Plasma Interleukin 6 Levels Predict Long-term Mortality in Aneurysmal Subarachnoid

doi:10.21203/rs.3.rs-1547705/v1

OBJECTIVE: Interleukin 6 (IL-6) is an inflammatory cytokine released into the periphery after stroke, involved in the prognosis of aneurysmal subarachnoid hemorrhage (aSAH). We aimed to explore the relationship between serum IL-6 with long-term mortality after aSAH.

METHODS: We retrospectively reviewed the medical records of 18824 SAH patients for collection of serum IL-6 levels during hospitalization from a large, single-center aSAH database of Sichuan University West China Hospital. Patient deaths were determined through a national death record registration system. The primary outcome was long-term mortality. Cox regression models were used to investigate univariate and multivariate relationships between predictors and outcomes. A propensity score-matched analysis was conducted to minimize bias from confounding variables.

RESULTS: In total, we included 1131 aSAH patients with 3288 records of IL-6 collections. Initial serum IL-6 values were elevated in all, ranging from 1.50 to 4522.00 pg/ml. After logarithmic transformation, the IL-6 was associated with long-term mortality (HR 1.32, 95% CI 1.21-1.44). The results maintained significant in the multivariate cox regression and propensity score-matched analysis (adjusted HR 1.23, 95% CI 1.11-1.36, p<0.001; IL-6 >103.00 pg/ml vs IL-6≤103. 00 pg/ml, PSM HR 1.94, 95% CI 1.48-2.55, p<0.001). Similar results were observed in the long-term mortality of survivors at discharge and 1-year mortality.

CONCLUSIONS: Serum IL-6 is independently associated with long-term mortality of aSAH patients. Our study provided new evidence for the investigation of inflammation after aSAH and the association of inflammatory cytokines with the long-term prognosis of aSAH and might support future management decisions.

intracranial aneurysm

subarachnoid hemorrhage

prognosis

interleukin

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating disease with high mortality and disability. Owing to the improvement in clinical management, short-term mortality has declined to approximately 25–30%[1, 2]. However, even after an initially favorable recovery from aSAH, survivors still experience a 1.5-fold excess long-term mortality in comparison to the general population[3]. As reported in 2014, long-term mortality of aSAH is 17.9% at 10 years, 29.5% at 15 years, and 43.6% at 20 years after aSAH[4]. Previous data for long-time outcomes of aSAH are scarce. Thus, finding a biomarker to identify patients at high risk of long-term mortality and facilitate prompt preventive strategies to improve prognosis is urgently required.

In general, an overactive immune response after aSAH put aSAH patients at risk for poor outcomes[5–8]. Of the various cytokines, interleukin 6 is abnormally elevated after aSAH in both cerebrospinal fluid (CSF) and peripheral blood[9, 10]. Several studies have revealed that aSAH patients with high serum IL-6 levels were more likely to develop complications and suffer unfavorable short-term outcomes[11–13]. Till now, there has been no investigation into the association between serum IL-6 and long-term mortality of aSAH. Our study aimed to examine the association between serum IL-6 and long-term mortality in aSAH patients in a large, single-center cohort with accurate and complete long-term data, obtained from the Household Registration Administration System, a national death record registration system.

Study Design and Data Source

We conducted a retrospective observational study from January 2009 to June 2019 using the electronic health record system of Sichuan University West China Hospital. Data was retrieved with the assistance of the information department, including medical history, diagnoses, resident admission notes, discharge notes, and laboratory and imaging examinations. The study was approved by the West China Hospital Institutional Review Board, with a waiver of informed consent due to minimal risk to patients. Treatment of patients was carried out according to standardized guidelines[14, 15].

Patient Selection

Patients diagnosed with aSAH were included in this study. SAH was identified by neuroimaging, including computed tomography, magnetic resonance imaging, angiography, or cerebrospinal fluid test. Aneurysms were identified by cerebral angiography, magnetic resonance angiography, or computed tomography angiography.

Exclusion criteria included (1) aneurysms caused by trauma or arteriovenous malformations, (2) fusiform aneurysms and nondefinitive aneurysms, and (3) aneurysms treated before ictus, (4) patients without peripheral IL-6 measurements, and (5) record of death missing.

