Effect of Early versus Delayed Use of Norepinephrine on Short-Term Outcomes in Patients with Traumatic Hemorrhagic Shock: A Propensity Score Matching Analysis

Figures & data

Figure 1 Flowchart of study design and patient selection.

Table 1 Comparison of Baseline Data of Patients Between Early Norepinephrine and Delayed Norepinephrine Before and After Propensity Score Matching

Variables	Before PSM			After PSM
	EN (n=176)	DN (n =180)	P-value	EN (n =154)	DN (n =154)	P-value
Age, years, (mean±SD)	48.5±15.8	50.0±13.1	0.006	50.2±12.4	51.0±11.5	0.512
Male sex, n (%)	93(52.8)	96(53.3)	0.926	78(50.6)	79(51.3)	0.744
CCI, point, median (IQR)	7(6–9)	7(6–9)	0.882	7(5–9)	8(6–9)	0.082
BMI, kg m^−2, median (IQR)	23.5(22.0–26.9)	23.5(22.0–26.9)	0.819	22.5(21.1–25.4)	22.5(21.4–25.9)	0.800
Complication, n (%)
Hypertension	58(32.9)	69(38.3)	0.001	54(35.1)	52(33.8)	0.709
Myocardial infarction	53(30.1)	48(26.7)	0.471	46(30.1)	45(26.7)	0.334
Congestive heart failure	51(29.0)	53(29.4)	0.932	43(30.0)	44(28.6)	0.632
Chronic pulmonary disease	43(24.4)	48(26.7)	0.629	38(24.6)	39(25.3)	0.504
Diabetes mellitus	41(23.3)	44(24.4)	0.799	36(23.4)	37(24.0)	0.321
Kidney disease	33(18.8)	37(20.6)	0.668	28(18.2)	29(18.8)	0.409
Cancer	6(3.4)	7(3.9)	0.809	4(2.6)	5(3.2)	0.422
Leukemia	9(5.1)	9(5.0)	0.961	6(3.9)	8(5.2)	0.221
Lymphoma	17(9.7)	23(12.8)	0.352	12(7.8)	14(9.1)	0.074
Metastatic cancer	21(11.9)	18(10.0)	0.560	16(10.4)	15(9.7)	0.177
Mechanism of injury, blunt, n (%)	144(81.8)	162(90.0)	0.008	134(87.0)	136(88.3)	0.428
Cause of injury, n (%)
Motor vehicles	40(22.7)	42(23.3)	0.892	35(22.7)	36(22.3)	0.118
Bikes	70(39.8)	73(40.6)	0.880	65(42.2)	64(41.6)	0.647
Pedestrian	25(14.2)	22(12.2)	0.380	21(13.6)	18(11.7)	0.209
Fall	36(20.5)	38(21.1)	0.879	31(20.1)	29(18.8)	0.355
Other	5(2.8)	5(2.8)	0.971	3(1.9)	4(2.6)	0.090
Pre-hospital status, median (IQR)
MAP (mmHg)	55(54.3–56.8)	59(56.2–59.7)	0.002	56(55.1–58.2)	55(54.1–56.3)	0.425
HR (beats min^−1)	105(104–110)	106(105–111)	0.551	102(100–109)	104(102–107)	0.633
Fluid amount (mL)	500(250–1000)	500(350–1000)	0.652	550(350–1000)	550(450–1000)	0.704
Intubation, n (%)	19(10.8)	21(11.7)	0.436	12(7.8)	13(8.4)	0.092
Initial GCS score, point	8(6–11)	13(10–15)	0.003	13(10–15)	14(11–15)	0.087
On-admission status, median (IQR)
MAP (mmHg)	58(55.8–61.2)	62(57.2–63.5)	0.001	62(59.2–64.5)	63(60.2–65.8)	0.644
HR (beats min^−1)	99(98–106)	98(96–105)	0.604	97(95–102)	98(96–103)	0.544
Intubation, n (%)	14(8.0)	16(8.9)	0.280	12(7.8)	10(6.5)	0.406
Initial GCS score, point	14(11–15)	14(10–15)	0.654	13(10–14)	12(11–15)	0.864
Hemoglobin, g dL^−1	6(4.9–9.4)	7(5.1–9.6)	0.001	7(6.8–11.6)	9(8.9–11.8)	0.325
Blood glucose, mg dL^−1	167(138.0–182.0)	167(141.5–182.0)	0.305	166(139.0–190.0)	168(148.5–192.0)	0.505
Blood lactate, mmol L^−1	3.7(3.2–4.1)	3.7(3.2–4.1)	0.705	3.9(3.4–4.5)	3.8(3.5–4.8)	0.542
Serum creatinine, mg dL^−1	1.5(1.3–1.8)	1.5(1.3–1.8)	0.847	1.4(1.2–1.7)	1.5(1.2–1.9)	0.759
Severity scores, point, median (IQR)
SOFA score 1st day	7(5–8)	9(7–9)	0.042	7(5–8)	8(7–9)	0.468
ISS score 1st day	23(16–38)	26(16–36)	0.021	30(19–42)	29(18–38)	0.074
APACHE III score 1st day	74(61.0–79.5)	78(63.0–81.0)	0.015	74(61.0–82.0)	75(62.0–81.0)	0.080
NE use, median (IQR)
Timing, hour	2.2(1.7–2.5)	4.3(3.7–6.5)	<0.001	2.3(1.7–2.5)	4.4(3.8–6.5)	<0.001
Maximum NE rate within 24h, ug kg^−1 min^−1	0.6(0.2–1.1)	0.6(0.3–1.0)	0.705	0.5(0.3–1.0)	0.6(0.2–1.1)	0.420
Total dose within 24h, mg	31(24–72)	30(20–72)	0.940	30(23–70)	31(24–73)	0.722
Target MAP need time, hour	8.2(6.4–10.4)	16.0(13.9–24.0)	<0.001	8.2(6.3–9.9)	15.0(12.6–17.0)	<0.001
Fluid resuscitation within 24h, median (IQR)
RBC, mL	1050(750–1650)	1350(750–1650)	0.629	1100(850–1800)	1250(765–1950)	0.084
Lyophilized plasma, mL	900(500–1100)	950(650–1150)	0.080	910(580–1150)	965(750–1020)	0.064
Fibrinogen, g	3(0–3)	3(0–3)	0.901	3(0–3)	3(0–3)	0.804
Platelet, units	2(0–2)	2(0–2)	0.899	1(0–2)	2(0–2)	0.083
Total of non-blood fluid infusion, mL	3027(1991–4492)	3760(2691–4637)	0.004	2930(1807–4451)	3770(2691–4637)	<0.001
Total of all fluid infusion, mL	5150(4041–7152)	6672(4700–7430)	<0.001	5155(4150–7200)	6500(4850–7690)	<0.001
Damage control surgery, n (%)	58(33.0)	60(33.3)	0.843	54(35.1)	59(38.3)	0.116

