Neutrophil-to-lymphocyte ratio’s early mortality predictive role:

A retrospective cohort study among intracerebral hemorrhage

patients

Author:
dr. Hendrawan Dian Agung Wicaksana

Supervisor:
dr. Sekar Satiti, SpS(K)
dr. Atitya Fithri Khairani, M.Sc., SpS
dr. Siti Farida Setyaningrum, SpS

Department of Neurology
Faculty of Medicine, Public Health, and Nursery
Universitas Gadjah Mada
Yogyakarta
2018
 Neutrophil-to-lymphocyte ratio’s early mortality predictive role:
A retrospective cohort study among intracerebral hemorrhage patients
Hendrawan Dian Agung Wicaksana1, Sekar Satiti2, Atitya Fithri Khairani3, Siti Farida Setyaningrum4
1Neurology Resident, Department of Neurology, Sardjito Hospital, Yogyakarta; Faculty of Medicine, Public Health, and
Nursery, Universitas Gadjah Mada, Yogyakarta, Indonesia
2Neurologist Consultant, Department of Neurology, Sardjito Hospital, Yogyakarta; Faculty of Medicine, Public Health, and

Nursery, Universitas Gadjah Mada, Yogyakarta, Indonesia

3Neurologist, Department of Neurology, Sardjito Hospital, Yogyakarta; Faculty of Medicine, Public Health, and Nursery,

Universitas Gadjah Mada, Yogyakarta, Indonesia

4Neurologist, Department of Neurology, Banyumas Public Hospital, Banyumas; Faculty of Medicine, Public Health, and

Nursery, Universitas Gadjah Mada, Yogyakarta, Indonesia

Background
Neutrophil-to-lymphocyte ratio is a simple and widely available laboratory parameter to assess
inflammatory status. It has been used as a marker of infectious pathology, and recent studies shows
its value in measuring prognostic feature in cancers and cardiovascular events. Role of neutrophil-to-
lymphocyte ratio in measuring clinical outcome of a stroke patient has been studied and showed a
good correlation, but its role in predicting early mortality in spontaneous intracerebral hemorrhage
patients is still questioned.

Objective
We conducted this study to investigate neutrophil-to-lymphocyte ratio’s role in predicting early
mortality spontaneous intracerebral hemorrhage patients.

Method
A total of 85 spontaneous intracerebral hemorrhage patients, admitted to stroke center in Sardjito
hospital from January 2018 to June 2018, were included in this retrospective observational cohort
study. Blood samples were taken at admission and neutrophil-to-lmphocyte ratio were calculated.
Patients were followed-up at 14 days from stroke onset. Primary end point was mortality.

Result
Twenty-two of 85 patients died during the follow-up period. The mean neutrophil-to-lymphocyte ratio
significantly increased among the mortality group compared to survival group (mean 13.84 vs 8.64, P
= 0.001). NIHSS on admission also has a significant difference between death and survival groups
(mean 21.59 vs 9.80, P < 0.001). Neutrophil-to-lymphocyte ratio has correlation with mortality (R =
0.300, P = 0.005). However this association was no longer significant after adjustment of confounding
variable (OR 1.083; 95% CI: 0.989-1.186, P = 0.085).

Conclusion
Neutrophil-to-lymphocyte ratio alone shouldn’t be used to predict early mortality. Factors such as
NIHSS on admission must be considered when determining prognosis. There was a trend towards
increased early mortality in the higher neutrophil-to-lymphocyte ratio, but this association did not
reach statistical significance.

Keywords: Neutrophil-to-lymphocyte ratio, NLR, mortality, spontaneous intracerebral hemorrhage,

hemorrhagic stroke
 Peran rasio netrofil-limfosit dalam prediksi mortalitas awal:
Penelitian kohort retrospektif pada pasien perdarahan intraserebral
Hendrawan Dian Agung Wicaksana1, Sekar Satiti1, Atitya Fithri Khairani1, Siti Farida Setyaningrum2
1Departemen Neurologi, RSUP Dr Sardjito, Yogyakarta; Fakultas Kedokteran, Kesehatan Masyarakat, dan Keperawatan,
Universitas Gadjah Mada, Yogyakarta, Indonesia
2Departemen Neurologi, RSUD Banyumas, Banyumas; Fakultas Kedokteran, Kesehatan Masyarakat, dan Keperawatan,

Universitas Gadjah Mada, Yogyakarta, Indonesia

Latar Belakang
Rasio netrofil-limfosit merupakan parameter laboratorium yang sederhana dan tersedia luas untuk
menilai status inflamasi. Rasio ini telah digunakan sebagai penanda dalam kondisi patologis infeksius,
dan penelitian terkini menunjukkan nilainya dalam mengukur prognosis dalam bidang cancer dan
kejadian kardiovaskular. Peran rasio netrofil-limfosit dalam mengukur luaran klinis pasien stroke telah
diteliti dan menunjukkan korelasi yang baik, namun perannya dalam memprediksi mortalitas awal
pada pasien perdarahan instraserebral spontan masih dipertanyakan.

