Is prognostic nutritional index mortality predictor in patients with acute stroke in the intensive care unit?

Aim: The prognostic nutritional index (PNI) is a simple and useful score for predicting the prognosis in various diseases such as cancers, ischemic heart disease, and pulmonary embolism.The aim of our study is to investigate the association between PNI level and mortality rates of patients with ischemic or hemorrhagic acute stroke (AS) admitted to the intensive care unit (ICU). Material and Methods: We retrospectively analyzed records for 102 patients with ischemic and hemorrhagic AS admitted to the ICU between January 2017, and January, 2018. Results: During the period,83.3% of 102 patients with ischemic AS, 45.1% were male.The patients were divided into two groups according to the cut-off PNI value (47.8). Patients in the low PNI group (PNI≤47.8) were older than high PNI group (PNI>47.8). Atrial fibrillation (p=0.02) and renal diseases (p=0.049) were observed more frequently in the low PNI group. APACHE II and SOFA scores were higher in the low PNI group. The length of mechanical ventilation, ICU and hospital stay were longer in the low PNI group (p<0.05). The ICU and hospital mortality rates were higher in the low PNI group (p<0.001). Presence of atrial fibrillation, high APACHE II and SOFA scores, low GCS and diastolic blood pressure, high neutrophil lymphocyte ratio and low PNI were determined as independent risk factors for mortality. Conclusion: This study presented that low PNI level was closely associated with mortality in patients with AS. Thus, PNI may be considered as a new indicator in determining the prognosis in patients with AS.


Introduction
Acute stroke (AS) is a central nervous system (CNS) disease characterized by acute neurological deficits caused by cerebral ischemic and/or hemorrhagic causes [1].Stroke is the first leading cause of disability.According to the World Health Organization data, stroke is the second most common cause of death after ischemic heart diseases.Worldwide, it is responsible for approximately 11% of total deaths [2].Because of the high mortality and morbidity rates associated with AS, the patients with AS are followed in intensive care unit (ICU) [3,4].
In recent years, some studies have been carried out with clinical findings, scoring systems, biochemical markers and imaging methods in order to predict the mortality of ischemic heart diseases, pulmonary embolism, acute kidney injury, cancers and strokes, which are diseases with high mortality [5,6,7,8,9,10].
The prognostic nutritional index (PNI) is a combined score used to evaluate the prognosis of diseases.It can be accepted as an indicator of nutritional and immune status of patients, which can be easily measured by serum albumin value and lymphocyte count.PNI has been associated with different inflammatory processes in previous studies [11,12,13].Clinical trials have shown that lower PNI was related with poor survival in cancer cases following surgery [3,6,8].There is a lack of studies and data about the relationship between the prognostic role of PNI and outcomes in patients with AS.
The aim of our study is to investigate the effect of PNI level on mortality of patients with ischemic or hemorrhagic AS admitted to Şanlıurfa Training and Research Hospital ICU between January 2017 and January 2018.

Material and Methods
The medical records of patients aged 18 years or more with ischemic and/or hemorrhagic acute stroke between January 2017 and January 2018 were retrospectively analyzed in our ICU.Patients younger than 18 years, who had acute infection and whose data were not available were excluded from the study.The patients were divided into 2 groups with the cut-off PNI value; those with a PNI ≤ 47.8 were included in the low PNI group, and those with a PNI>47.8 in the high PNI group The primary outcome of the study was to investigate the effect of PNI level on ICU and hospital mortality of patients with AS.
The secondary outcome was to determine the demographic characteristics, the need for mechanical ventilation, length of ICU and hospital stay of the patients with AS.
The following data were obtained from electronic medical Hemoglobin, lymphocyte, arterial blood gas (lactate), glucose, albumin, CRP, prognostic nutritional index, TSH, Free T4, Vitamin B12, folate, HbA1c, total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), and Low-density lipoprotein cholesterol (LDL-C) were assessed within first 24 h of ICU admission Acute stroke is defined as the acute onset of focal neurological findings in a vascular territory as a result of underlying cerebrovascular disease.The primary end points were the incidence of ICU or hospital mortality.Hospital mortality was defined 30-day mortality as death from any cause after discharge.PNI was calculated by using following formula: "Serum albumin levels (g/dl) x 10 + total lymphocyte count in peripheral blood (per mm3) x 0.005" for each patient [3,11,13].PNI was calculated on ICU admission.

