Neutrophil-to-lymphocyte ratio predicted cerebral infarction and poor discharge functional outcome in aneurysmal subarachnoid hemorrhage: A propensity score matching analysis
- Department of Neurosurgery, Neuroscience Center Siloam Hospital, Tangerang, Banten, Indonesia
- Department of Radiology, Faculty of Medicine, Universitas Pelita Harapan, Tangerang, Banten, Indonesia.
Julius July, Department of Neurosurgery, Neuroscience Center Siloam Hospital, Faculty of Medicine, Universitas Pelita Harapan, Jenderal Sudirman Boulevard 20, Tangerang, Banten, Indonesia 15810.
DOI:10.25259/SNI_127_2023Copyright: © 2023 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Patrick Putra Lukito1, Julius July1, Vanessa Angelica Suntoro1, Jeremiah Hilkiah Wijaya1, Audrey Hamdoyo1, Nyoman Aditya Sindunata2, Rusli Muljadi2. Neutrophil-to-lymphocyte ratio predicted cerebral infarction and poor discharge functional outcome in aneurysmal subarachnoid hemorrhage: A propensity score matching analysis. 26-May-2023;14:182
How to cite this URL: Patrick Putra Lukito1, Julius July1, Vanessa Angelica Suntoro1, Jeremiah Hilkiah Wijaya1, Audrey Hamdoyo1, Nyoman Aditya Sindunata2, Rusli Muljadi2. Neutrophil-to-lymphocyte ratio predicted cerebral infarction and poor discharge functional outcome in aneurysmal subarachnoid hemorrhage: A propensity score matching analysis. 26-May-2023;14:182. Available from: https://surgicalneurologyint.com/surgicalint-articles/12337/
Background: Neutrophil-lymphocyte-ratio (NLR) and platelet-lymphocyte-ratio (PLR) have emerged as potential biomarkers in predicting the outcomes of aneurysmal subarachnoid hemorrhage (aSAH). Since a study was never conducted on the Southeast Asian and Indonesian population, we designed the present study to evaluate the potential of NLR and PLR in predicting cerebral infarction and functional outcomes and find the optimal cutoff value.
Methods: We retrospectively reviewed patients admitted for aSAH in our hospital between 2017 and 2021. The diagnosis was made using a computed tomography (CT) scan or magnetic resonance imaging and CT angiography. Association between admission NLR and PLR and the outcomes were analyzed using a multivariable regression model. A receiver operating characteristic (ROC) analysis was done to identify the optimal cutoff value. A propensity score matching (PSM) was then carried out to reduce the imbalance between the two groups before comparison.
Results: Sixty-three patients were included in the study. NLR was independently associated with cerebral infarction (odds ratio, OR 1.197 [95% confidence interval, CI 1.027–1.395] per 1-point increment; P = 0.021) and poor discharge functional outcome (OR 1.175 [95% CI 1.036–1.334] per 1-point increment; P = 0.012). PLR did not significantly correlate with the outcomes. ROC analysis identified 7.09 as the cutoff for cerebral infarction and 7.50 for discharge functional outcome. Dichotomizing and performing PSM revealed that patients with NLR above the identified cutoff value significantly had more cerebral infarction and poor discharge functional outcome.
Conclusion: NLR demonstrated a good prognostic capability in Indonesian aSAH patients. More studies should be conducted to find the optimal cutoff value for each population.
Keywords: Biomarker, Cerebral infarction, Functional outcome, Neutrophil-lymphocyte-ratio, Subarachnoid hemorrhage
Despite the significant advances in the management of aneurysmal subarachnoid hemorrhage (aSAH), its mortality remains as high as 20%.[
A good screening model is required to stratify those high-risk patients that would benefit from a preventive treatment while taking the risk of additional side effects. The widely used parameters, the Hunt and Hess scale, the World federation of neurosurgical societies (WFNS) scale, and the modified Fisher (mFisher) scale, only take into account the patient’s clinical and radiographical characteristics. With the elucidation of the complex biological process behind infarction,[
We retrospectively collected the data for all aSAH patients admitted to our hospital between 2017 and 2021. Our hospital was one of the tertiary referral centers for neurosurgical patients in Indonesia. We excluded patients with non-aSAH, those aged <18 years old, those that had an infection on admission, and those that did not undergo either coiling/clipping procedure. Patients were diagnosed with a head computed tomography (CT) scan or magnetic resonance imaging (MRI) and supplemented by a CT angiographic study. This study was approved by the Local Ethics Committee at the Local Institutional Research Board. No informed consent was required due to the retrospective nature and exclusion of patients’ identifier.
