The association of the plasma iron and neuron-specific enolase combination and the 28-day neurological outcome after cardiopulmonary resuscitation: a prospective study of iron metabolism disturbances

doi:10.5847/wjem.j.1920-8642.2025.106

Abstract

Abstract:

BACKGROUND: Iron metabolism dyshomeostasis is associated with ferroptosis and ischemia-reperfusion injury. We aim to investigate post-cardiac arrest changes in plasma iron metabolism-related parameters and their prognostic value for 28-day neurological outcomes.

METHODS: In this prospective observational cohort study, plasma iron metabolism-related parameters (iron, ferritin, hepcidin, soluble transferrin receptor [sTfR], total iron binding capacity [TIBC], and transferrin saturation), interleukin-6, and neuron-specific enolase (NSE) were assessed in 120 patients after restoration of spontaneous circulation (ROSC) on days 1 and 3 of intensive care unit (ICU) admission and in 40 healthy controls. The primary outcome was poor 28-day neurological prognosis.

RESULTS: Compared to controls, post-ROSC patients exhibited significant plasma iron metabolism disturbances, including decreased iron, TIBC, transferrin saturation, with elevated hepcidin, ferritin, sTfR, interleukin-6, and NSE on day 1 after ICU admission (P<0.05 for all). On day 28 post-ROSC, patients with poor neurological outcomes (71/120) presented more pronounced alterations than those with good neurological outcomes. Binary logistic analysis revealed that a plasma iron concentration ≤11.2 µmol/L (odds ratio [OR] 0.607, 95% confidence interval [CI] 0.455-0.808) and an NSE concentration ≥20.5 ng/mL (OR 1.020, 95% CI 1.005-1.035) on day 1 of ICU admission were associated with 28-day poor neurological outcomes. The plasma iron-NSE combination showed better predictive performance (area under the curve=0.935, sensitivity 89.8%, specificity 84.5%).

CONCLUSION: Early post-ROSC plasma iron metabolism disturbances combined with NSE elevation were associated with the 28-day neurological prognosis, suggesting the therapeutic potential of targeting the iron metabolism pathway.

Key words: Cardiopulmonary resuscitation, Iron metabolism, Neurological outcome

Yi Jiang, Jianyong Wu, Ying Liu, Xianfei Ji, Ping Gong. The association of the plasma iron and neuron-specific enolase combination and the 28-day neurological outcome after cardiopulmonary resuscitation: a prospective study of iron metabolism disturbances[J]. World Journal of Emergency Medicine, 2025, 16(6): 559-566.

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Variables	Control	Good neurological outcome	Poor neurological outcome
Variables	(n=40)	(n=49)	(n=71)
Age, years	66 (43, 78)	67 (39, 81)	69 (41, 83)
Male	12 (30%)	24 (49%)	39 (55%)
Comorbidities
Hypertension	-	23 (47%)	30 (42%)
Coronary artery disease	-	14 (29%)	24 (34%)
Diabetes	-	7 (14%)	24 (34%)
Chronic pulmonary disease	-	2 (4%)	5 (7%)
Cardiac arrest cause
Others	-	14 (29%)	19 (27%)
Respiratory	-	12 (24%)	15 (21%)
Cerebral	-	6 (12%)	9 (13%)
Cardiac	-	17 (35%)	28 (39%)
Out-of-hospital CA	-	25 (51%)	40 (56%)
Witnessed CA	-	21 (43%)	23 (32%)
Initial cardiac rhythm
Ventricular tachycardia	-	3 (6%)	2 (3%)
Ventricular fibrillation	-	8 (16%)	7 (10%)
Asystole and pulseless activity	-	27 (55%)	25 (35%)
Unknown	-	11 (23%)	37 (52%)
CPR duration, min	-	10 (5, 21)	18 (10, 30)^a
Length of hospital stay, d	-	13 (4, 19)	6 (2, 12)^a
PaO₂/FiO₂	-	231 (156, 274)	173 (162, 238)^a
Lactate, mmol/L	-	2.5 (1.7, 5.0)	6.7 (2.7, 12.7)^a
Creatinine, μmol/L	-	109 (83, 137)	153 (104, 251)^a
SOFA score	-	6 (4, 9)	10 (9, 13)^a