Statistical analysis
The statistical analysis was performed using The Statistical Package for Social Sciences 25.0 (version 25.0; SPSS Inc., Chicago, IL, USA).Frequencies were expressed as numbers (n) and percentages (%).Variables are expressed as mean values ± standard deviation.Categorical variables between the two groups were analyzed with the chi-square test.The nonparametric continuous variables between two groups were compared by Mann-Whitney test or Student-t test.Logistic regression (univariate and multivariate) was used to assess the independent relationship between PNI and ICU/hospital mortality.The receiver operating characteristic (ROC) curve was carried out to determine the optimal cut-off value of PNI.Factors affecting mortality were determined by univariate and multivariate logistic regression analyses.A value of p<0.05 was considered statistically significant.
This study was approved by the Harran University Clinical Research and Ethics Committee (project no: HRU/20.11.11) in accordance with the principles of the Declaration of Helsinki.

Results
During the period, 102 patients with AS, 46 (45.1%) were male and 56 (54.9%) were female.The mean age of the study cohort was 66.8±12.7 years (between 31 and 93 years).The patients in the low PNI group were older than those in the high PNI group (70.1±13.6 vs. 65.0±11.9,p=0.025).Eighty-five patients (83.3%) had ischemic and 17 patients (16.7%) had hemorrhagic AS.Hypertension (81.4%) was the most common comorbidity.Atrial fibrillation (34.2% vs. 14.1%, p=0.02) and renal diseases (7.9% vs.0%, p=0.049) were observed more frequently in the low PNI group than the high PNI group.Table 1  Laboratory data including total cholesterol, LDL-C, folate, lymphocyte, albumin, CRP-albumin ration were lower; troponin, CRP, NLR and PLR were higher in the low PNI group compared to the high PNI group (Table 3).

