The association between neutrophil percentage and albumin ratio and early deterioration of neurological function after thrombolysis in acute ischemic stroke patients

doi:10.21203/rs.3.rs-4943094/v1

Aim

To investigate the correlation between neutrophil percentage to albumin ratio (NAPR) and early deterioration of neurological function after intravenous thrombolysis in acute ischemic stroke patients.

Methods

A retrospective analysis was conducted on 322 acute ischemic stroke patients who received intravenous thrombolysis at the Second Affiliated Hospital of Dalian Medical University from January 2021 to May 2024. 39 patients who experienced early neurological function deterioration (END) after ateplase thrombolysis, while the control group consisted of 283 patients whose symptoms improved after intravenous thrombolysis,we called early neurological improvement(ENI).Collect baseline data and blood parameters for statistical analysis.

Results

Compared with the control group, patients with higher initial NIHSS scores and NPAR had a higher incidence of early END after using thrombolysis (p = 0.041; P < 0.001).

Conclusion

NPAR is associated with early neurological deterioration after intravenous thrombolysis in acute ischemic stroke. Patients with higher NPAR are more prone to occur early neurological deterioration. NPAR is a cost-effective and useful biomarker for predicting early neurological deterioration in patients with acute ischemic stroke after intravenous thrombolysis.

Acute ischemic stroke

Intravenous thrombolysis

Early deterioration of neurological function

Neutrophil percentage to albumin ratio

NPAR

Cerebrovascular disease (CVD) is the second leading cause of death in the world and the leading cause of disability in adulthood.[1]Acute ischemic stroke(AIS) is a major component of cerebrovascular disease worldwide.[2]A number of clinical trials have proved the efficacy and benefit of intravenous thrombolysis with recombinant tissue plasminogen activator (r-tPA) in acute ischemic stroke (AIS) patients within 4.5 h from symptom onset[3, 4].Intravenous administration of r-tPA is now recommended as the primary choice for AIS patients within the time window.It has been reported that rapid recovery, which is described as early neurological improvement (ENI), can be observed in AIS patients within the first 24h after intravenous thrombolysis.[5, 6]However, there are still several patients whose symptoms would worsen and neurological deficits may aggravate within 24 h after intravenous thrombolysis, named as early neurological deterioration (END)[7-9]. END and ENI are relevant to the prognosis of patients[10, 11].

Numerous studies have demonstrated that neuroinflammatory response plays an essential role in the pathophysiology of ischemic stroke[12-15].Neutrophil percentage to albumin ratio(NPAR),neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio(PLR), and lymphocyte to monocyte ratio (LMR) have recently been reported as potential novel biomarkers of baseline inflammatory process and could serve as outstanding predictors in various of diseases prognosis[16, 17]. In neurological realm,NPAR,NLR, PLR, and LMR may have the ability to predict degree of intracranial artery stenosis,the occurrence of ischemic stroke-associated infection,3-month poor functional outcome after intracranial hemorrhage (ICH)[18].

At present,intravenous thrombolysis is the primary choice for AIS patients within the time window.There’re some researches indicated that NLR, PLR, LMR and systemic inflammation response index(SIRI) may have the ability to predict functional outcome in AIS patients treated with intravenous thrombolysis(IVT)[19-21], but END results in the increasing likelihood of mortality and morbidity[11],it is significant to explore the most accurate measurable biomarker of post-thrombolysis early neurological outcomes in AIS patients.Our previous research had found that NPAR can predict the degree of intracranial artery stenosis,which predicting accuracy is better than NLR,PLR,LMR.Therefore,this study is to investigate the correlation between neutrophil percentage to albumin ratio (NAPR) and early deterioration of neurological function after intravenous thrombolysis in acute ischemic stroke patients,and further evaluate if its predicting accuracy is better than previous biomarkers.