Exposure variable

The exposure variable of this study was serum IL-6. Peripheral blood was collected and measured for serum IL-6 by the West China Hospital Stroke Unit as an alternative infection biomarker as part of a hospital-wide clinical initiative. We collected all IL-6 records during hospitalization. There were 3288 records of IL-6 collections in total. We divided them into five phases: T1 (< 24h) n = 156, T2 (24-72h) n = 356, T3 (day3-6) n = 986, T4 (day7-14) n = 1139 and T5 (day15-30) n = 654. We explored peak IL-6 levels during hospitalization for each patient and furtherly examined the correlation between peak IL-6 levels at five phases with the primary outcome.

Primary and secondary outcomes

The primary outcome was long-term mortality (defined as all-cause mortality at the longest follow-up). Secondary outcomes were mortality at discharge, short-term mortality (defined as 1-year mortality), short-term and long-term mortality in survivors at discharge, and in-hospital neurological complications. Neurological complications included delayed cerebral ischemia, rebleeding, seizures, and hydrocephalus.

Delayed cerebral ischemia was defined as a new focal neurological impairment or a new infarct on CT or MRI, not attributable to other causes. Rebleeding was defined as increased hemorrhage volume confirmed by a repeat computed tomography or magnetic resonance imaging scan.

Follow-up

We used personal identification numbers to identify death records from Sichuan province's Household Registration Administration System. All death records were extracted through the Household Registration System, which should document a citizen’s date of death within one month as required. Therefore, it drastically reduced the loss of follow-up in this study. Suppose the identification number of patients in the electronic medical record system was wrong or non-existent, or their household registration was not in Sichuan province, their household registration cannot be found and these patients are excluded from the study. The median follow-up was 3.8 years for all participants, the longest follow-up period was 10.2 years, and the censoring date was April 1, 2021.

Statistical Analysis

Serum IL-6 levels were log-normalized and boxplots were drawn to illustrate the time course during 1-month hospitalization. For subgroup analysis of different aSAH patient-associated characteristics, post-SAH complications, and clinical outcomes, data were dichotomized into two groups and analyzed by unpaired t-test.

Baseline cohort characteristics were presented as proportions and means (SDs) or medians (interquartile ranges). We computed between-group comparisons with ANOVA or chi-square test. All tests of significance were 2-sided, and P < 0.05 was considered statistically significant. Multiple imputations were used to impute missing data of continuous variables, and for categorical variables, missing data were coded as other.

We performed Cox regression models to analyze unadjusted and adjusted associations between outcomes and IL-6 levels in each group. Univariable Cox regression was utilized to determine factors influencing the outcomes (P < 0.10), implemented into a multivariable Cox regression model. Factors were considered independently associated when they remained statistically significant. Confounders adjusted in the multivariable model were examined in previous studies and clinical practice, including age, sex, smoking, alcohol abuse, hypertension, diabetes mellitus, coronary heart disease (CHD), chronic obstructive pulmonary disease (COPD), chronic renal failure (CRF), aneurysm location (anterior circulation, posterior circulation), size of the aneurysm, systolic blood pressure (SBP), blood glucose, Hunt & Hess grade, Fisher grade, external ventricular drain, and operation of the aneurysm (no treatment, clip, coil). Additionally, we added in-hospital infection as a confounder for sensitivity analysis to examine whether serum IL-6 was associated with mortality in aSAH patients independently of in-hospital infection.

Furthermore, we developed a propensity score matching to minimize bias using all confounders. Patients were stratified by the cut-off value of IL-6 levels. We performed a 1:1 nearest neighbor matching without replacement with the caliper width set as 0.20 SD. Characteristics of both groups were compared using standardized mean difference, and a difference > 0.1 was considered meaningful.

Kaplan-Meier curves and log-rank tests of the time to event data were used to examine mortality at the longest follow-up. Whether the association between IL-6 and long-term mortality differed across various subgroups was determined by subgroup analysis and p for interaction was calculated.

Receiver operator characteristic (ROC) analysis was performed to assess the ability of IL-6 levels, age, modified Fisher grade, and the multivariable model for IL-6 levels to distinguish between long-term survivor and death. The DeLong test was used to compare areas under the curve (AUCs). The optimal cut-off value of IL-6 was identified by the maximum Youden index.

All analyses were conducted using R software (version 4.1.0, R Foundation for Statistical Computing).

