The Association Between Serum Anion Gap and All-Cause Mortality in Disseminated Intravascular Coagulation Patients: A Retrospective Analysis

Figures & data

Table 1 Baseline Characteristics of Participants

AG, mmol/L	Group 1 (4.00–11.00)	Group 2 (12.00–13.00)	Group 3 (14.00–17.00)	Group 4 (18.00–48.00)	P-value	P-value*
Number	642	540	787	685
Age, mean (SD), years	61.03 (15.78)	61.51 (16.79)	60.50 (16.46)	59.42 (15.91)	0.123	0.073
Weight, mean (SD), kg	77.78 (18.99)	80.04 (19.95)	81.20 (21.17)	83.15 (23.38)	<0.001	0.001
Sex, n (%)
Female	270 (42.06%)	214 (39.63%)	345 (43.84%)	253 (36.93%)	0.047	-
Male	372 (57.94%)	326 (60.37%)	442 (56.16%)	432 (63.07%)
Ethnicity, n (%)
White	451 (70.25%)	379 (70.19%)	532 (67.60%)	445 (64.96%)	0.002	-
Black	27 (4.21%)	52 (9.63%)	56 (7.12%)	53 (7.74%)
Hispanic	38 (5.92%)	20 (3.70%)	28 (3.56%)	25 (3.65%)
Asian	22 (3.43%)	17 (3.15%)	27 (3.43%)	22 (3.21%)
Others	104 (16.20%)	72 (13.33%)	144 (18.30%)	140 (20.44%)
Causes of DIC
Sepsis	307 (47.82%)	275 (50.93%)	458 (58.20%)	467 (68.18%)	<0.001	-
Cardiovascular diseases	164 (25.55%)	106 (19.63%)	108 (13.72%)	57 (8.32%)
Trauma	29 (4.52%)	33 (6.11%)	46 (5.84%)	35 (5.11%)
Others	142 (22.12%)	126 (23.33%)	175 (22.24%)	126 (18.39%)
Scoring systems, mean (SD)
SOFA	6.57 (2.71)	6.90 (2.95)	7.88 (3.48)	10.26 (4.10)	<0.001	<0.001
SAPSII	37.83 (13.18)	39.26 (13.80)	42.87 (14.90)	52.37 (17.08)	<0.001	<0.001
JAAM-DIC	4.72 (0.74)	4.79 (0.79)	4.93 (0.94)	5.12 (1.04)	<0.001	<0.001
SIRS	2.92 (0.94)	3.04 (0.94)	3.15 (0.88)	3.30 (0.82)	<0.001	<0.001
Comorbidities, n (%)
Hypertension	286 (44.55%)	230 (42.59%)	336 (42.69%)	270 (39.42%)	0.292	-
COPD	109 (16.98%)	77 (14.29%)	128 (16.26%)	80 (11.68%)	0.028	-
Diabetes	113 (17.60%)	119 (22.04%)	165 (20.97%)	176 (25.69%)	0.004	-
Renal failure	49 (7.63%)	57 (10.58%)	111 (14.10%)	120 (17.52%)	<0.001	-
Liver disease	203 (31.62%)	159 (29.50%)	282 (35.83%)	330 (48.18%)	<0.001	-
MBP, mean (SD), mmHg	76.68 (9.93)	77.61 (10.80)	77.90 (11.38)	76.93 (12.37)	0.145	0.097
Temperature, mean (SD),°C	36.87 (0.63)	36.97 (0.72)	36.90 (0.71)	36.71 (0.86)	<0.001	<0.001
SPO2, mean (SD), %	97.61 (2.26)	97.56 (2.14)	97.19 (2.29)	96.39 (4.96)	<0.001	<0.001
Laboratory parameters, mean (SD)
Hemoglobin, g/dL	9.51 (1.93)	9.91 (2.04)	9.95 (2.32)	10.31 (2.37)	<0.001	<0.001
Hematocrit, %	27.83 (5.68)	28.99 (5.89)	29.16 (6.96)	30.61 (7.09)	<0.001	<0.001
RDW, %	15.73 (2.38)	16.05 (2.68)	16.25 (2.70)	16.42 (2.79)	<0.001	<0.001
Platelet, 10^9/L	88.06 (70.73)	89.53 (71.87)	99.30 (96.94)	118.63 (139.91)	<0.001	<0.001
WBC, 10^9/L	10.05 (17.82)	9.65 (12.01)	12.72 (26.68)	13.60 (15.69)	<0.001	<0.001
APTT, seconds	45.05 (25.22)	42.89 (23.54)	44.11 (25.72)	50.58 (29.90)	<0.001	<0.001
PT, seconds	17.17 (4.52)	16.67 (3.97)	17.56 (6.96)	20.15 (10.49)	<0.001	<0.001
PT-INR	1.67 (0.62)	1.76 (3.08)	1.76 (0.94)	2.13 (1.36)	<0.001	<0.001
Creatinine, mEq/L	0.88 (0.52)	1.11 (1.00)	1.52 (1.22)	2.57 (2.33)	<0.001	<0.001
Urea nitrogen, mg/dL	19.98 (13.25)	22.94 (14.29)	30.36 (20.67)	46.72 (35.80)	<0.001	<0.001
Glucose, mg/dL	140.14 (63.39)	138.80 (54.79)	152.98 (71.68)	167.25 (97.83)	<0.001	<0.001
Potassium, mmol/L	4.15 (0.82)	4.05 (0.77)	4.12 (0.78)	4.39 (0.92)	<0.001	<0.001
Sodium, mmol/L	136.81 (5.34)	138.18 (4.93)	137.61 (5.43)	138.03 (6.26)	<0.001	<0.001
Bicarbonate, mg/dL	23.99 (3.80)	23.02 (3.75)	21.36 (4.22)	17.30 (4.90)	<0.001	<0.001
Treatments, n (%)
CRRT	13 (2.02%)	19 (3.52%)	63 (8.01%)	131 (19.12%)	<0.001	-
Vasopressor drugs	315 (49.07%)	255 (47.22%)	369 (46.89%)	439 (64.09%)	<0.001	-
Mechanical ventilation	432 (67.29%)	358 (66.30%)	502 (63.79%)	509 (74.31%)	<0.001	-
In-hospital mortality, n (%)	91 (14.17%)	97 (17.96%)	174 (22.11%)	311 (45.40%)	<0.001	-
30-day mortality, n (%)	97 (15.11%)	98 (18.15%)	197 (25.03%)	314 (45.84%)	<0.001	-
90-day mortality, n (%)	138 (21.50%)	146 (27.04%)	251 (31.89%)	356 (51.97%)	<0.001	-

