Materials and Methods

1. Type of Study

It’s an observational prospective study, conducted in the emergency department of Sahloul University Hospital in Sousse in collaboration with the Hematology Laboratory over a period of two years, from November 2017 to November 2019.

2. Study Population

During our study, we included all patients admitted to the emergency department with a clinical presentation of a CVA (Cerebrovascular Accident) /Stroke within four hours of onset.

Thrombolysis Alert is launched from the triage room by the triage staff. The first medical contact (FMC) takes place right away with a verification of eligibility criteria followed by the alerting of AMAL team (a multidisciplinary team for the thrombolysis of ischemic strokes in which we identify referents from each specialty: A pre-hospital emergency physician, a hospital emergency physician, a neurologist and a radiologist).

A neurological exam is performed, blood is drawn then the patient is immediately rushed to the radiology department where they undergo a cerebral CT scan. The CT scan reading must be obtained rapidly in order to confirm the ischemic nature of the CVA. After a final verification of the neurological exam and contraindications of thrombolysis, a collegial decision is taken. The thrombolysis will concern patients admitted within the eligible time range, with no contraindications of fibrinolytic agent (RT-PA) and judged as having a low risk of hemorrhage by evaluating the ASPECT radiological score (ASPECT Score <7)

We included in this study patients admitted with a clinical presentation of stroke, within four hours of symptoms onset with a cerebral CT scan showing no cerebral hemorrhage.

Patients were excluded from the study if they were past the four-hour limit or if the time of onset is unknown, have a sever impaired consciousness from the beginning requiring a respiratory assistance, have an infection starting within two weeks prior to admission, take immunosuppressant, suffer from an auto immune disease, hemopathy or neoplasia or if the CT scan showed a cerebral hemorrhage.

Data Collection:

Data was collected from the local registry RAVReS (Registry of the management of CVA in the Sahel Region / Registre de prise en charge de l’AVC dans la Région du Sahel). We collected patients identity, age, address, telephone number, Medical history of cardiovascular disease, long term treatment; Vital parameters in triage, NIHSS score at admission which is a diagnostic and prognosis score of CVA that allows an evaluation of the intensity of neurological signs in order to follow the the evolution.

Time frames: deficit onset to admission, admission to alerte, admission to CT scan, onset to thrombolysis. Results of the CT scan, ASPECT Score.

Biological findings: CBC; neutrophils, lymphocytes (Analyzed using the same Automated Hematology Analyzer XN-1000), Coagulation panel.

Time and Place of thrombolysis.

The Primary outcome was the modified Rankin Score (mRS) at 30 days: The modified Rankin Score or modified Rankin Scale is a score used to measure the degree of handicap following a stroke in a patient. This scale of invalidity has six levels from 0 in patients with no symptoms to 5 in patients with a major handicap and total dependance. There is also 6^th level for patients who do not survive; [And Short term mortality: Defined as the mortality at 30 days]

Secondary outcomes was the NIHSS at 24 hours: we divided our patients into three subgroups depending on the variation of NIHSS score in the 24 hours following the thrombolysis; Success: Regression of more than 50% of the initial NIHSS score; Partial success: Regression of less than 50% of the initial NIHSS score; Failure: stagnation or worsening of neurological status evaluated by the NIHSS score.

Statistical Analysis

The statistical analysis was conducted by the SPSS software version 21.0. We first carried out a descriptive study. The definition of the trends was carried out using the mean and the median, standard deviation and interquartile (IQR 25%, 75%)

For the analytical study, we used hypothesis test: Chi 2 statistical test for the comparison of qualitative variables. The correlation study between two quantitative variables was done by calculating the Pearson coefficient of correlation. P value was considered significant at a value of ≤ 0.05

ROC curve was drawn using SPSS 21.0. In order to obtain an evaluation of the performance of the NLR, from the ROC curve, we used the area under the curve (AUC) to evaluate the sensitivity and the specificity of the NLR in evaluating short term mortality.

RESULTS :

Figure 1: Flow chart

The demographic characteristics were similar between the two groups: The mean age of the population who received fibrinolytics was 69, compared to 68.4 in the other group. There were no significant differences in demographic and clinical characteristics, although, there were more men in the thrombolysis group (p=0.054).

