Troponin elevation is a potential marker for patients with acute ischemic stroke in intensive care unit: a retrospective observational trial

doi:10.21203/rs.3.rs-3343991/v1

Background

Cerebral apoplexy is an acute medical disease, and the main clinical manifestations of it are cerebral ischemia and hemorrhagic injury. Some biomarkers have been implicated as the mechanisms of ischemic stroke. Recent studies have shown that troponin is elevated in acute stroke patients. What’s more, increased plasma inflammatory cytokine levels and leukocytes have been reported in ischemic stroke.

Methods

Based on the previous researchs, we explored the serum levels of biochemical indicators, inflammatory cytokines as well as cardiac risk factors to further reveal the biomarkers in patients with cerebral apoplexy in or out intensive care unit (ICU) setting. At the same time, we investigated the biomarkers that related to prognosis of patients with cerebral apoplexy in ICU by multivariable logistic regression analysis.

Results

We found that there was no statistically significant difference in Hb, HCT, PLT, HCY, ALT, AST, Alb, BUN, CRE, UA, TAG, TC, HDL or LDL. Whereas NE and D-dimer in patients with AIS from ICU were significantly increased. In ICU, cTnl in patients who finally dead was significantly increased. Compared with patients alive, we also found that the elevated troponin is a risk factor for death in patients with acute ischemic stroke (AIS).

Conclusions

Due to the acute stroke patients with higher neutrophils, D dimer were more likely to enter into the ICU, cTnI elevation is associated with poor prognosis of patients in ICU. Patients with inflammation, thrombosis and elevated cTnI levels should be closely monitored and received appropriate care to improve their conditions.

acute ischemic stroke

intensive care unit

inflammation

cTnI

Cerebral apoplexy (also known as stroke or cerebrovascular accident) is an acute medical disease with the main clinical manifestations of cerebral ischemia and hemorrhagic injury. Acute ischemic stroke (AIS) which accounts for approximately 68% of all strokes is caused by permanent brain injury secondary to disruption of blood flow [1, 2]. Ischemic stroke remains a major cause of disability and the second cause of deaths throughout the world [3]. Therefore, determining the potential targets for the treatment of ischemic stroke is an unmet need.

Some biomarkers have been implicated as the mechanisms of ischemic stroke. The elevation of cardiac troponin I (cTnI) can indicate the disruption of integrity of myocardial cell membrane and injury to myocardial cells. However, recent studies have shown that troponin was elevated in 10–30% of acute stroke patients [4–6]. Increased plasma inflammatory cytokine levels and leukocytes have been reported in ischemic stroke [7, 8]. If the condition of stroke patients continues to progress, they need to get into intensive care units (ICUs) for the treatment. It was reported that more than 5 million patients are treated in ICU annually in the United States [9]. It is generally being recognized that preventing mortality should be considered an optimal outcome of an ICU stay. However, to the best of our knowledge, no previous study has explored any biomarkers that may be implicated as the mechanisms that make ischemic stroke enter to ICU.

Based on the previous researches, we explored the serum levels of biochemical indicators, inflammatory cytokines as well as cardiac risk factors to further reveal the biomarkers in patients with cerebral apoplexy in or out ICU setting. At the same time, we also investigated the biomarkers related to prognosis of patients with cerebral apoplexy in ICU by using multivariable logistic regression analysis. The present study highlights the importance of inflammatory responses in the evaluation of the risk of cerebral apoplexy, and suggests that anti-inflammatory interventions may be beneficial for the treatment of patients with cerebral apoplexy.

Study Population

The consecutive patients who were admitted to the Qianfoshan Hospital, Shandong Province, China due to AIS from May 2018 to December 2019 were retrospectively evaluated. 27 patients with AIS (15 men, mean age 75 years) from ICU and 43 patients with AIS (26 men, mean age 74 years) from neurology were enrolled. The study protocol was approved by Qianfoshan Hospital.