Our study had obtain ethical procedures and patient group approval from the Clinical Research Ethics Committee of Dalian Medical University before the study (Acceptance number：KY2024-176-01)

In this study, a retrospective analysis was conducted on 322 patients who received intravenous thrombolysis at the Second Affiliated Hospital of Dalian Medical University from January 2021 to May 2024 due to acute cerebral infarction. Among them, 52 patients experienced END after intravenous thrombolysis, including 39 patients who received ateplase thrombolysis and 13 patients who received urinary kallikrein thrombolysis,while the control group consisted of 283 patients with ENI. ENI was defined as a National Institutes of Health Stroke Scale (NIHSS) score decreased ≥4 or complete recovery 24 h after thrombolysis treatment. END was defined as any increase in the NIHSS score or a decrease in the NIHSS score <4 at the 24 h after thrombolysis treatment compared with that at admission.AIS patients were diagnosed with head imaging including CT and MRI, and the diagnostic criteria for AIS is based on Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018[22]. The indications and contraindications for intravenous thrombolysis are also based on Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018[22]. Collect baseline data and blood parameters for statistical analysis. Inclusion Criteria:①Age 18-80 years old;②The presence of acute cerebral infarction within the thrombolysis time window;③Intravenous thrombolytic therapy with alteplase;Exclusion Criteria:①Diagnosed with infectious disease 72 hours before admission or 3 days after admission;②Cancer patients or patients with immune system diseases;③Recent use of immunosuppressants and steroid medications;④Severe systemic diseases, such as liver and kidney dysfunction;⑤Those who have recently undergone major surgery or severe trauma.

Data Collection and Analysis

Assess the patient's age, gender, National Institutes of Health Stroke Scale (NIHSS), blood parameters (neutrophil percentage, neutrophils, lymphocytes, monocytes, platelets, albumin), and record NPAR, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic inflammatory response index (SIRI) values. SIRI=(neutrophil count * monocyte count)/lymphocyte count.

Statistical Analysis

Analyze the obtained data using the SPSS 27.0 (SPSS Inc, Chicago, Illinois, USA) software package program. The consistency between the variables used in the study and the normal distribution was tested by Kolmogorov's Smirnov test. Continuous variables are represented by mean ± standard deviation, while categorical variables are represented by numbers and percentages. Compare categorical variables with Chi squared tests and Fisher's exact tests, and compare continuous variables with Student-t and Mann Whitney U-tests. Compare two or more groups of patients using Kruskal Wallis test and one-way analysis of variance (one-way analysis of variance A). Use Tukey HSD, Bonferroni, and Tamhane's T2 test to determine the groups that cause significance. Statistical analysis was conducted on the data obtained in this study, with a confidence interval of 95% and p<0.05 considered significant.

The cases included in the study were divided into two groups: the first group (patients with acute cerebral infarction whose symptoms improved within 24 hours after alteplase thrombolysis) and the second group (patients with acute cerebral infarction who developed END within 24 hours after alteplase thrombolysis). All statistical parameters of each group are shown in Table 1. When these two groups were compared with each other in variables, there was no statistical difference in age (P=0.116) and gender (P=0.240). However, there were significant statistical differences in the initial NIHSS score, NPAR value, NLR value, PLR value, LMR value, and SIRI value (p=0.041, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, respectively) Compared with the other group, patients in the second group(developed END within 24 hours after alteplase thrombolysis) was older (69.21±11.46) and had a higher initial NIHSS score (4.38±3.5);The percentage of neutrophils(70.64±6.56) and neutrophils(4.99±1.29) in the second group were statistically higher than the first group(53.96±6.24,3.61±0.82 respectively).There was a statistically significant difference in neutrophil percentage and neutrophil count between Group 1 and Group 2 (P<0.001).

Compared with the first group, the NPAR (1.74±0.23), NLR (3.41±1.44), PLR (135.2±36.95), and SIRI (1.22±0.57) values in the second group were statistically higher. The LMR (6.12±1.73) value of the first group is statistically higher. When comparing NPAR, NLR, PLR, and SIRI between two groups, the differences between the two groups were statistically significant (P<0.001).We plotted the median NPAR in bunches and it indicates that the NPAR mean for the second group is significantly larger than that for the first group.Table 1 Figure 1.

Multifactor Logistic Regression Analysis of Early Deterioration Of Neurological Function In Post-thrombolysis

Multivariate logistic regression analysis was conducted with the early neurological deterioration in post-thrombolysis. The results show that NPAR is an independent risk factor for early neurological deterioration after intravenous in acute ischemic stroke.Table 2

ROC curve analysis of various indicators for predicting early neurological deterioration in acute ischemic stroke after intravenous thrombolysis

To further compare the predictive efficacy of various indicators on early neurological deterioration after intravenous thrombolysis in acute ischemic stroke patients, this study conducted ROC curve analysis on NPAR, NLR, SIRI. The results showed that the optimal diagnostic value for NPAR was 1.4065, the optimal diagnostic value for NLR was 1.9711, and the optimal diagnostic value for SIRI was 0.8115. The curves showed statistical differences (P<0.001). The AUC of NPAR,NLR,SIRI are respectively 1.000(P＜0.001),0.947(P=0.011),0.852(P＜0.001) Table 3