Of the 6228 patients with aSAH admitted to Sichuan University West China Hospital, during the 10 years, a total of 1131 aSAH patients with IL-6 records were included in this study (eFigure1). Baseline characteristics stratified by the long-term mortality were shown in Table 1. At the longest follow-up,73.6% patients (n=833) survived and 26.4% patients (n=298) dead. In demographics, deaths were older (p<0.001) and had higher SBP (p=0.03). In medical history, the dead had a higher proportion of COPD (p<0.001). As expected, there were significantly more patients with clinically and radiologically severe SAH among the deaths (p<0.001 and p=0.001, respectively). More patients of death performed external ventricular drain at admission (p<0.001). However, there was no significant difference in the location and size of aneurysms (p=0.85 and p=0.11, respectively). Patients who received treatment for aneurysms were more likely to survive (p<0.001). Higher blood glucose was found in deaths (p<0.001). The occurrence of in-hospital infection in deaths was 80.2% (n=239). The difference was statistically significant compared with survivors (p<0.001).

The time course of IL-6 levels during hospitalization was illustrated in Figure 1a. Considering the great individual variation, IL-6 levels were presented after logarithmic transformation. In our series, initial serum IL-6 values were elevated in all. The IL-6 values ranged between 1.50 and 4522.00 pg/ml. The median IL-6 level was 39.37 pg/ml and the Inter-Quartile Range was 67.97 pg/ml. During the further clinical course, a substantial rise in IL-6 concentrations was observed on day 2 after SAH, and IL-6 peaks were found on days 2-5, day 13-14, day17, day26, and day29. For subgroup analysis, we compared daily IL-6 levels between low Hunt & Hess grade (I-III) and high Hunt & Hess grade (IV-V), cases with hydrocephalus and without hydrocephalus, and survivors and deaths at the longest follow-up (Figure 1b-d). Statistics differences were found on days 0-2 between different Hunt & Hess grade groups, on days 0,2, 5, 17, 24, 28, and 30 between groups with hydrocephalus or not, and on days 0-2, 5-6, 8-9, 11, 13, 17-18, 20 and 26 between different long-term outcome groups.

IL-6 peak during hospitalization was associated with long-term mortality (HR 1.32 95% CI 1.21-1.44). After adjusting all variates influencing the outcome, including age, smoking, alcohol abuse, SBP, CRF, COPD, Fisher grade, Hunt & Hess grade, external ventricular drain, treatments, blood glucose, and in-hospital infection (Table 2), IL-6 peak still predicted long-term mortality (adjusted HR 1.23 95% CI 1.11-1.36, p<0.001). In the sensitivity analysis of survivors at discharge (Table 4), the finding remained robust even after adjustment (adjusted HR 1.17 95% CI 1.05-1.31, p=0.004).

The correlation between IL-6 peaks at 5 different phases (T1-5) and long-term mortality were furtherly studied (Table 3). In univariate Cox regression analysis, log IL-6 peaks of T1-5 were all significantly associated with long-term mortality (T1 HR 1.76 95% CI 1.27-2.44; T2 HR 1.47 95% CI 1.21-1.77; T3 HR 1.26 95% CI 1.09-1.45; T4 HR 1.27 95% CI 1.12-1.45; T5 HR 1.55 95% CI 1.27-1.88). After adjusting for all covariates in the multivariable Cox regression analysis, findings remained robust at T3-5 (T3 adjusted HR 1.19 95% CI 1.01-1.39, p=0.03; T4 adjusted HR 1.25 95% CI 1.09-1.44, p=0.002; T5 adjusted HR 1.53 95% CI 1.25-1.87, p<0.001). After dichotomized into two groups using the best cut-off values, IL-6 peaks of all phases were significantly associated with long-term mortality after adjustment (T1 adjusted HR 2.84 95% CI 1.06-7.61, p=0.04; T2 adjusted HR 1.76 95% CI 1.06-2.92, p=0.03; T3 adjusted HR 1.81 95% CI 1.27-2.58, p<0.001; T4 adjusted HR 2.43 95% CI 1.74-3.39, p<0.001; T5 adjusted HR 3.47 95% CI 1.99-6.03, p<0.001). In the propensity score-matched analysis, findings remained significant at T2,4-5 (T2 PSM HR 1.84 95% CI 1.02-3.31, p=0.04; T4 PSM HR 2.22 95% CI 1.46-3.38, p<0.001; T5 PSM HR 2.95 95% CI 1.64-5.29, p<0.001).