Note: P* indicated U-test.

Abbreviations: AG, anion gap; SOFA, sequential organ failure assessment; SAPSII, simplified acute physiology score II; JAAM, Japanese Association of Acute Medicine; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; COPD, chronic obstructive pulmonary disease; MBP, mean blood pressure; RDW, red blood cell distribution; WBC, white blood cell; APTT, activated partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio; CRRT, continuous renal replacement therapy.

Figure 1 Flowchart of subject screening.

Table 2 Univariate and Multivariate Results by Cox Regression

Exposure	Non-Adjusted Model HR, 95% CI, P	Minimally-Adjusted Model HR, 95% CI, P	Fully-Adjusted Model HR, 95% CI, P
In-hospital mortality
Anion gap	1.08 (1.07–1.10) <0.0001	1.09 (1.07–1.10) <0.0001	1.05 (1.04–1.07) <0.0001
Anion gap (quartiles)
Q1	1.0 (Ref)	1.0 (Ref)	1.0 (Ref)
Q2	1.19 (0.90–1.59) 0.2268	1.17 (0.88–1.56) 0.2719	1.07 (0.80–1.44) 0.6444
Q3	1.32 (1.02–1.70) 0.0336	1.32 (1.02–1.70) 0.0340	1.02 (0.78–1.33) 0.8943
Q4	2.92 (2.31–3.69) <0.0001	3.00 (2.37–3.79) <0.0001	1.83 (1.38–2.43) <0.0001
P for trend	1.47 (1.37–1.59) <0.0001	1.49 (1.38–1.61) <0.0001	1.22 (1.11–1.34) <0.0001
30-day mortality
Anion gap	1.10 (1.08–1.11) <0.0001	1.10 (1.09–1.11) <0.0001	1.06 (1.04–1.07) <0.0001
Anion gap (quartiles)
Q1	1.0 (Ref)	1.0 (Ref)	1.0 (Ref)
Q2	1.22 (0.92–1.62) 0.1586	1.22 (0.92–1.62) 0.1635	1.06 (0.79–1.41) 0.6963
Q3	1.74 (1.37–2.22) <0.0001	1.76 (1.38–2.24) <0.0001	1.23 (0.95–1.59) 0.1122
Q4	3.92 (3.12–4.92) <0.0001	4.04 (3.22–5.08) <0.0001	1.97 (1.49–2.60) <0.0001
P for trend	1.64 (1.52–1.77) <0.0001	1.66 (1.54–1.79) <0.0001	1.26 (1.15–1.39) <0.0001
90-day mortality
Anion gap	1.09 (1.08–1.10) <0.0001	1.09 (1.08–1.10) <0.0001	1.05 (1.03–1.07) <0.0001
Anion gap (quartiles)
Q1	1.0 (Ref)	1.0 (Ref)	1.0 (Ref)
Q2	1.29 (1.02–1.63) 0.0306	1.29 (1.02–1.63) 0.0320	1.15 (0.91–1.46) 0.2496
Q3	1.59 (1.29–1.96) <0.0001	1.61 (1.31–1.98) <0.0001	1.15 (0.92–1.43) 0.2170
Q4	3.27 (2.69–3.99) <0.0001	3.39 (2.78–4.13) <0.0001	1.73 (1.35–2.20) <0.0001
P for trend	1.50 (1.41–1.60) <0.0001	1.52 (1.43–1.62) <0.0001	1.18 (1.09–1.28) <0.0001

