ABSTRACT
Background
Intracerebral hemorrhage (ICH) has a high mortality and morbidity in the world. C-Reaction Protein (CRP) has been demonstrated to be an independent risk factor and could predict the severity and outcome of ischemic stroke. In our study, we aimed to find out the relationship between CRP levels and the severity and outcome of patients with ICH.
Methods
This study comes from the Chinese Stroke Center Alliance (CSCA). Patients’ basic characteristics and laboratory examination results, including the concentration of CRP were taken from August 2015 to July 2019. Chi-square test and Logistic regression were used to analyze the relationship between different CRP levels and clinical outcome.
Results
A total of 9589 patients with acute ICH were enrolled in our study. In the logistic regression analysis, we found out that high CRP level is an independent risk factor for the prevalence of severe ICH and in-hospital death. After adjusting sex, age and other relevant stroke risk factors, the difference still exists (Severe ICH: odd ratio (OR) (95% confidence interval (CI) = 1.14 (1.04–1.26), P = 0.0076 for CRP between 3-10mg/l group and 1.64 (1.46-1.84), P<0.0001 for CRP>10mg/l group. In-hospital death: OR(95%CI)= 2.03(1.39–2.95), P=0.0002 for CRP>10mg/l group).
Conclusions
High CRP level was independently associated with poorer clinical outcome and higher in-hospital death in patients with ICH.
Background
The Global Burden of Disease (GBD) Study 2016 has shown that stroke is a leading cause of mortality and disability worldwide. The highest age-standardized incidences of stroke were observed in east Asia, especially China [Citation1]. For different subtypes of stroke, intracerebral hemorrhage (ICH) has a higher mortality and morbidity than ischemic stroke (IS) in China. Patients with ICH suffered a poorer prognosis and heavier economic burden since the disease happened [Citation2]. However, compared with ischemic stroke, fewer studies have focused on the prevention and therapy on the ICH event until now [Citation3,Citation4]. C-reactive protein (CRP) is a sensitive inflammation marker for many diseases. Previous studies have shown that elevated CRP levels increase the occurrence and severity of patients with ischemic stroke. On the progress of ICH, an inflammatory reaction has also happened due to the hemorrhage of cerebral vascular, but there is little evidence about the relationship between CRP and ICH [Citation5,Citation6]. So in our study, we aimed to find out the relationship between CRP levels and the severity of patients with ICH.
Methods
Study design and population
The Chinese Stroke Center Alliance (CSCA) is a national, hospital-based, multicenter, voluntary, multi-faceted intervention and continuous quality improvement (QI) initiative. A number of 1,476 hospitals and 100,6798 patients participated in this study from August 2015 to July 2019. For the enrolled patients, the inclusion criteria include the following: (1) are aged 18 years or older; (2) have a primary diagnosis of acute stroke/TIA confirmed by brain images, including IS, transient ischemic attack (TIA), ICH or subarachnoid hemorrhage (SAH); (3) are within 7 days of symptom onset; (4) are admitted either directly towards or through the emergency department. Patients with cerebral venous sinus thrombosis or non-cerebrovascular diseases were excluded. Other details of the study design were reported in our protocol [Citation7].
Of the 100,6798 patients, 8,5705 (8.51%) was acute spontaneous intracranial hemorrhage. We chose the CRP subgroup patients (n = 1,3968) in our study and excluded 4379 patients who had a history of stroke. Finally, there were 9589 ICH patients included in our CRP and ICH study population.
Assessment of CRP level and other laboratory examinations
Blood samples were collected within EDTA tubes and serum tubes at admission for each patient. CRP was measured by a particle immunoturbidimetric assay in each hospitals’ laboratories. According to the Centers for Disease Control and Prevention and American Heart Association, CRP level was categorized into three groups: CRP ≤3 mg/l, CRP = 3–10 mg/l, and CRP >10 mg/l [Citation8].
Other laboratory examinations, including fasting blood glucose (FBG), hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were also collected during the period of hospitalization.