Table1 Baseline Characteristics and Clinical Data of Enrolled Patients

	1	2	P Value
Age	66.15±11.15	69.21±11.46	P＜0.001
Gender			P=0.987
Male	153（54.1%）	26（66.7%）
Female	130（45.9%）	13（33.3%）
Initial NIHSS score	2.5±2.04	4.38±3.5	P=0.041
Neutrophil percentage	53.96±6.24	70.64±6.56	P<0.001
Neutrophil	3.61±0.82	4.99±1.29	P<0.001
Lymphocyte	2.46±0.69	1.57±0.37	P=0.011
Monocyte	0.42±0.1	0.37±0.13	P=0.026
Platelet	214.67±59.84	206±55.24	P=0.014
NPAR	1.22±0.13	1.74±0.23	P<0.001
NLR	1.54±0.41	3.41±1.44	P<0.001
PLR	92.15±31.45	135.28±36.95	P=0.654
LMR	6.12±1.73	4.69±2.08	P=0.586
SIRI	0.65±0.27	1.22±0.57	P<0.001

Table 2 Multifactor Logistic Regression Analysis of END after intravenous thrombolysis

GROUP	B	SE	Wald	P	Exp(B)	95% CI
Neutrophil Percentage	-0.024	0.01	6.081	P=0.014	0.977	0.959	0.995
Albumin	-1.768	0.471	14.069	P＜0.001	0.171	0.068	0.43
NPAR	0.302	0.1	9.199	P=0.002	1.353	1.113	1.644

Table 3 The ROC curve of NPAR,NLR,SIRI for END after intravenous thrombolysis

Index	AUC	Best truncation value	95%CI	P Value	Sensitivity	Specificity
NPAR	1.000	1.4065	1.102-1.423	P<0.001	1	1
NLR	0.947	1.9711	0.898-0.996	P=0.011	0.923	0.896
SIRI	0.852	0.8115	0.770-0.934	P<0.001	0.821	0.812

In this retrospective observational study, we investigated the association between NPAR and early neurological deterioration in patients with AIS who were treated with intravenous thrombolysis. We found that NPAR was positively associated with poor outcomes. The predictive value of NPAR was significantly higher than that of NLR, PLR, LMR and SIRI.

At present, a number of clinical trials have proved the efficacy and benefit of intravenous thrombolysis with recombinant tissue plasminogen activator (r-tPA) in acute ischemic stroke (AIS) patients within 4.5 h from symptom onset[3, 4].Intravenous administration of r-tPA is now recommended as the primary choice for AIS patients within the time window.However, there are still several patients who will not benefit from intravenous thrombolysis after experiencing early neurological deterioration[7-9]. END is closely relevant to the prognosis of acute cerebral infarction patients[10, 11].

In our study,we proved that NPAR is significantly related to early deterioration of neurological function after intravenous thrombolysis in acute ischemic stroke patient.A high NPAR is a marker that is effective in terms of the prediction of unfavorable short-term results in AIS patients after IVT.The higher NPAR value indicates that the patients appear to symptoms worsening or risk developing intracranial hemorrhage easier.The symptoms of patients with higher NPAR will more severe and need longer time to recovery,the efficacy of thrombolysis for these patients is poor even though they didn’t experience END.While the symptoms of patients with lower NPAR are minor,they will hardly appear to END and will relieve very fast even though appear to deteriorate at the very first and will barely worsen again，the efficacy of thrombolysis for these patients is obvious.We also found NLR,PLR,LMR,SIRI have the same results as NPAR,the higher NLR,PLR,LMR,SIRI value indicates that it will experience END easier.It has accordance with previous study results[22-25].We further compared NPAR with previous classical biomarkers including NLR, PLR, LMR, SIRI, we found the predicting accuracy of NPAR is better than others.Previous studies have also proven that NPAR have a better predicting ability in 3-month poor functional outcome in AIS patients with reperfusion therapy[26].