Because the study at present was a retrospective design, the written informed consent was waived. The following inclusion criteria were used for the patients with AIS: fulfilled the World Health Organization definition criteria for the sudden neurological deficit that has a presumable vascular etiology; Brain computed tomography (CT) scan or was normal or diffusion-weighted imaging magnetic resonance imaging (MRI) showed acute ischemic changes. At admission, measurement of biochemical indicators, inflammatory cytokines and ECG were routinely performed in all patients. The following inclusion criteria were used for all patients: evidence of acute coronary syndrome, impaired renal function (estimated glomerular filtration rate < 60 mL/min per 1.73 m2), congestive heart failure (having a history of heart failure or reduced ejection fraction ≤ 40%), hepatic and endocrinal diseases as assessed by clinical history, physical examination or routine laboratory test.

Measurement of plasma biochemical indicators

Peripheral blood was drawn from patients with AIS, and white blood cells, neutrophils, platelets, homocysteine, alanine aminotransferase, aspartate aminotransferase, urea, creatinine, uric acid, D-dimer, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, hemoglobin content were extracted and measured in the laboratory.

Cardiac investigation

Serum troponin I was measured as a part of routine laboratory testing on admission. The significant elevation of the level of troponin I was considered if it was ≥ 24 ng/l. All patients underwent 12-lead ECG at admission, and the data were analyzed by cardiologists according to a modified version of the Minnesota code. Corrected QT intervals (QTc) were defined as prolonged if the QTc in lead II was ≥ 460 ms in women and ≥ 450 ms in men.

Statistical analysis

Categorical variables were compared with the chi-square test for the difference in rates between different groups (comparison between patients admitted to the ICU and those not admitted to the ICU); for numerical variables, the normality test was performed first, and the test was used for the two groups if they were in line with the normal distribution. For the comparison of the mean values, the non-parametric rank sum test was used to compare the differences between the two groups for the numerical variables that did not conform to the normal distribution. Incorporate the above-mentioned meaningful variables into the backward stepwise unconditional logistics regression model to analyze the factors affecting whether to stay in the ICU. Multivariable logistic regression analyses were performed to identify predictors affecting the death of patients transferred to ICU. p < 0.05 was considered to be significant. All statistical analyses were performed using SPSS 17.0 for Windows (SPSS Inc, Chicago, IL).

Demographic characteristics and medical history in patients with AIS from ICU and neurology were shown in Table 1. A total of 27 patients with AIS from ICU and 43 patients with AIS from neurology were recruited for the present clinical study. The mean of their age was 75 and 74 years in cerebral apoplexy patients from ICU and neurology, respectively. The numbers of males and females in the two groups were approximately equal. There were no statistical differences in medical history (hypertension/diabetes/ Atrial fibrillation/ Chronic kidney disease), life habits (smoking/drinking) or ECG changes of as-included patients.

There was no statistically significant difference in Hb, HCT, PLT, HCY, ALT, AST, Alb, BUN, CRE, UA, TAG, TC, HDL or LDL. Whereas WBC, NE and D-dimer in patients with AIS from ICU were significantly increased when compared with patients from neurology (P < 0.05, Table 2). The three variables of WBC, NE and D-dimer were included in stepwise backward logistic regression. In Step 1, all three variables were included, and the P value (Sig.) of WBC was the least significant, which was removed in Step 2. In step 2, the NE and D-dimer showed significant results (P < 0.05, Table 3). The increasing of neutrophil percentage and D-dimer were predictive for worse prognosis in patients with AIS, which means they were more likely to be admitted to the ICU.

When the condition of patients with AIS continues to deteriorate, they need to get into ICU for further treatment. A total of 13 patients with AIS from ICU were dead and 14 patients got better. There was no statistically significant difference in their age, gender, medical history (hypertension/diabetes/ Atrial fibrillation), life habits (smoking/drinking), ECG changes, Hb, HCT, PLT, HCY, ALT, AST, Alb, BUN, CRE, UA, TAG, TC, HDL, LDL, WBC, NE or D-dimer. Whereas Tnl in patients who finally dead was significantly increased when compared with patients who are alive (P < 0.05, Table 4 and Table 5). Tnl was divided into high and low groups to analyze the impact of Tnl on the death of patients with AIS in ICU, and we found that elevated troponin is a risk factor for death in patients with AIS (P < 0.05, OR is 29.250, and 95%CI is 2.789,306.811, as shown in Table 6).