Discussion
In our cohort study, the patients in the low PNI group were older than the high PNI group.Atrial fibrillation and renal  diseases were higher in the low PNI group than the high PNI group.APACHE II and SOFA scores were higher and GCS (on ICU admission or discharge) and DBP were lower in the low PNI group than the high PNI group.Need of IMV, enteral nutrition and the frequency of complications were higher in the low PNI group than the high PNI group.Total cholesterol, LDL-C, folate, lymphocyte, albumin, CRP-albumin ration were lower; troponin, CRP, NLR and PLR were higher in the low PNI group compared to the high PNI group.The length of MV, ICU and hospital stay were longer and the ICU and hospital mortality rates were higher in the low PNI group compared to the high PNI group.Presence of atrial fibrillation, high APACHE II and SOFA scores, low GCS and DBP, high NLR and low PNI were independent risk factors for mortality.
Malnutrition is a common clinical condition in AS patients.In these patients, prevalence of malnutrition at admission is around 33% [9,14,15].International guidelines recommend nutritional assessment in patients with ischemic AS.Many tools are available for nutritional assessment, but their routine usage is not easy.Therefore, as an easily obtainable nutritional marker, PNI is more feasible in patients with ischemic AS.It is calculated based on peripheral lymphocytes counts and the serum albumin.Thus, PNI may cause awareness in the clinician about the nutritional status of patients with AS [9].
In our study, the patients in the low PNI group were older than the high PNI group.Elderly patient may have low oral intake and low albumin levels.Albumin is a negative acute phase reactant in inflammatory events.In inflammatory conditions such as acute stroke, albumin levels are often low [5,6,9,12,16,17,18].These can be explained by the low PNI observed in elderly patients.
Although there are data on the relationship between malnutrition and arrhythmias, there is no clear explanation for the underlying pathophysiology [17,19,21].This relationship can be explained by two possible mechanisms.Malnutrition is associated with chronic inflammation.Some studies have reported that chronic inflammation is associated with arrhythmias [3,17,20].The other mechanism is electrolyte imbalance, trace element and vitamin deficiency that can be seen in the presence of malnutrition causing arrhythmia [17,19].Therefore, in our cohort, atrial fibrillation was higher in patients with poor nutritional status.Presence of atrial fibrillation was an independent risk factor for mortality.
Renal diseases were higher in the low PNI group than the high PNI group of our cohort.Hypoalbuminemia is a comprehensive result of inflammation and insufcient intake of protein and calories in patients with chronic diseases.Malnutrition has been reported to be closely related to inflammation in patients with end-stage renal diseases.We think that low PNI may also be associated with chronic renal diseases [21].
PNI is associated with poor prognosis in many diseases involving the inflammatory process [4,5,6,9].APACHE and SOFA are also severity scores used to predict prognosis in patients admitted to the ICU [22,23].It is expected that patients with low PNI will have higher severity scores.GCS is the clinical scale that shows the state of consciousness in patients with cerebrovascular diseases.High GCS score is associated with a good prognosis.
In our study, APACHE II and SOFA scores were higher and GCS was lower in the low PNI group than the high PNI group similar previous studies [3,23].In addition, high APACHE II, SOFA and low GCS scores were independent risk factors for mortality.
In inflammation, albumin escapes into the interstitial space due to increased capillary permeability.Low albumin in the intravascular space can cause low oncotic pressure and decreased blood pressure [21,24].Hypoalbuminemia in malnutrition may also cause hypotension with a similar mechanism [16,24].For these reasons, DBP was lover in the low PNI group in our patient cohort, and low DBP was a predictor of mortality.
Nutritional status is considered an indicator of general health status, including immune adequacy, protein turnover, and physical condition.Malnutrition is an important health problem often associated with a poor prognosis.A reduced immune system function may cause respiratory dysfunction, delayed wound healing, edema and cachexia.There are clinial trials reporting that PNI predicts adverse clinical outcomes in cerebrovascular disease [3,9,25].In the low PNI group, the need for IMV may be higher due to respiratory muscle weakness and dysfunction [9,14].Oral intake may also reduce due to decreased swallowing function [9,15].Therefore, the risk of pneumonia may increase due to both decreased respiratory muscle function and reduced swallowing function.In our cohort, need of IMV, enteral nutrition and pneumonia were higher in the low PNI group than the high PNI group.
Malnutrition is a common clinical condition in AS patients.In these patients, the prevalence of malnutrition at admission is around 33% [9,14,15].Malnutrition can cause loss of muscle strength and sarcopenia in critically ill patients [26,27].The need for invasive mechanical ventilation may increase due to atrophy of the respiratory muscles [27].The length of MV, ICU and hospital stay may be prolonged due to sarcopenia [3,25,26].In our cohort, the length of MV, ICU and hospital stay were longer in the low PNI group than the high PNI group.
Malnutrition is an independent prognostic index of incidence and mortality in patients with various cancers, myocardial infarction, undergoing cardiovascular surgery and acute kidney injury [3,5,9,10,11,12].The PNI is a score that reflects the nutritional and immunological status based on serum albumin level and lymphocyte count.Several studies have reported that PNI is associated with poor prognosis and increased mortality [3,6,7,9].Low PNI value is associated with mortality in AS patients [3,4,9,23].So, the ICU and hospital mortality rates were higher in the low PNI group compared to the high PNI group In our cohort, And low PNI was an independent risk factor for mortality NLR is a ratio easily calculated by dividing the peripheral blood neutrophil count by the lymphocyte count.NLR is increased in many clinical statuses that have inflammation.High NLR is a risk factor associated with mortality [28,29].In our study, we reported that high NLR was an independent risk factor for mortality similar to the literature, In our study, we found the PNI cut-off value to be 47.8.It was similar to previous studies of patients with stroke and cerebral sinus vein thrombosis [3,9,25].While PNI was lower in patients with pulmonary embolism [7], and infective endocarditis [30], it was similar in patients with colorectal cancer and undergoing cardiovascular surgery [12,18] and higher in patients with lung cancer [6] compared to our study.Therefore, it is difficult to determine a fixed prognostic PNI value.PNI value may be variable according to disease types and age groups.It should be evaluated within each clinical trial.
This study has some limitations.It was a retrospective study.It was conducted at a single center, which limits the generalizability of the results.The data were collected from the digital patient records.

Conclusion
Our study reported that low PNI was associated with poor prognosis and an independent prognostic factor for survival of patients with AS.Nutritional, inflammatory and immunological conditions are very important for longterm outcomes in patients with AS.PNI is an easy and costeffective nutritional marker as it is obtained using only blood parameters.Therefore, it can be a useful tool for nutritional assessment in clinical trials.
and nursing records: patient age; sex; comorbidities (hypertension, diabetes mellitus, hypercholesterolemia, renal disease, malignancy, chronic obstrucitve pulmonary disease and smoking); stroke type and number of stroke attack; Acute Physiology and Chronic Health Evaluation System (APACHE II) score; Sequential Organ Failure Assessment (SOFA) score;

Table 4 .
Univariate Logistic Regression Analysis of Independent Predictors of Mortality in Patients with Acute Stroke APACHE: Acute Physiology and Chronic Health Evaluation, SOFA: Sepsis-Related Organ Failure Assessment, GCS: Glasgow Coma Scale, PNI: Prognostic Nutrition Index,

Table 3 .
Laboratory Values of Patients with Different PNI