Abbreviations: PSM, propensity score matching; EN, early norepinephrine; DN, delay norepinephrine; SD, standard deviation; CCI, Charlson comorbidity index; BMI, body mass index; MAP, mean arterial pressure; HR, heart rate; GCS, Glasgow Coma Scale; SOFA, sequential organ failure assessment; ISS, injury severity score; APACHE, acute physiology, age, chronic health evaluation; RBC, red blood cell; NE, norepinephrine.

Figure 2 Comparison of the characteristics of patients in the early group and the delayed group. The timing of norepinephrine use (A); Target mean arterial pressure need time (B); APACHE III score 1st day (C); SOFA score 1st day (D); The total of non-blood fluid infusion (E); Total of all fluid infusion (F). ^###Compared with dEN, P<0.001.

Abbreviations: MAP, mean arterial pressure, APACHE, acute physiology, age, chronic health evaluation. SOFA, sequential organ failure assessment. eNE, early norepinephrine; dNE, delay norepinephrine.

Table 2 Comparison of Clinical Outcomes of Patients Between Early Norepinephrine and Delayed Norepinephrine Before and After Propensity Score Matching

Outcomes	Before PSM			After PSM
	EN (n=176)	DN (n=180)	P-value	EN (n=154)	DN (n=154)	P-value
Primary endpoints
24-hour mortality, n (%)	54(30.7)	81(45.0)	<0.001	46(29.9)	69(44.8)	<0.001
Secondary endpoints
In-hospital mortality, n (%)	38(21.6)	43(23.8)	0.072	32(18.2)	39(25.3)	0.065
Acute kidney injury within 24h, n (%)	40(22.7)	45(25.0)	0.053	36(23.4)	40(26.0)	0.054
Continuous renal replacement therapy-free day, median (IQR)	15(12–21)	12(10–18)	0.062	16(13–22)	13(11–19)	0.074
Invasive mechanical ventilation-free day, median (IQR)	20(16–24)	18(14–21)	0.112	21(18–25)	19(16–22)	0.114
Hospital length of stay, day, median (IQR)	14(9–16)	15(12–23)	0.125	14(10–15)	14(12–21)	0.216
ICU length of stay, day, median (IQR)	5(3–7)	6(4–10)	0.420	5(2–7)	6(6–9)	0.337

Abbreviations: PSM, propensity score matching; EN, early norepinephrine; DN, delay norepinephrine; ICU, intensive care unit; IQR, interquartiles (25–75).

Figure 3 Receiver operating characteristic (ROC) curves of ISS score (A), APACHE III (B), SOFA score (C), Total of non-blood fluid infusion (D), Total of all fluid infusion (E), and Timing of NE use (F) for 24h mortality in patients with THS.

Abbreviations: ISS, injury severity score; APACHE, acute physiology, age, chronic health evaluation; SOFA, sequential organ failure assessment; NE, norepinephrine.

Table 3 The Streg Regression Model Analysis Based on Traumatic Hemorrhagic Shock Patients with 24 Hour-Mortality

Variables	HR	95% CI	Z-value	P-value
ISS score 1st day	1.04	1.02–1.06	4.39	<0.001
APACHE III score 1st day	1.03	1.01 −1.04	3.24	0.002
Sofa score 1st day	1.18	1.02–1.36	2.11	0.023
Initial blood lactate	1.22	1.09–1.36	3.97	<0.001
Total of non-blood fluid infusion	1.00	0.92–1.11	2.88	0.008
Delay norepinephrine	1.24	1.13–1.36	3.04	0.004

Abbreviations: HR, hazard ratio; CI, confidence interval; ISS, injury severity score; SOFA, sequential organ failure assessment; APACHE, acute physiology, age, chronic health evaluation.

Figure 4 Kaplan-Meier survival estimates based on 24h mortality. After propensity score matching (A); Before propensity score matching (B).