Additionally, we explored the association between IL-6 peak during hospitalization and in-hospital neurological complications (eTable 3) or short-term mortality (Table 4). Patients with higher IL-6 peaks were more likely to develop hydrocephalus, and rebleeding (OR 1.18 95% CI 1.06-1.30; OR 1.21 95% CI 1.06-1.38, respectively). After adjustment of covariates, there was no significant association between IL-6 peak and neurological complications. In the propensity score-matched analysis, findings only remained prominent in hydrocephalus (PSM OR 1.86 95% CI 1.26-2.74, p=0.002). Besides, IL-6 peak well predicted short-term mortality within all patients or survivors at discharge (adjusted HR 1.36 95% CI 1.22-1.52, p<0.001; adjusted HR 1.32 95% CI 1.17-1.49, p<0.001, respectively). Findings maintained consistent in the propensity score-matched analysis (IL-6 >103.00 pg/ml, PSM HR 2.54 95% CI 1.83-3.53, p<0.001; IL-6 >102.85 pg/ml, PSM HR 1.84 95% CI 1.29-2.62, p=0.001, respectively).

Kaplan-Meier analysis showed that death during follow-up was more frequent in patients with higher IL-6 levels (p < 0.001; Figure 2a). It also illustrated that patients with IL-6 levels stratified by IL-6 levels had significantly worse long-term survival except for deaths at discharge (p < 0.001; Figure 2b).

We further assessed interactions by variables on serum IL-6 (Figure 3). The interaction was present regarding the aneurysm size and in-hospital infection (p=0.05, p=0.02, respectively). There was no significant effect modification of the association between D-dimer level and mortality on the basis of age (p = 0.39), aneurysm location (p = 0.11), Fisher grade (p=0.44), Hunt & Hess grade (p=0.36), or aneurysm treatment (p = 0.10).

Finally, ROC analysis was performed to determine the ability of IL-6 to distinguish between long-term survivors and deaths (eFigure 2). We compared the ROC curves for IL-6, Fisher grade, and the multivariable IL-6 model (adding all variables significant in multivariable Cox regression analysis). IL-6 showed better ability to predict long-term mortality than Fisher grade (AUC _IL-6=0.63, 95% CI 0.59-0.67 vs AUC _{Fisher grade}=0.56, 95% CI 0.53-0.59, p= 0.004). As expected, multivariable IL-6 model improved the performance of IL-6 (AUC _{multivariable IL-6 model}=0.74, 95% CI 0.71-0.67 vs AUC _{Fisher grade}=0.74, 95% CI 0.71-0.77, p< 0.001).

In this large, single-center cohort study, we reported a systematic analysis of the association of serum IL-6 with mortality among patients with aSAH and we found serum IL-6 was an independent predictor of long-term mortality after aSAH. Additionally, we found that serum IL-6 was associated with short-term mortality after aSAH and neurological in-hospital complications.

Many previous studies explored the association between IL-6 and aSAH, but they focused on complications [12, 13, 16, 17]and short-term outcomes[7, 11, 18]. To our knowledge, there is no data available for discussion about IL-6 and long-term mortality of aSAH patients. However, in cardiovascular[19, 20] and oncology diseases[21–23], we were aware of several studies reporting serum IL-6 as a predictor of long-term mortality. Excessive inflammation has been proved to involve in the pathological process and prognosis of aSAH[24–28]. Furthermore, the proinflammatory cytokines released by aSAH will also deteriorate the development of other pre-existing diseases, then influencing both short-term and long-term outcomes of aSAH patients[4, 29–31]. Many other serum biomarkers have been found to predict long-term mortality of aSAH[32–37].

It was well-known that serum IL-6 elevates after systemic infection. However, many previous studies about the association of IL-6 and aSAH outcomes didn’t adjust this important covariate, reducing the credibility of their conclusions[11, 12, 16–18]. In our study, we proved serum IL-6 predicted both short-term and long-term mortality and neurological complications of aSAH patients after adjustment of in-hospital infection. We even verified our conclusions in the subgroup analysis of survivors at discharge. Interestingly, we noted patients with higher IL-6 levels without in-hospital infection were at higher risk of long-term mortality than those with in-hospital infection. It furtherly supported that the association between high IL-6 levels and long-term mortality of aSAH patients was independent of systemic infection.