Table1. Demographic and clinical characteristics

The distribution of medical history between the two groups (thrombolysed and non thrombolysed) seemed homogenous. We noted however a significant difference in the history of vascular events (History of Stroke, TIA or MI).

*Table 2. Medical history of patients in two groups

*MI: Myocardial Infarction

** AOMI (Obliterating arteriopathy of the lower limbs)

We divided our population into 3 subgroups: 45% Success, 24, 3% relative success and 30, 7% failure.

Success Group was defined as Patients with a NIHSS score at 24 hours that decreased more than 50% of the initial score. They represent 45% of the total number of thrombolysed patients.

Relative Success Group was defined as Patients with an improvement in NIHSS score at 24 hours, but by less than 50% of the initial socre. They represent 24.3% of the total number of thrombolysed patients.

Failed Thrombolysis Group was defined as Patients with an NIHSS score at 24 hours equal to above the inital NIHSS. They represent 30.7% of the total number of thrombolysed patients.

In the group with successful thrombolysis, the mean NLR was 2.8 with a median of 2.18. For those with relatively successful thrombolysis; the mean NLR was 3.46 and a median of 3.03. As for the group with failed thrombolysis, the mean NLR was higher with a mean of 6.62 and a median of 3.83. The differences were statistically significant between the different subgroups.

We noted a significant association between mRs at 1 month and NLR at admission; full recovery with no residual deficit at a mean NLR of 2.6, death was constant for a mean NLR of 11.93 or above. The difference was very significant (p=0.006).

Figure 2. Correlation between NLR at admission and mRS at 1 month

NLR and short term mortality:

The NLR is a sensitive indicator of mortality (sensitivity of 85.7%), but poorly specific (specificity of 48.6%; Area under the Curve of 0.672).

Figure 3. NLR at admission and mortality at 1 month

Age over 75 years was identified as a predictive factor of failed thrombolysis with a significant p across different subgroups.

Masculine sex is not a predictive factor of failure nor success of thrombolysis

Cardiovascular risk factors do not represent a predictive factor of failed thrombolysis.

Hyperglycemia is a predictive factor of failed thrombolysis with a significant p (<0.001) across different subgroups.

Elevated initial NIHSS score is a predictive factor of failed thrombolysis with a significant p between the different subgroups.

The NLR seemed to have a tight correlation with the period following thrombolysis of an ischemic stroke. In fact, there was a correlation between NLR at admission and NIHSS score at 24 hours, the higher the NLR rate, the higher was the risk of failed thrombolysis.

A high level of NLR is predictive of a bad functional prognosis in the short term and a higher mortality too.

In addition to the factors mentioned above, there was time frame. The success of thrombolysis was linked to an early admission .The earlier the admission was, the higher the chance of successful thrombolysis.

In the multivariate Analysis; it was found that predictive factors of failed thrombolysis according to this study are Advanced age (>75 years), hyperglycemia, high initial NIHSS, high NLR and a delayed thrombolysis.

Table 3. predictors of thrombolysis success

Discussion :

The aim of our study consists in evaluating the NLR as an independent predictive factor of success or failure of thrombolysis in ischemic strokes.

The demographic and clinical characteristics of our patients showed a homogenous distribution between the two groups (those who underwent thrombolysis and those who did not).

From our study, we were able to demonstrate that the NLR at admission is tightly linked to the mortality rate and functional handicap in patients with ischemic stroke; An elevated NLR is an independent predictive factor of thrombolysis failure and a poor functional prognosis at 1 month; and that the success rate was constant from an NLR less than or equal to 2.8.

In this study, 164 patients were included with a mean age of 68.9 years. A feminine predominance (64.2%) was noted with a sex ration of 0.57

These numbers were in accordance with different numbers mentioned in the literature. We do, however, note a difference regarding sex predominance:

Our study population is characterized by a feminine predominance, contrary to different study populations.

Table3. The average age of patients and their distribution according to sex in the litterature

Patients with cardiovascular risk factors represent 75.8% of our population divided as follows; HT 75.8%, Diabetes 42.7%, dyslipidemia 16.9%, AF (Atrial Fibrillation)30.6%, coronary artery disease 14.5%) with a median of NIHSS score at admission of 6.