Assessment of epidemiological information, ICH condition, and complicating diseases
Patient demographics, history of diseases, complicating diseases during hospitalization and condition at discharge were all collected by their local attending doctors, and uploaded to a unified web-based patient data collection and management tool. All the definition of diseases and scores were all standardized by the system and online data were checked by the researchers timely [Citation7].
NIHSS (National Institutes of Health Stroke Scale) and GCS (Glasgow Coma Score) scores were also made by their professional neurologists after the ICH patients arrived at the hospital. A NIHSS score ≥15 or GCS ≤12 was defined as a severe stroke, and compared with the mild stroke group in our study [Citation9,Citation10].
Data management and statistical analysis
The data management system is the SAS software (version 9.3; SAS Institute, Cary, North Carolina, USA). All the continuous variables have been checked for the normality test, and all resulted as normal distribution since the large sample size. Descriptive statistics include mean and range deviation for continuous variables and percentage of total for categorical variables. Chi-square test was used for comparison of categorical variables and ANOVA was used for continuous variables. Logistic regression was used to analyze the relationship between different CRP levels and clinical outcome. The null hypothesis was rejected for P < 0.05.
Patient and public involvement
Since the primary purpose of the CSCA is to facilitate QI. At the local level, data collection by the site is seen as a QI tool. Participating hospitals received either healthcare quality assessment and research approval to collect data in CSCA without requiring individual patient informed consent under the common rule or a waiver of authorization and exemption from their Institutional Review Board. Participants did not involve in the design, recruitment or conduct of the study and were not aware of the results of the study. Notably, informed consent may lead to a sampling bias, which can jeopardize the validity and generalizability of the database.
Results
Out of the study population of 9589 patients, there were 6086 (63.5%) males and 3503 (36.5%) females. All the patients were Asian, and most of them were ethnic Han (n = 9048). A number of 4184 (43.6%), 3182 (33.2%) and 2223 (23.2%) patients were distributed to CRP ≤3, 3<CRP≤10, and CRP ≥10 mg/l groups separately. The baseline characteristics of the patients are shown in . Patients with higher CRP levels had a higher percentage of male, old age, low education level, low income, smoking habits and a lower percentage of Han ethnic. The blood concentration of FBG, HbA1c and lipids were elevated as the CRP level elevated (all P-values <0.05). Other characteristics, test results and complicating diseases had no significant difference or regularity among groups ().
Table 1. Baseline characteristics of enrolled patients
In the second step, we compared the complicating diseases and hospital course at discharge among different CRP levels. As we can see in , the occurrence rate of hematoma evacuation, recurrence of ICH during hospitalization, hydrocephalus, pneumonia, poor swallow function and deep vein thrombosis became higher as the CRP level elevated from ≤3 to 3–10 and >10 mg/l (P < 0.05). Patients with higher CRP concentrations seemed stay longer in hospital and cost more expenditure, and the routine disposition rate became lower in these patients, which indicated a poor result after their ICH happened.
Table 2. Analysis of complicating diseases and ICH-related indexes among different CRP levels
In the third step, we analyzed the association between ICH severity and CRP levels. In CRP between 3 and 10 mg/l group, the NIHSS score is obviously higher and GCS score is obviously lower than CRP ≤3 mg/l group. In CRP >10 mg/l group, the NIHSS score is obviously higher and GCS score is obviously lower than both CRP between 3 and 10 mg/l group and CRP ≤3 mg/l group. For the index of in-hospital death rate, CRP >10 mg/l had 2.7%, CRP between 3 and 10 mg/l had 1.8%, and CRP ≤3 mg/l had 1.3%, which CRP >10 mg/l had the highest rate and CRP <3 mg/l had the lowest (). In the logistic regression analysis, we found that high CRP level is an independent risk factor for the prevalence of severe ICH (odds ratio (OR) (95% confidence interval (CI)) = 1.15 (1.04–1.27), P = 0.0054 for CRP between 3 and 10 mg/l group and 1.62 (1.44–1.81), P < 0.0001 for CRP >10 mg/l group) and in-hospital death (OR (95% CI) = 2.20 (1.52–3.19), P < 0.0001 for CRP >10 mg/l group). After adjusting sex, age and other relevant stroke risk factors, the difference still exists (severe ICH: OR (95% CI) = 1.14 (1.04–1.26), P = 0.0076 for CRP between 3 and 10 mg/l group and 1.64 (1.46–1.84), P < 0.0001 for CRP >10 mg/l group. In-hospital death: OR (95% CI) = 2.03 (1.39–2.95), P = 0.0002 for CRP >10 mg/l group) ().