Our study has several strengths. Our study collected most records of IL-6 levels of aSAH patients and included more covariates than previous studies. Furthermore, our study is the first to systematically explore the association between serum IL-6 and long-term mortality of aSAH patients. We employed multivariable Cox regression and propensity score-matched analysis to minimize the bias from confounders. Our death records data is accurate and complete, without loss to follow-up.

Nevertheless, our study has several limitations. Due to its retrospective observational design, the timing and number of peripheral blood draw for serum IL-6 levels are not consistent for all patients. Furthermore, we only collected the all-cause mortality rather than cause-specific mortality. Moreover, we found the interindividual range of serum IL-6 was still wide among aSAH patients, which might hinder the interpretation in daily clinical routine.

In summary, high serum IL-6 was associated with long-term and short-term mortality and neurological complications in aSAH patients. Our study provided new evidence for the investigation of inflammation after aSAH and the association of inflammatory cytokines with the long-term prognosis of aSAH and might support future management decisions.

Ethical Approval and Consent to participate:

The ethics committee of West China Hospital (No. 20191133).

Human and Animal Ethics:

Not applicable.

Consent for publication:

The consent to publish this manuscript has been received from all participants.

Availability of supporting data:

Not applicable.

Competing interests:

None.

Funding:

This work is supported by the National Key R&D Program of China (2018YFA0108604), the project of the health commission of Sichuan province (19PJ003), the project of the Sichuan Science and Technology Bureau (2020YFS0490), the Science and Technology Department Project of Sichuan Province (2021YJ0015), the 1·3·5 projects for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (21HXFH046), and Clinical Incubation Program of West China Hospital, SCU (2018HXFU008).

Authors' contributions:

Study concept and design: Renjie Zhang, Yu Zhang, Chao You, Lu Ma, Fang Fang

Acquisition, analysis, or interpretation of data: Renjie Zhang, Yu Zhang, Zheran Liu, Yiyan Pei, Yan He, Jiayi Yu

Statistical analysis: Renjie Zhang, Yu Zhang, Zheran Liu

Drafting of the manuscript: Renjie Zhang

Critical revision of the manuscript for important intellectual content: All authors

Acknowledgements:

None.

Authors' information:

Authors: Dr. Renjie Zhang1, Dr. Yu Zhang1,3, Dr. Zheran Liu2, Dr. Yiyan Pei2, Dr. Yan He2, Dr. Jiayi Yu4, Prof. Chao You1, Prof. Lu Ma1, Prof. Fang Fang1

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Table 1

Baseline characteristics stratified by long-term mortality

Characteristics	All	Survivor	Death	P value
Characteristics	(n=1131)	(n=833)	(n=298)	P value
Demographics
Age, y, mean (SD)	56.34 (11.86)	55.21 (11.53)	59.51 (12.22)	<0.001
Male, n (%)	388 (34.3)	276 (33.1)	112 (37.6)	0.19
Smoking, n (%)				0.11
Current	52 (4.6)	44 (5.3)	8 (2.7)
Ever	209 (18.5)	147 (17.6)	62 (20.8)
Never	870 (76.9)	642 (77.1)	228 (76.5)
Alcohol abuse, n (%)	212 (18.7)	150 (18.0)	62 (20.8)	0.33
SBP, mmHg, mean (SD)	147.05 (25.31)	146.08 (24.91)	149.79 (26.27)	0.03
Medical history, n (%)
Hypertension	314 (27.8)	223 (26.8)	91 (30.5)	0.24
Diabetes	83 (7.3)	60 (7.2)	23 (7.7)	0.87
CHD	27 (2.4)	18 (2.2)	9 (3.0)	0.54
CRF	11 (1.0)	5 (0.6)	6 (2.0)	0.07
COPD	117 (10.3)	64 (7.7)	53 (17.8)	<0.001
Aneurysm characteristics
Posterior location, n (%)	272 (24.0)	202 (24.2)	70 (23.5)	0.85
Size of aneurysm, cm, mean (SD)	0.75 (0.68)	0.73 (0.60)	0.81 (0.88)	0.11
Hemorrhagic characteristics, n (%)
Fisher grade III-IV	736 (65.1)	519 (62.3)	217 (72.8)	0.001
Hunt & Hess grade IV-V	218 (19.3)	109 (13.1)	109 (36.6)	<0.001
External ventricular drain	46 (4.1)	17 (2.0)	29 (9.7)	<0.001
Treatment of aneurysms, n (%)
Clip	870 (76.9)	668 (80.2)	202 (67.8)	<0.001
Coil	81 (7.2)	57 (6.8)	24 (8.1)
No treatment	180 (15.9)	108 (13.0)	72 (24.2)
Biology, mean (SD)
Glucose, mmol/L	7.38 (2.65)	7.11 (2.34)	8.13 (3.25)	<0.001
Complications, n (%)
Infection in hospital	778 (68.8)	539 (64.7)	239 (80.2)	<0.001