Stroke is one of the most common causes of death in the world, only followed by ischemic heart disease[15]. the risk factors of stroke include hypertension, hyperlipidemia, diabetes mellitus and smoking. When the condition of stroke patients continues to deteriorate, they need to get into intensive care units (ICUs) for the treatment. In our study, acute stroke patients with higher neutrophils, D dimer were more likely to enter the ICU. It can be seen that inflammation and thrombosis were the main reasons of taking charge.

Inflammatory factors are secreted by inflammatory cells and have been reported to be associated with the morbidity and severity of cerebral apoplexy [10, 11]. The mechanism may be related to the following two aspects: (1) The massive accumulation and adhesion of white blood cells making blood vessels narrow or blocked, which can affect the patency of local blood circulation and hinders the establishment of collateral circulation; (2) white blood cell activate a large amount of platelet activating factors, and oxygen free radicals and proteolytic enzymes are then released to participate in tissue damage [12]. Smolderen reported that after the body was subjected to various stimuli and undergoes stress injury, the white blood cell count will increase and will easily aggregate after activation. The aggregated white blood cells cause microcirculation disorders and further aggravate myocardial ischemia [13]. Patients with arteriosclerotic cerebral infarction were accompanied by secondary myocardial damage, which was specifically manifested as changes in the electrical activity of the heart and disorders of heart function, that is, brain-heart syndrome. Cerebral heart syndrome can cause or aggravate the brain and cardiovascular diseases of patients, and even the sudden death maybe caused. It is extremely dangerous for elderly patients. The body's inflammatory response has been confirmed to reflect an important danger signal of cardiovascular and cerebrovascular diseases. Patients with high white blood cell counts have a higher risk to death [14].

Stroke patients entering into the ICU will receive active treatment; nevertheless, some patients get better while others die. So what factors are related to the prognosis of patients? We retrospectively analyzed the factors that affect the prognosis of stroke patients in the ICU. Our research shows that patients with elevated troponin had a worse prognosis. With stroke and IHD sharing same risk factors, it is not unexpected to see the two diseases in one patient. Many studies have shown elevated serum troponin in significant proportion of acute stroke patients [16]. A possible explanation for elevated troponin levels in patients with AIS may be a coincidence of acute coronary syndromes leading to the elevated circulating troponin levels [17]. The vulnerability of the heart to brain-derived stress could be an alternative explanation for elevated troponin [18, 19]. Activation of the sympathetic adrenal system may be an important factor for myocardial injury in patients with AIS [20]. Another meta-analysis showed that AIS patients with elevation of cTnT or cTnI were associated with an increased risk for all-cause mortality. AIS patients with cardiac troponin elevation had a 2.54-times and 89% higher risk of in-hospital deaths and follow-up all-cause mortality, respectively [3]. However, the etiology of troponin elevation in acute stroke is not fully understood. It has been hypothesized that damages to centers regulating autonomic function can cause autonomic dysregulation resulting in sympathetic overflow and neurogenic myocardial injury [21]. Another study shown that the elevation of cTnI, might be associated with increase in the percentage of neutrophils, indicating that patients with stroke who have relatively strong inflammatory responses are at an increased risk for myocardial injury [22]. Other studies have shown that elevated cardiac troponin during acute stroke was associated with the presence of chronic diseases, such as congestive heart failure, chronic obstructive pulmonary disease, pulmonary embolism, sepsis, chronic renal failure, and atrial fibrillation [3]. Silenting myocardial infarction could have contributed to the poor prognosis of these patients.

We did not measure the size of infarction, and the determination of outcome was not in the design of our study. It is speculated that the injury of the autonomic nerve function center will result in the dysfunction of autonomic nerve, which can lead to the overflow of sympathetic nerve and the injury of neurogenic myocardial [23]. Nevertheless, some previous studies did not corroborate those results, in their studies, they found no correlation between stroke location and troponin level [20]. Limitations of our study mainly including the sample size is small, the design is a single-center study, and the lack of long-term follow-up.

In summary, acute stroke patients with higher neutrophils, D dimer were more likely to enter into the ICU, and the elevation of cTnI is associated with the poor prognosis of patients in ICU. Patients with inflammation, thrombosis and elevated cTnI levels should be closely monitored and receive appropriate care to improve their conditions.