We collected patients’ admission baseline characteristics from the medical records. These included demographic data, emergency room findings (i.e., signs and symptoms, Glasgow coma scale [GCS], blood pressure, and WFNS scale), and laboratory parameters. The severity of aSAH was determined by the WFNS scale and was classified as severe (WFNS scale 3–5) and non-severe (WFNS scale 1–2). We only collected admission laboratory parameters. We used the full blood count differentials and platelet count to identify and calculate NLR and PLR. We also collected data on routine laboratory examinations such as hemoglobin, urea, and electrolytes. We did not plan to analyze other laboratory examinations such as random blood glucose, liver enzymes, lactate, or albumin because those examinations were not routinely performed in our center, so not all patients were examined for those parameters. We collected patients’ radiological images from our electronic database and used the mFisher scale to evaluate the bleeding extent. We collected patients’ discharge data from the medical records.
The diagnosis of aSAH was established on admission using either a head CT scan or MRI. Non-aSAH was excluded using CT-angiography. We identified iatrogenic infarcts by radiologically examining patients 24–48 h after the procedure and differentiated them from infarcts that occurred afterward. During the patients’ stay, an additional radiographic evaluation could be ordered according to the judgment of the treating neurosurgeon. A final radiographical evaluation was done on all patients before their discharge.
During the data collection process, a radiologist blinded to the patient’s data performed another reading of the radiographic image to confirm the diagnosis of aSAH, grade them using the mFisher scale, and identify any intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), or cerebral infarction. In our study, we followed the definition for cerebral infarction as proposed by Vergouwen et al.[
Patients diagnosed with aSAH underwent either a coiling or clipping procedure, according to the judgment of the treating neurosurgeon at the time. Standard supportive and symptomatic medical therapies were given to all patients along with prophylaxis nimodipine in the intensive care setting after the procedure. Patients were then transferred to the medical ward and discharged following stabilization and improvement of clinical condition.
Cerebral infarction was the primary outcome of this study. In addition, we also evaluated patients’ discharge functional outcome. We used the modified Rankin scale (mRS), and we classified poor outcome at discharge as an mRS score of 3–6, representing functional dependence.
Patients’ baseline characteristics, clinical condition on admission, radiographic characteristics, and laboratory parameters were categorized according to the presence of cerebral infarction and discharge functional outcome. Categorical variables were compared using Chi-square or Fisher’s exact test. Continuous variables were analyzed for their distribution and were compared using Student’s t-test or Mann–Whitney U-test according to their distribution. Any variables showing statistical significance in the bivariate analysis were analyzed in a multivariate logistic regression model. We then performed a receiver operating characteristic (ROC) analysis to determine their respective cutoff value. All statistical significance was set at P < 0.05.
We then dichotomized the patient’s data according to the identified cutoff value. To reduce confounding bias, we performed a propensity score matching (PSM) with a 1:1 match ratio and caliper 0.15. We included demographic data such as age and sex, clinical parameters such as GCS, WFNS scale, blood pressure, ICH, IVH, mFisher scale, treatment (clipping or coiling), and those variables that were statistically significant in the initial multivariate analysis as covariates. Balance diagnostic was performed using p-value and standardized difference according to the formula outlined by Austin.[
We identified 73 aSAH patients who underwent coiling or clipping procedures in our center between 2017 and 2021. We excluded seven patients due to incomplete laboratory data, one patient due to incomplete discharge data, one patient that died before treatment, and one adolescent patient [
Association of NLR and PLR with outcomes
In the multivariate logistic regression [
We included NLR, severe WFNS score, and urea level in the model for poor discharge functional outcomes. We found that NLR was independently associated with discharge poor functional outcome (OR 1.175 [95% CI 1.036–1.334] per 1-point increment; P = 0.012). Severe WNFS scale was also independently associated with discharge poor functional outcome (OR 3.830 [95% CI 1.107–13.247]; P = 0.034).
