSAB, SOFA0 and ∆M (M0-M3) were also found to be statistically significant between the p-H-D group and the p-L-D group . The ICU stay and 90-day mortality in the p-H-Bac group were significantly higher than those in the p-L-Bac group (all P<0.001). The Xbac discriminated bacteremia with an AUC of 0.797, specificity of 90.7% and sensitivity of 62.5%. The ICU stay (P<0.002) and 90-day mortality (P<0.001) in the p-H-D group were significantly higher than those in the p-L-D group. The X90d-m predicted 90-day mortality with an AUC of 0.873, specificity of 90.0% and sensitivity of 69.2%. Kaplan–Meier curve analysis showed significantly shorter survival times in the p-H-D group than in the p-L-D group (Figure 4).
Table 4. Comparisons of identified risk factors in the validation set
Variables
|
p-H-Bac
(n=91)
|
p-L-Bac
(n=100)
|
P1
|
p-H-D
(n=31)
|
p-L-D
(n=160)
|
P2
|
TBSAB
|
71.0 (55.0, 87.0)
|
50.0 (34.3, 68.5)
|
<0.001
|
90.0(77.0, 95.0)
|
57.0 (44.3, 70.8)
|
<0.001
|
SOFA0
|
3.0 (2.0, 4.0)
|
1.0 (0.0, 2.0)
|
<0.001
|
4.0 (3.0, 6.0)
|
2.0 (0.3, 3.0)
|
<0.001
|
∆M
|
0.62 (0.3, 0.97)
|
0.23 (-0.06, 0.64)
|
<0.001
|
1.1 (0.8, 2.0)
|
0.3 (0.0, 0.7)
|
<0.001
|
WPR0
|
6.7 (4.7, 11.1)
|
5.4 (3.8, 7.3)
|
0.003
|
6.1 (3.2, 7.3)
|
6.0 (4.1, 8.9)
|
0.35
|
M3
|
0.46 (0.3, 0.66)
|
0.78 (0.60, 1.03)
|
<0.001
|
0.5 (0.3, 0.9)
|
0.7 (0.4, 0.9)
|
0.29
|
T3-37
|
2.0 (1.3, 2.5)
|
1.1 (0.5, 1.9)
|
<0.001
|
2.1 (1.4, 2.4)
|
1.4 (0.6, 2.1)
|
<0.001
|
Legend: p-H-Bac, predicted high risk of bacteremia group, p-L-Bac, predicted low risk of bacteremia group, p-H-D, predicted high risk of deceased group, p-L-D, predicted low risk of deceased group, TBSAB, total body surface area of burn, SOFA0, sequential organ failure assessment score on admission, ∆M, value of monocyte count before the first surgery minus monocyte at 3 days after the first surgery, WPR0, white blood cell-to-platelets ratios at the day before the first surgery, M3, monocyte counts at 3 days after the first surgery, T3-37, deviation of temperature from 37 degrees Celsius at 3 days after the first surgery.