Ethics Approval And Consent To Participate

The study protocol was approved by Qianfoshan Hospital and was in accordance with the principles described in the Declaration of Helsinki. The study protocol was described to each subject and written informed consents were obtained. All participants were of Chinese Han descent.

Consent For Publication

Not applicable

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, Weiwei Huang, upon reasonable request.

Conflict of interests

The authors declare that they have no competing interests.

Founding

Shandong Medical and Health Science and Technology Development Project（2017WS189）

Research supports from Chinese Sleep Research Society Hansoh Project.

Author Contributions

The authorship requirements have been met and the fnal manuscript was approved by all authors. Qiu developed the project, carried out the statistical analysis, and wrote the manuscript. Yang interpreted the results and edited the manuscript. Wu interpreted the results and edited the manuscript. Huang provided study supervision, contributed to the study concept, interpreted the results and edited the manuscript.

Acknowledgements

We would like to thank Drs FANG TANG, Dr JIAHUI LAO, at Department of Health Management, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering Laboratory for Health Management, for their valuable inputs in data analysis.

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Table1. Comparison of demographic characteristics and medical history in patients with AIS

		Total (n=70)	Admission to ICU (n=27)	No admission to ICU (n=43)	p value
Age, years Male gender	41		75(67, 76) 15	74(67, 80) 26	0.629 0.437
Smoke	24		9(60%)	15(57%)	0.552
Alcohol	25		11(26%)	14(52%)	0.329
Hypertension	52		18(%)	34(%)	0.190
Diabetes mellitus	30		9(%)	21(%)	0.152
Atrial fibrillation	22		8(%)	14(%)	0.506
Chronic kidney disease	3		0(%)	3(0)	0.225
ST-T abnormal	36		16(%)	20(%)	0.214
T wave abnormal	9		4(%)	5(%)	0.483
Qwave abnormal	12		5(%)	7(%)	0.526

Data are presented as median (interquartile range) or n(%) unless other indicated. p＜0.05 indicated statistically significant difference.

Table 2. Comparison of laboratory examination results in patients of AIS

	Admission to ICU (n=27)	No admission to ICU (n=43)	p value
WBC, *10⁹/L	10.61(8.64, 12.865)	8.12(6.53, 9.49)	0.001^﹡
NE, %	81.46 ± 8.64	70.04 ± 12.26	0.01^﹡
Hb, g/L	133(115.5, 145)	135(119.5, 148)	0.433
HCT, %	40.71 ± 6.68	41.26 ± 6.72	0.741
PLT, *10⁹/L	251(161.5, 283)	215(167, 256.5)	0.507
HCY,	14.3(11.6, 23.1)	15.15(12.58,19.03)	0.801
ALT, U/L	13.5(11.9, 23.1)	21.05(13.35, 31.35)	0.293
AST, U/L	27.2(18.25, 42.32)	21.85(17.78, 32.35)	0.296
Alb, g/L	37.34 ± 5.57	38.94 ± 4.49	0.198
BUN, mmol/L	6.3(4.75, 7.95)	5.4(4.5, 7)	0.319
CRE, umol/L	78(61.75, 93.55)	69(58.9, 86.5)	0.546
UA, umol/L	269(222.8, 319.75)	314(235.8, 360.7)	0.165
TAG, mmol/L	0.94(0.74, 1.235)	1.02(0.87, 1.66)	0.102
TC, mmol/L	4.27 ± 1.26	4.15± 1.38	0.692
HDL, mmol/L	1.19(0.875, 1.275)	1.04(0.83, 1.31)	0.344
LDL, mmol/L	2.53 ± 0.91	2.33 ± 0.89	0.374
D-D, ng/mL	7.17(1.33, 9.57)	0.82(0.43, 1.46)	0.001^﹡
TnI, ng/ml	0.37 ± 0.48	0.58 ± 0.49	0.079

Data are presented as mean±SD or median (interquartile range) or n(%). p＜0.05 indicated statistically significant difference. WBC:white blood cell; NE: neutrophilic granulocyte percentage; Hb: hemoglobin; HCT: hematocrit; PLT: platelets; HCY: homocysteine; ALT: glutamic-pyruvic transaminase; AST: glutamic oxalacetic transaminase; Alb: albumin; BUN: blood urea nitrogen; CRE: creatinine; UA: uric acid; TAG: triglyceride; TC: total cholesterol; HDL: high density lipoprotein; LDL-C: low-density lipoprotein; D-D: D dimer.