Tujuan
Penlitian ini dilakukan untuk menginvestigasi peran rasio netrofil-linfosit dalam memprediksi
mortalitas awal pada pasien perdarahan intraserebral spontan.

Metode
Total 85 pasien perdarahan intraserebral spontan, yang masuk unit stroke RSUP Dr Sardjito dari
Januari 2018 hingga Juni 2018, dimasukkan dalam penelitian kohort retrospektif observasional ini.
Sampel darah diambil pada saat masuk dan rasio netrofil dan limfosit dihitung. Pasien difollow-up
sampai hari ke 14 dari onset stroke. Hasil akhir yang dicari adalah mortalitas.

Hasil
Dua puluh dua dari 85 pasien meninggal selama masa follow-up. Rerata rasio netrofil-limfosit secara
bermakna meningkat pada grup mortalitas dibanding grup yang hidup (rerata 13.84 v 8.64, P = 0.001).
NIHSS pada admisi juga memiliki perbedaan bermakna pada grup mortalitas dan hidup (rerata 21.59
v 9.80, P < 0.001). Rasio netrofil-limfosit memiliki korelasi dengan mortalitas (R = 0.300, P = 0.005).
Namun hubungan ini tidak lagi bermakna setelah memperhitungkan variabel perancu (OR 1.083; 95%
CI: 0.989-1.186, P = 0.085).

Kesimpulan
Rasio netrofil-limfosit saja tidak seharusnya digunakan dalam memprediksi mortalitas awal. Faktor
seperti NIHSS pada saat masuk harus dipertimbangkan pada saat menentukan prognosis. Terdapat
kecenderungan peningkatan mortalitas awal pada rasio netrofil-limfosit yang tinggi, namun hubungan
ini tidak mencapai kemaknaan statistik.

Kata kunci: Rasio netrofil-limfosit, RNL, mortalitas, kematian, perdarahan intraserebral spontan,
stroke hemoragik
 Neutrophil-to-lymphocyte ratio’s early mortality predictive role:
A retrospective cohort study among intracerebral hemorrhage patients

Background
Stroke still have a high mortality number. There are 7.2 million people with stroke and nearly 800
thousands new and recurrent attack every year in United States, and more than 100 thousands
peoples dies because of stroke1. In Indonesia 7 of 1000 people have stroke2 with incidence 51.6 per
100 0003. Mortality rate for stroke patients in Indonesia is 15.9%, and this number increased to 23.5%
at population older than 65 years old3.
There a lot factors that independently associated with poor outcome of spontaneous
intracerebral hemorrhage patients, including female gender4–7, older age8–11, infratentorial origin of
hematoma10,11, larger volume10,11, presence of intraventricular hemorrhage10,11, decreased level of
consciousness10,11, and higher NIHSS score7,12–14. Laboratory parameters were used to predict outcome
in other vascular disease, such as neutrophil-to-lymphocyte ratio, albumin level15–19, leucocyte count20,
C-reactive proteins19, and neutrophil-to-lymphocyte ratio21–23. Neutrophil-to-lymphocyte ratio had
been used to predict clinical outcome of both vascular and nonvascular disease such as infectious
diseases24,25 and cancers26,27. It also has been used to predict outcome in ischaemic stroke28–35, and
also spontaneous ICH36–40.
Netrophil-to-lymphocyte ratio is simple laboratory parameter that widely available that do
not need any additional cost28,38,41. It derived from routine blood analysis28. Neutrophil and
lymphocyte represent inflammatory status of an individual. Inflammation plays an important role in
stroke and contributing secondary brain injury38,40.

Objective
We conducted this study to investigate neutrophil-to-lymphocyte ratio’s role in predicting early
mortality spontaneous intracerebral hemorrhage patients.

Method
This study is a retrospective observational cohort to assess role of neutrophile-to-lymphocyte ratio in
predicting mortality of spontaneous intracerebral hemorrhage within 14 days of stroke onset.

Participants and Study Outcome

We identified patients admitted to stroke center in Sardjito Hospital, Yogyakarta, Indonesia from
January to June 2018 for stroke syndrome caused by acute spontaneous intracerebral hemorrhage
diagnosed by non contrast CT scan of the brain within 72 hours of stroke onset. All patients underwent
routine blood sampling at emergenct department. Neutrophil-to-lymphocyte ratio derived from this
blood sampling. Age, gender, NIHSS on admission, hematoma location (categorized as supratentorial
and infratentorial), hematoma volume (cut off 30 cc), and surgical intervention were also recorded.
Primary outcome measure was mortality of all cause within 14 days of stroke onset.