Table 3. Analysis of CRP and the severity of ICH
Table 4. Adjusted odd ratios of CRP for the presence of ICH severity and in-hospital death
Discussion
The current study demonstrated that high CRP level was independently associated with more severe ICH condition, more complicating diseases during hospitalization and higher in-hospital death rate in patients with ICH. These suggest the possibility that in patients with ICH, high CRP concentration plays an inferior role in the development and progress during the acute phase of ICH.
CRP is an indicator of both acute and chronic inflammation, which may promote vascular injury for most cardiovascular diseases [Citation11,Citation12]. Previous studies have reported that elevated CRP level is associated with poor outcome in ischemic stroke [Citation6], intracranial arterial stenosis [Citation13], subarachnoid hemorrhage [Citation14], and acute coronary artery diseases [Citation15], while for ICH, the effect of CRP was still controversial. Mario and his colleagues found that plasma CRP production increases markedly at 48 to 72 hours after the onset of ICH and is related to the outcome [Citation16]. Lopponen also pointed out that elevated CRP on admission is an independent predictor of an unfavorable outcome for ICH patients [Citation17]. Di’s research demonstrated that CRP >10 mg/l is independently predictive of early hematoma growth and early neurological worsening [Citation18]. However, Zhou concluded from a meta-analysis that elevated baseline CRP levels exhibit no clear effect on hemorrhagic stroke [Citation6]. Bernstein also found no significant difference between different CRP level and ICH mortality [Citation19]. Our previous studies from a Chinese population had come to the same conclusion that there is no significant relationship between the occurrence of ICH and elevated CRP level [Citation20]. Since our study is a multicenter and continuous QI initiative study. It has a very huge population which nearly 10 thousand ICH patients included in our study, and no other intervention or special attention was given to the study group. So the results could reflect the relationship more real than other previous published clinical studies. In our study, we use the NIHSS and GCS at admission to evaluate the severity of ICH, and the rate of in-hospital death is used as the worst outcome index. We found that the NIHSS increased and GCS decreased as the CRP level elevated. Patients with a higher CRP concentration tended to have a more severe ICH condition and higher rate of in-hospital death. What is more, some complicating diseases during hospitalization, such as hematoma evacuation, recurrence of ICH, hydrocephalus, pneumonia, poor swallow function, length of stay and hospital expenditure, were all increased as the CRP level elevated, which was also an indirect evidence of the relationship between elevated CRP and severe ICH.
The physiological role of CRP in stroke, especially ICH is not well understood. CRP is an acute response protein produced by liver after inflammation, infection or injury of the body. ICH occurs when a brain vessel ruptures and the blood leaks into the surrounding brain tissues. Blood components form a growing hematoma and active some inflammatory cells, such as microglia and astrocytes cells [Citation21,Citation22]. These could cause an inflammatory response immediately. The acute inflammatory response can occur in several minutes after ICH and then trigger systemic inflammation because of the physiological and pathological response to the hematoma. Patients with ICH shared the similar process of inflammation response pathway in the second injury with ischemic stroke patients after the primary injury. In the second injury process, the microglial activated and some blood-derived inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin-1β infiltrated and released [Citation23]. CRP is influenced and regulated by the expression of these related cytokines [Citation5]. The inflammation pathway, together with the cytotoxic, excitotoxic and oxidative pathways, play an important role in the development of brain edema, tissue damage, blood–brain barrier disruption, massive brain cell death and other pathophysiological consequences [Citation22,Citation24–26]. All these processes result in poor outcomes for ICH.