Variables	Control (n=40)	Post-ROSC patients
Variables	Control (n=40)	Day 1 (n=120)	Day 3 (n=110)
Hepcidin, ng/mL	21.2 (20.0, 22.8)	160.4 (146.3, 178.2)^a	97.5 (79.1, 103.1)^ab
Ferritin, ng/mL	30.3 (29.5, 31.4)	216.6 (191.9, 235.7)^a	577.3 (553.5, 591.6)^ab
sTfR, nmol/L	15.1 (14.5, 15.5)	20.8 (17.3, 24.7)^a	20.4 (17.3, 22.6)^a
Iron, µmol/L	16.2 (14.5, 20.4)	7.7 (6.2, 10.0)^a	6.9 (5.4, 9.3)^a
TIBC, µmol/L	46.6 (42.1, 49.3)	35.9 (27.8, 42.4)^a	34.6 (24.7, 43.2)^a
Transferrin saturation, %	37 (32, 42)	22 (17, 29)^a	22 (15, 31)^a
IL-6, pg/mL	5.3 (3.8, 6.6)	105.5 (46.7, 144.6)^a	64.2 (31.1, 88.8)^ab
NSE, ng/mL	9.2 (7.6, 11.3)	33.5 (17.1, 111.7)^a	97.0 (22.6, 172.3)^ab

Variables	Good neurological outcome		Poor neurological outcome
Variables	Day 1 (n=49)	Day 3 (n=49)	Day 1 (n=71)	Day 3 (n=61)
Hepcidin, ng/mL	146.1 (124.6, 155.4)	84.8 (69.7, 95.7)^a	171.2 (160.0, 188.3)^b	99.7 (95.3, 105.3)^ab
Ferritin, ng/mL	182.8 (65.5, 204.8)	572.4 (534.6, 586.2)^a	227.5 (214.8, 242.5)	582.0 (558.2, 595.1)^a
sTfR, nmol/L	21.7 (17.3, 24.7)	20.8 (16.9, 23.2)	19.9 (16.9, 24.7)	20.3 (17.3, 22.5)
Iron, µmol/L	8.7 (6.5, 11.7)	7.8 (5.6, 11.3)	7.5 (6.0, 8.9)^b	6.5 (4.9, 8.7)^b
TIBC, µmol/L	36.0 (31.0, 44.6)	37.0 (29.8, 42.3)	35.8 (24.7, 41.1)	33.1 (22.2, 43.5)
Transferrin saturation, %	22 (16, 31)	23 (15, 31)	22 (18, 27)	21 (15, 31)
IL-6, pg/mL	43.2 (34.7, 101.1)	27.9 (23.1, 59.8)^a	130.2 (100.7, 148.4)^b	77.0 (78.0, 188.0)^ab
NSE, ng/mL	16.9 (15.5, 21.4)	22.7 (19.4, 112.9)^a	66.1 (31.9, 263.0)^b	99.7 (78.0, 188.0)^ab

Variables	β	Wald	P-value	OR	95% CI
IL-6	0.017	4.672	0.031	1.017	1.002-1.033
Hepcidin	0.038	4.994	0.025	1.038	1.005-1.073
Ferritin	0.024	4.162	0.041	1.024	1.001-1.048
Iron	-0.500	11.666	0.001	0.607	0.455-0.808
NSE	0.020	6.841	0.009	1.020	1.005-1.035
SOFA score	0.400	4.315	0.038	1.491	1.023-2.175
Constant	-13.024	14.637	<0.001	0.000

Variables	AUC	95% CI	Cut-off	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Youden (%)	PLR	NLR
IL-6	0.832^a	0.753-0.911	63.1 pg/mL	91.5	67.3	80.3	84.6	58.8	2.80	0.13
Hepcidin	0.843^b	0.767-0.919	152.0 ng/mL	93.0	65.3	79.5	86.5	58.3	2.68	0.11
Ferritin	0.769^c	0.676-0.862	203.7 ng/mL	84.5	69.4	80.0	75.6	53.9	2.76	0.22
Iron	0.852^d	0.782-0.922	11.2 µmol/L	98.6	61.2	78.7	96.8	59.8	2.54	0.02
NSE	0.845^e	0.776-0.915	20.5 ng/mL	87.3	73.5	82.7	80.0	60.8	3.29	0.17
SOFA score	0.797^f	0.716-0.878	9.5	66.2	83.7	75.5	63.1	49.9	4.06	0.40
Iron+NSE	0.935	0.895-0.975	-	89.8	84.5	92.3	80.0	74.3	5.79	0.12