Statistical analysis
Comparisons were made through Student t test and chi square test. Spearman correlation test was
used to correlate continuous variables. Multivariate analysis were made using logistic regression.
Result were significant for P value < 0.05. Analysis was performed using SPSS version 22.

Result
A total of 85 patients enrolled in this study, with mean of age was 60.65 years old. There were 36
female (42.3%). Twenty two patients (22.88%) died during follow-up period.

Table 1. Baseline characteristics

Variable Total Dead Survived P value
Total sample 85 22 63
Age in years old, mean 60.65 63.82 59.55 0.199
Female gender (%) 36 (42.35) 8 28 0.509
NLR, mean 9.99 13.84 8.64 0.001
NIHSS on admission, mean 12.85 21.59 9.81 < 0.001
Supratentorial ICH location (%) 69 (81.17) 18 51 0.929
ICH volume above 30cc (%) 19 (22.35) 8 11 0.067
Surgery intervention (%) 8 (9.41) 1 7 0.364

The means of age, neutrophil-to-lymphocyte ratio, and NIHSS on admission is higher among
mortality group compared to survival group (mean 63.82 vs 59.55, P = 0.199; mean 13.84 vs 8.64, P =
0.001; mean 21.59 vs 9.81, P < 0.001; respectively). Only mean of age was not significantly different
between two groups. Among both gender, supratentorial and infratentorial ICH location, ICH volume
above and below 30cc, and receive surgical intervention and conservative treatment were not
significantly different between mortality and survival group (P = 0.509, P = 0.929, P = 0.067, P = 0.364,
respectively).
There was correlation between neutrophil-to-lymphocyte ratio and mortality (R = 0.300, P =
0.005). Neutrophil-to-lymphocyte ratio has odds ratio to mortality 1.118 (95% CI 1.038-1.204, P =
0.003). We also checked correlation between NIHSS on admission and mortality. Correlation analysis
showed that NIHSS strongly correlated with mortality (R = 0.538, P < 0.001) with odds ratio 1.192 (95%
CI 1.096-1.296, P < 0.001). Neutrophil-to-lymphocyte ratio itself correlated to NIHSS on admission (R
= 0.358, P = 0.001)
Multivariate analysis using logistic regression models were performed to adjust for baseline
confounders. NIHSS on admission retain its correlation significancy after adjustment using logistic
regression (OR 1.178; 95% CI: 1.081 – 1.282, P < 0.001), meanwhile neutrophil-to-lymphocyte ratio’s
correlation with mortality no longer significant after adjustment of confounder covariate (OR 1.083;
95% CI: 0.989-1.186, P = 0.085).

Table 2. Association between variables and mortality

Unadjusted Adjusted
Variable
OR (95% CI) P value OR (95% CI) P value
NLR 1.118 (1.038-1.204) 0.003 1.083 (0.989-1.186) 0.085
NIHSS on admission 1.192 (1.096-1.296) < 0.001 1.178 (1.081-1.282) < 0.001

Discussion
The main finding of this study are neutrophil-to-lymphocyte ratio has a correlation to mortality, but
this association is confounded by other factor, and NIHSS on admission was independenty associated
with early mortality. Our finding contradict with previous study that showed that neutrophil-to-
lymphocyte ratio was an independent parameter associated with in-hospital mortality in intracerebral
hemorrhage patients37,38. This difference may be attributed to usage of cut-offs on neutrophil-to-
lymphocyte ratio as our study did not use these cut-offs. Based on this previous study, different cut-
offs can generate different outcome measures, so determining optimal cut-off is recommended in
order to reducing bias in a study. A cut-off also also may have a better use in clinical setting.
Nevertheless, this study did not change recommendation from previous study that stating physicians
should focus on patients with increased neutrophil-to-lymphocyte ratio as these patients appear to
represent a population at risk for infectious complications and increased short-mortality38. A higher
neutrophil-to-lymphocyte ratio correlates with higher NIHSS on admission, which more related with
clinical outcome of stroke patients. This finding is in line with previous studies that showed higher
neutrophil-to-lymphocyte ratio is associated with poor clinical outcome36,37,40. So its may have a better
result not to omitting patients with higher neutrophil-to-lymphocyte ratio from intensive care or
aggressive treatment into palliative care at early stage.

Conclusion
Neutrophil-to-lymphocyte ratio alone shouldn’t be used to predict early mortality. Factors such as
NIHSS on admission must be considered when determining prognosis. There was a trend towards
increased early mortality in the higher neutrophil-to-lymphocyte ratio, but this association did not
reach statistical significance.
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