The complicating diseases after ICH always indicate a worse outcome. In our study, we found that high CRP level is associated with many ICH-related diseases. Patients with an operation at the acute phase of ICH indicate they have a huge or growing hematoma and the hematoma has already affected their consciousness. These patients usually have a poorer prognosis than those undergoing conservative treatment, and the poorer prognosis patients have a higher level of CRP as well [Citation27]. For the recurrence of stroke, few studies focused on the ICH. Some previous studies showed that high CRP is associated with a high recurrence of stroke and control the level of CRP could decrease the recurrence of ischemic stroke [Citation28,Citation29]. We found that high CRP level is also related to the recurrence of ICH at the acute phase during hospitalization, which means an acute inflammation response may have an inferior effect on the hematoma and disturb the stability of hemodynamics of the cerebral vascular. A severe ICH or brainstem hemorrhage could cause dysphagia of the patient. They suffered a poor swallow function and infect the pneumonia more easily. Patients with these acute infections also have a high CRP level and CRP elevation may provide valuable short-term prognostic information [Citation30]. Since our study is a QI study, we also gathered the medical quality–related information. We found that patients with a high CRP level tends to spend more days and cost more in hospital. This is in coincidence with other results, which indicated patients with a high CRP have a poor outcome after ICH.
Strengths and limitations of this study
Potential limitations of our study should be discussed. First, the patients enrolled in our study were coming from the hospitals that participate in the CSCA voluntarily. Some secondary and smaller hospitals had no access due to the limited ability, so some bias may exist. We will collect more hospitals in our future study. Second, since there are many different level hospitals involved in the study, we only test the CRP concentration, not the high-sensitivity CRP concentration in our study. Some more accurate results and analysis could not be present in this study. We will then find out the relationship between high-sensitivity CRP and ICH in our other study populations. Third, the follow-up information is vacant now, so we could not find out the relationship between different periods of CRP level and different periods of prognosis of the ICH patients. We then plan to focus the acute phase in this study and study the long-term effect of CRP on ICH in our other study population as well.
In conclusion as a summary, the present study showed high CRP level to be independently associated with poorer outcome and higher in-hospital death rate in patients with ICH. These results suggest the possibility that in patients with acute ICH, high CRP concentration plays an inferior role in the development after ICH onset.
Contributorship statement
Dandan Wang and Jing Wang analyzed and interpreted the data and drafted the manuscript. Zixiao Li, Xingquan Zhao and Yongjun Wang conceived and designed the research. Xingquan Zhao and Yongjun Wang handled funding and supervision. Hongxiu Gu and Kaixuan Yang acquired the data. All authors contributed to the article and approved the submitted version.
Data availability statement
The data that support the findings of this study are available from the corresponding author upon reasonable request http://paper.ncrcnd.ttctrc.com/default/project-detail?id=290
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
Notes on contributors
Dandan Wang
Dandan Wang, MD. She is major in neurology, especially in stroke. She works in department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Jing Wang
Jing Wang, MD. She is major in neurology, especially in stroke. She works in department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Zixiao Li
Zixiao Li, MD. He is major in neurology, especially in stroke and medical quality management. He works in department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, and China National Clinical Research Center for Neurological Diseases as well. He is in charge of the medical quality management in our department.
Hongqiu Gu
Hongqiu Gu, MD. He is major in statistics, and works in China National Clinical Research Center for Neurological Diseases.
Kaixuan Yang
Kaixuan Yang, She is major in statistics, and works in China National Clinical Research Center for Neurological Diseases.
Xingquan Zhao
Xingquan Zhao, MD. He is major in neurology, especially in stroke. He works in department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, and China National Clinical Research Center for Neurological Diseases as well. He is the chief of our department.
Yongjun Wang
Yongjun Wang, MD. He is major in neurology, especially in stroke. He works in department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, and China National Clinical Research Center for Neurological Diseases as well. He is the chief of our hospital.
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