SBP, systolic blood pressure; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; SD, standard deviation

Table 2

Univariate and multivariate cox regression analysis for long-term mortality

Characteristics	Unadjusted		Multivariable Regression Adjustment
Characteristics	HR (95% CI)	P value	HR (95% CI)	P value
Demographics
Age	1.03(1.02- 1.04)	<0.001	1.03(1.01- 1.04)	<0.001
Male	1.22(0.92- 1.60)	0.17	NA	NA
Smoking
Ever	2.32(1.03- 5.21)	0.04	2.44(1.03- 5.78)	0.04
Never	1.95(0.91- 4.21)	0.09	2.03(0.90- 4.57)	0.09
Alcohol abuse	1.20(0.86- 1.67)	0.29	NA	NA
SBP	1.01(1.00- 1.01)	0.03	1.00(0.99- 1.01)	0.93
Medical history
Hypertension	1.20(0.90- 1.61)	0.21	NA	NA
Diabetes	1.08(0.65- 1.78)	0.77	NA	NA
CHD	1.41(0.63- 3.17)	0.41	NA	NA
CRF	3.40(1.03-11.23)	0.04	3.49(0.94-12.99)	0.06
COPD	2.60(1.76- 3.84)	<0.001	1.82(1.15- 2.89)	0.01
Aneurysm characteristics
Posterior location	0.96(0.70- 1.31)	0.79	NA	NA
Size of aneurysm	1.17(0.96- 1.42)	0.11	NA	NA
Hemorrhagic characteristics
Fisher grade III-IV	2.05(1.37- 3.07)	<0.001	1.60(1.03- 2.48)	0.04
Hunt & Hess grade IV-V	3.83(2.81- 5.22)	<0.001	2.48(1.73- 3.54)	<0.001
External ventricular drain	5.17(2.80- 9.57)	<0.001	3.45(1.77- 6.72)	<0.001
Treatment of aneurysms
Clip	0.45(0.32- 0.64)	<0.001	0.57(0.39- 0.85)	0.005
Coil	0.63(0.36- 1.11)	0.11	0.93(0.50- 1.74)	0.82
Biology
Glucose, mmol/L	1.15(1.09- 1.20)	<0.001	1.06(1.01- 1.12)	0.03
Log (IL-6), pg/mL	1.32(1.21-1.44)	<0.001	1.23(1.11-1.36)	<0.001
Complications, n (%)
Infection in hospital	2.21(1.61- 3.04)	<0.001	1.20(0.84- 1.71)	0.31

SBP, systolic blood pressure; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; HR, hazard rate; NA, not available

Table 3

Unadjusted and adjusted associations between IL-6 peaks at different phases and long-term mortality