Table 3. Logistic regression analysis of prognosis in patients with AIS

	B	OR	95%CI	p value
NE, %	7.891	2673.101	1.005,3.189	0.032^﹡
D-D, ng/mL	0.434	1.544	1.013-1.150	0.002^﹡

Table 4 Comparison of demographic characteristics and medical history in dead and alive patients in ICU

		Total (n=27)	dead (n=14)	alive (n=13)	p value
Male gender	15		7	8	0.704
Smoke	9		4	5	0.695
Alcohol	11		6	5	1.000
Hypertension	18		9	9	0.555
Diabetes mellitus	9		4	5	0.695
Coronary heart disease	5		3	2	0.538
Atrial fibrillation	8		4	4	0.615
ST-T abnormal	16		8	8	0.564
T wave abnormal	4		2	2	0.673
Qwave abnormal	5		2	3	0.648

Data are presented as n(%) unless other indicated. p＜0.05 indicated statistically significant difference.

Table 5. Comparison of laboratory examination results in dead and alive patients in ICU

	Dead (n=14)	Alive (n=13)	p value
Age, years	75.5(66.0, 76.0)	72.0(67.5, 78.5)	0.595
TnI, ng/ml	0.78(0.053, 4.33)	0.025(0.017, 0.22)	0.005﹡
WBC, *109/L	10.45(8.67, 15.29)	10.61(8.46, 12.02)	0.356
NE, %	86.0(73.0, 91.8)	80.9(75.35, 86.55)	0.286
Hb, g/L	135.43 ± 28.96	129.08 ± 19.79	0.515
HCT, %	41.57 ± 7.98	39.78 ± 5.44	0.505
PLT, *109/L	262.5(160.2, 322.5)	249.0(152.0, 278.5)	0.544
HCY,	17.6(11.6, 36.9)	12.5(10.75,17.60)	0.109
ALT, U/L	13.5(12.12, 33.17)	14.0(11.2, 32.45)	0.942
AST, U/L	28.4(19.07, 42.83)	25.0(15.95, 42.9)	0.467
Alb, g/L	37.21 ± 6.03	37.49 ± 5.53	0.904
BUN, mmol/L	7.0(4.78, 7.87)	5.9(4.0, 9.15)	0.808
CRE, umol/L	76.9(66.05, 100.87)	78(54.25, 88.35)	0.207
UA, umol/L	276.3(221.2, 334.1)	263(205.8, 319.75)	0.560
TAG, mmol/L	0.97(0.81, 1.50)	0.83(0.57, 1.27)	0.254
TC, mmol/L	4.39 ± 1.36	4.15± 1.24	0.624
HDL, mmol/L	0.98(0.87, 1.24)	1.24(0.91, 1.53)	0.198
LDL, mmol/L	2.70 ± 0.96	2.35 ± 0.89	0.341
D-D, ng/mL	8.11(4.99, 15.12)	2.38(0.78, 8.61)	0.152

WBC:white blood cell; NE: neutrophilic granulocyte percentage; Hb: hemoglobin; HCT: hematocrit; PLT: platelets; HCY: homocysteine; ALT: glutamic-pyruvic transaminase; AST: glutamic oxalacetic transaminase; Alb: albumin; BUN: blood urea nitrogen; CRE: creatinine; UA: uric acid; TAG: triglyceride; TC: total cholesterol; HDL: high density lipoprotein; LDL-C: low-density lipoprotein; D-D: D dimer. ﹡:p< 0.05

Table 6. Logistic regression analysis of troponin

	B	OR	95%CI	p value
TnI	3.376	29.250	2.789,306.811	0.005^﹡

No competing interests reported.

Troponin elevation is a potential marker for patients with acute ischemic stroke in intensive care unit: a retrospective observational trial

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Introduction

Materials and methods

Statistical analysis

Results

Discussion

Declarations

References

Tables

Additional Declarations

Status:

Version 1