This elevated percentage in our population is comparable to those in the literature.

Table4.  Cardiovascular risk factors and initial NIHSS in the littérature

In our study, we did not search the association between NLR at admission and the volume of infarction since we included patients admitted within the time frame with a clinical presentation of stroke, hence the limited number of completed stroke.

A previous retrospective study including 126 patients demonstrated that the NLR has been associated with the volume of infarction and the gravity of the stroke regardless its etiology.(14)

  In this study, we did not identify the association between NLR at admission and hemorrhagic transformation given the limited number of patients presenting this complication during the hospitalization.

Recently, an increase in NLR has been identified as an independent factor of symptomatic hemorrhage (15) or of mediocre outcome at 3 months in patients who received IV thrombolysis.

In 2016, Guo Z et al published a prospective study, 189 patients were included, they concluded that a high NLR is predictive of a hemorrhagic transformation in patients treated by IV thrombolysis (16)

In 2017, Zhang et al published a meta-analysis of 9 studies. They demonstrated that a high level of NLR is associated with a poor functional prognosis at 3 months and a higher risk of hemorrhagic transformation.(17)

We undertook this study to evaluate if NLR was associated with a functional handicap in the short term in patients who have been victim of a stroke. We concluded that the NLR is predictive of a poor functional prognosis in the short term: higher the NLR, higher the mRs was.

This relationship has been studied in a relatively limited number of patients who suffered a stroke. The literature on the association between NLR and functional prognosis is insufficient.

In 2013, S. GÖkhan et al published a descriptive study that included 868 patients (from 2009 to 2011), they concluded that the NLR could be used as a simple and an easy marker to predict the mortality and short-term prognosis in patients admitted with TIA, ischemic and hemorrhagic stroke (18).

In 2018, sungwook yu et alpublished in the « Journal of the Neurological Sciences » evaluating the relationship between NLR at admission and functional prognosis (mRs and mortality rate at discharge). They demonstrated that a higher level of NLR is associated with a higher mortality rate and a poor functional prognosis during the hospitalization. (19)

In 2014, Brooks SD et al, studied the predictive value of NLR and the functional prognosis at 3 months in patients admitted for stroke and having received an endovascular treatment. They included 116 patients and they proved that an NLR at admission> 5.8 is predictive of a poor prognosis (evaluated by the mRs) at 90 days (20).

In our study, we did not search for this correlation. A previous study conducted in 2015 by Zhao et al (21) published a prospective study including 346 patients; they concluded that the higher the NLR, the longer the hospitalization.

In this study, we demonstrated that NLR is a poorly specific yet sensitive predictive factor of mortality in the short term. Previous studies on patients who suffered from a stroke have also proposed the prognostic value by mortality prediction of the NLR. Furthermore, an elevated NLR at admission has always been associated with a higher mortality in the 60 days following an acute ischemic stroke.

In 2014, Serhat Tokgoz et al (13)published a retrospective study regarding 151 patients demonstrating a predictive value of mortality of the NLR in the short term, with constant mortality from an NLR of 4.8.

In 2018, sungwook YU et al proved that the NLR, from a threshold of 2.36 is predictive in the short term of a longer hospitalization, a higher rate of handicap (evaluated by the modified Rankin score) and a higher rate of mortality in ischemic stroke by referring to a database at « Royal Northshore Hospital » in Australia from January 2009 to March 2013. They included 454 patients admitted with a clinical presentation of TIA or ischemic stroke (19).

It is also important to point out the limits of our study: It is a monocentric, observational study. It is therefore subject to different selection bias; having included a limited sample.

Despite these limitations, we can draw from our study that the NLR, a costless, reliable, and independent predictive factor at admission could help when it comes to thrombolysis decision in ischemic strokes.

To go further and better employ this ratio, a prospective study should be conducted.

We could also search for treatments that could affect this ratio to improve the management of ischemic strokes. We desperately need new therapies to fight ischemic strokes, whose prevalence might increase in the coming decades with the aging of the population.

Conclusion:

NLR is tightly associated with the progression of ischemic strokes; it can be a predictive factor of success or failure of thrombolysis.

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