We performed an ROC analysis for NLR and PLR [
For PLR, the best cutoff value for predicting delayed cerebral ischemia (DCI) was 213.5 (Youden’s index 0.319; AUC 0.657 [95% CI 0.518–0.796]; P = 0.041). It had 63.6% sensitivity, 68.3% specificity, 51.9% PPV, and 77.8% NPV. For predicting poor discharge functional outcome, the best PLR cutoff value was 252.0 (Youden’s index 0.363; AUC 0.630 [95% CI 0.494–0.767]; P = 0.087). It had 45.0% sensitivity, 91.3% specificity, 90.1% PPV, and 47.1% NPV. However, the ROC analysis of PLR and poor discharge functional outcome did not reach statistical significance.
Outcomes in the PS-matched cohort
The balance diagnostic of the created PS-matched cohort are shown in
Based on the results of our literature search and several systematic reviews,[
Platelet has also been implicated in the development of cerebral infarction through the formation of microthrombi and increased inflammation level.[
We also found that a higher NLR value was independently associated with poor discharge functional outcome. Although we could only evaluate functional outcome on discharge, this result was in-line with other studies that evaluated outcome over a more extended period.[
We identified 7.09 and 7.50 as the optimal cutoff value for cerebral infarction and discharge functional outcome, respectively. Dichotomizing patients according to this cutoff value in the PS-matched cohort also showed a significantly higher proportion of patients in the NLR value group having the observed outcomes. The reported cutoff value from other studies ranged from 4.0 to 14.0, either for infarction or functional outcome.[
The difference between our cutoff value for cerebral infarction with those aforementioned studies could also be attributed to the difference in outcome criteria. Three studies used the term DCI, which focused more on focal neurological impairment and unexplainable decrease in consciousness,[
Our result supported the prognostic importance of NLR as a biomarker for cerebral infarction and poor functional outcomes. However, rather than replacing the widely used WFNS and mFisher scale, we suggested using NLR in combination with those two scales. As mentioned above, clazosentan and heparin have been studied for preventing cerebral vasospasm and infarction. Several clinical trials for clazosentan have produced conflicting results. The Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage (CONSCIOUS)-3 trials demonstrated that clazosentan reduced vasospasm-related morbidity and all-cause mortality but did not affect the long-term functional outcome.[
Our study has several limitations. The retrospective and single-center nature of our study could have introduced confounding bias. We tried to minimize this by performing multivariate analysis and PSM and still found an independent association between NLR and cerebral infarction and functional outcome. However, unknown confounding bias could still have emerged and affected our findings. Another limitation is that we did not have our patients’ follow-up data after discharge, so we cannot analyze functional outcome over a longer period. Finally, since our hospital mainly served privately insured patients, this led to the small number of samples in our study, which could reduce the confidence in our result. Conducting a large-scale study in Indonesia is difficult as, currently, there is no national cohort on aSAH. However, building on our result, we hope that larger studies in Indonesia and other developing countries could be conducted in the future.
NLR is independently associated with cerebral infarction and poor discharge functional outcome. There is a significant disparity between studies regarding the reported cutoff value. As there is a possibility that NLR is affected by racial differences, we suggest that more research be conducted, especially in the developing countries. NLR’s low cost and ease would serve as an especially important prognostic marker in those countries. In addition, since prophylaxis treatment is possibly affected by patients’ severity, we suggest future research to incorporate NLR with WFNS and mFisher scale to classify aSAH patients’ severity better.
The Institutional Review Board (IRB) permission obtained for the study.
There are no conflicts of interest.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.
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