Timepoints	IL-6, mean (SD), pg/ml	Classifications of IL-6	Events, n (%)	Unadjusted		Multivariable Regression Adjustment		Propensity Score Adjustment
Timepoints	IL-6, mean (SD), pg/ml	Classifications of IL-6	Events, n (%)	Unadjusted HR	P value	Adjusted HR	P value	Adjusted HR	P value
T1 (<24h)	109.72 (460.83)	log (IL-6)	NA	1.76 (1.27-2.44)	0.001	1.4 (0.89-2.20)	0.15	NA	NA
T1 (<24h)	109.72 (460.83)	IL-6>18.93	35/113 (31%)	4.79 (2.24-10.24)	<0.001	2.84 (1.06-7.61)	0.03	3.30 (0.34-31.79)	0.30
T2 (24-48h)	197.61 (517.78)	log (IL-6)	NA	1.47 (1.21-1.77)	<0.001	1.25 (0.99-1.58)	0.06	NA	NA
T2 (24-48h)	197.61 (517.78)	IL-6>122.20	72/265 (27.2%)	2.94 (1.84-4.68)	<0.001	1.76 (1.06-2.92)	0.03	1.84 (1.02-3.31)	0.04
T3 (3-6d)	191.87 (614.89)	log (IL-6)	NA	1.26 (1.09-1.45)	0.001	1.19 (1.01-1.39)	0.03	NA	NA
T3 (3-6d)	191.87 (614.89)	IL-6>48.54	154/638 (24.1%)	1.94 (1.36-2.75)	<0.001	1.81 (1.27-2.58)	0.001	1.44 (0.96-2.16)	0.08
T4 (7-14d)	144.60 (539.53)	log (IL-6)	NA	1.27 (1.12-1.45)	<0.001	1.25 (1.09-1.44)	0.002	NA	NA
T4 (7-14d)	144.60 (539.53)	IL-6>100.02	147/563 (26.1%)	2.53 (1.83-3.51)	<0.001	2.43 (1.74-3.39)	<0.001	2.22 (1.46-3.38)	<0.001
T5 (15-30d)	134.91 (565.15)	log (IL-6)	NA	1.55 (1.27-1.88)	<0.001	1.53 (1.25-1.87)	<0.001	NA	NA
T5 (15-30d)	134.91 (565.15)	IL-6>22.12	88/258 (34.1%)	3.30 (1.92-5.68)	<0.001	3.47 (1.99-6.03)	<0.001	2.95 (1.64-5.29)	<0.001

SD, standard deviation; HR, hazard rate; NA, not available

Table 4

Associations between IL-6 peaks and mortality in all patients and survivors at discharge

Outcomes	Classifications of IL-6	Events, n (%)	Unadjusted		Multivariable Regression Adjustment		Propensity Score Adjustment
Outcomes	Classifications of IL-6	Events, n (%)	Unadjusted HR	P value	Adjusted HR	P value	Adjusted HR	P value
1-year mortality	log (IL-6)	NA	1.44 (1.30-1.58)	<0.001	1.36 (1.22-1.52)	<0.001	NA	NA
1-year mortality	IL-6>103.00pg/ml	219/1131 (19.4%)	3.01 (2.30-3.95)	<0.001	2.36 (1.78-3.13)	<0.001	2.54 (1.83-3.53)	<0.001
Long-term mortality	log (IL-6)	NA	1.32 (1.21-1.44)	<0.001	1.23 (1.11-1.36)	<0.001	NA	NA
Long-term mortality	IL-6>103.00pg/ml	298/1131 (26.3%)	2.44 (1.94-3.07)	<0.001	1.90 (1.50-2.42)	<0.001	1.94 (1.48-2.55)	<0.001
1-year mortality of survivors at discharge	log (IL-6)	NA	1.38 (1.23-1.54)	<0.001	1.32 (1.17-1.49)	<0.001	NA	NA
1-year mortality of survivors at discharge	IL-6>102.85pg/ml	157/1065 (14.7%)	2.82 (2.05-3.87)	<0.001	2.20 (1.59-3.06)	<0.001	1.84 (1.29-2.62)	0.001
Long-term mortality of survivors at discharge	log (IL-6)	NA	1.25 (1.14-1.38)	<0.001	1.17 (1.05-1.31)	0.004	NA	NA
Long-term mortality of survivors at discharge	IL-6>102.85pg/ml	236/1065 (22.2%)	2.22 (1.72-2.86)	<0.001	1.74 (1.33-2.27)	<0.001	1.53 (1.15-2.04)	0.004

HR, hazard rate; NA, not available

No competing interests reported.

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Plasma Interleukin 6 Levels Predict Long-term Mortality in Aneurysmal Subarachnoid

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Abstract

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Introduction

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Study Design and Data Source

Patient Selection

Exposure variable

Primary and secondary outcomes

Follow-up

Statistical Analysis

Results

Discussion

Conclusion

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