Inflammation plays a essential point in ischemic stroke.[2, 27]During the acute phase of AIS, neutrophils are the earliest inflammatory cells that are abundantly present in cerebral microvessels, and their subsequent release of reactive oxygen species (ROS) is thought to be the main cause of reperfusion injury after AIS[28-32]. Some studies found that serum albumin played a key role in scavenging ROS[33, 34]and might exert an anti-inflammatory effect by inhibiting neutrophil spreading[35,36].Post-ischemic inflammation and oxidative stress play essential roles in the response to brain ischemia-reperfusion injury in patients with AIS after reperfusion therapy[37].Leukocyte is the most vital ingredient within inflammation, whereas neutrophils make up the major part of leukocytes.So,previous research demonstrated that higher neutrophils percentage indicates worse short-term prognosis in ischemic stroke. In cardiac realm,it is closely associated with complexity of coronary stenosis, cardiovascular mortality.[38-41]Lower serum albumin concentration was also proved to have a close connection to bad clinical outcomes in various disease.[42, 43]NPAR is calculated as neutrophil percentage numerator divided by serum albumin concentration.For it,the area of cardiology had demonstrated that it as a combination of acute inflammation and recent malnutrition marker, was effective in short-term prognostic judgment of many diseases.[44]There are findings suggest that it have prognostic value in pneumonia,3-month poor functional outcome after intracranial hemorrhage (ICH).[45]In serious patients with coronary artery disease (CAD), the higher NPAR level was closely correlated with the higher rate of day, 90-day, and 365-day all-cause death.We can find the result above in a retrospective study of 2020,3106 serious patients with CAD were enrolled. Patients with higher NPAR level presented more comorbidities or history of hypercholesterolemia, chronic heart failure(CHF), atrial fibrillation(AF), chronic obstructive pulmonary disease(COPD), prior myocardial infarction(MI), and prior stroke. Moreover, more ICU LOS and lower cumulative survivals with higher NPAR tertiles.[46]

Studies have also shown that NPAR can predict all-cause mortality of acute ischemic stroke patients in the short or long term who received reperfusion therapy.The data from the latest MIMIC-III (Multiparameter Intelligent Monitoring in Intensive Care) database.It collects the vital signs, medications, demographic information and other essential data of the patients admitted to intensive care unit (53,423 distinct admissions) from 2001 to 2012 in the Beth Israel Deaconess Medical Center (BIDMC, Boston).[26, 47]In other studies，they found a positive correlation between higher NPAR on admission and the occurrence of ischemic stroke-associated infection，NPAR can also remained as independent predictors of SAI.The incidence of SAI was higher in the high NPAR group compared to the low NPAR group.[48]Furthermore,studies have shown that NPAR was related to severe sepsis and severity of acute kidney injury.[49-51]

Our study has some limitations. First, this was a single-center retrospective study, which could lead to selection bias.Second, the interval between symptom onset and admission measurement of blood samples might lead to bias. However,we adjusted for this variable in multivariable analysis, and the result was significant. Third, regarding AUC, the cut-off value of its sensitivity and specificity was fairly low, and the clinical significance of NPAR may be limited. Fourth, although we adjusted for potential confounders using multivariate models, neutrophils may be influenced by infectious diseases,hematological or rheumatic disorders, and a history of long-term immunosuppressant drug use. Due to the retrospective study design, we could not adjust for these variables in our study. Fifth, we could not explore the association between NPAR and early neurological deterioration in this study due to limited data.

In summary, elevated NPAR are associated with early deterioration of neurological function after intravenous thrombolysis in acute ischemic stroke. It is an independent risk factor of intravenous thrombolysis in acute ischemic stroke and can serve as an economical, easily obtainable, and useful biomarker for predicting the early deterioration of neurological function after intravenous thrombolysis in acute cerebral infarction.

Acknowledgements. All patients volunteered to participate in this study.

● Funding :Not applicable

● Conflict of interest/Competing interests (check journal-specific guidelines for which heading to use) :not applicable

● Ethics approval and consent to participate:This study has been approved by the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University, and the acceptance number is KY2024-176-01

● Consent for publication:The authors and all subjects are consent for publication

● Data availability:Not applicable

● Materials availability:Not applicable

● Code availability:Not applicable

● Author contribution:The authors were responsible for collecting data to write articles and ensuring that the participants would benefit indirectly, as the results of the study could be used in patients with similar medical conditions.Hui Song is the major author,GuiJun Song is the first corresponding author.Hui Song and Guijun Song wrote the main manuscript text and Hui Song prepared figures 1-5 and tables 1-6. All authors reviewed the manuscript.

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No competing interests reported.

The association between neutrophil percentage and albumin ratio and early deterioration of neurological function after thrombolysis in acute ischemic stroke patients

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