Notes: Non-adjusted model: no covariates were adjusted for. Minimally-adjusted model: we only adjusted for age and sex. Fully-adjusted model: we adjusted for age, sex, ethnicity, causes of DIC, SOFA score, SAPSII score, renal failure, CRRT, vasopressor drugs, mechanical ventilation, APTT, PT-INR, bicarbonate, creatinine, potassium, urea nitrogen, and RDW.

Abbreviations: CI, confidence interval; Ref, reference.

Figure 2 Non-linear relationship between AG and in-hospital mortality (A), 30-day mortality (B), and 90-day mortality (C) of DIC patients.

Table 3 Subgroup Analysis of the Relationship Between AG and 30-Day Mortality

Characteristic	Number of Patients	HR (95% CI)	P-value	P for Interaction
Sex
Female	1,050	1.05 (1.03–1.08)	<0.0001	0.7543
Male	1,530	1.06 (1.04–1.08)	<0.0001
Age (years)
<60	1,226	1.06 (1.04–1.09)	<0.0001	0.2294
≥60	1,354	1.04 (1.02–1.07)	0.0005
Care unit
CCU	196	1.02 (0.93–1.11)	0.7084	0.4727
CSRU	476	1.14 (1.03–1.25)	0.0084
MICU	1,268	1.05 (1.02–1.07)	0.0004
SICU	386	1.05 (1.00–1.10)	0.0469
TSICU	263	1.07 (1.00–1.13)	0.0505
Causes of DIC
Sepsis	1,465	1.04 (1.02–1.06)	0.0003	0.1526
Cardiovascular diseases	424	1.11 (1.02–1.21)	0.0126
Trauma	140	1.09 (1.00–1.19)	0.0582
Others	551	1.09 (1.04–1.15)	0.0004
COPD
No	2,193	1.05 (1.03–1.07)	<0.0001	0.3802
Yes	387	1.08 (1.03–1.13)	0.0028
Diabetes
No	2,091	1.05 (1.03–1.07)	<0.0001	0.2487
Yes	561	1.08 (1.04–1.12)	0.0003
Renal failure
No	2,254	1.05 (1.03–1.07)	<0.0001	0.0310
Yes	326	1.10 (1.06, 1.14)	<0.0001
CRRT use
No	2,359	1.06 (1.03–1.08)	<0.0001	0.7379
Yes	221	1.05 (1.01–1.08)	0.0053
Vasopressor drugs use
No	1,229	1.05 (1.02–1.09)	0.0023	0.9986
Yes	1,351	1.05 (1.03–1.08)	<0.0001
Mechanical ventilation use
No	810	1.07 (1.04– 1.11)	0.0001	0.2795
Yes	1,770	1.05 (1.03–1.07)	<0.0001

Abbreviations: CCU, Coronary Care Unit; CSRU, Cardiac Surgery Recovery Unit; MICU, Medical Intensive Care Unit; SICU, Surgical Intensive Care Unit; TSICU, Trauma/Surgical Intensive Care Unit; DIC, disseminated intravascular coagulation; COPD, chronic obstructive pulmonary disease; CRRT, continuous renal replacement therapy.