Association Between Neck Circumference and Poor Outcome in Spontaneous Intracerebral Hemorrhage Patients: A Prospective Observational Study.

Background: Obesity is one of the major risk factors of intracerebral hemorrhage (ICH). Neck circumference (NC) is an indicator of obesity, and little is known about the role of NC in patients with ICH. This study aimed to assess the association between NC and functional outcome in ICH patients. Methods: We prospectively analyzed data of ICH patients who received treatment at our institution from January 2018 to November 2019. Patients were categorized as two groups according to 180-day Modied Rankin Scale (MRS) score. Univariate and multivariate analyses were performed to assess whether NC was associated with poor outcome in ICH patients. Receiver operating characteristic (ROC) curve analysis was performed to manifest the signicance of NC in predicting the functional outcome of ICH patients. Results: A total of 312 patients were enrolled in our study. Multivariate logistic regression analysis indicated that NC was an independent predictor of 180-day poor functional outcome (odds ratio [OR] = 1.205, 95% condence interval [CI]: 1.075-1.350, p = 0.001). ROC analysis revealed that NC could predict poor functional outcome at 6 months. Conclusion: NC is an independent predictor of unfavorable functional outcome at 6 months in ICH patients.


Background
Spontaneous intracerebral hemorrhage (ICH) is a devastating healthcare event accounting for 10-15% of all strokes [1,2], which has the characteristics of high mortality and morbidity and limited treatment options [3].Obesity is one of the major risk factors of stroke [4], and is associated with increased morbidity and mortality in the general population [5,6].However, obesity appears to have a survival advantage in patients with certain diseases including heart failure, coronary artery disease, and chronic kidney disease [7][8][9].In addition, recent studies has linked this phenomenon, known as the "obesity paradox", to ICH [10,11].
Body mass index (BMI) was an indicator that most commonly used to assess obesity.Whereas, previous studies have showed that neck circumference (NC) could be used as a simple, feasible and stable evaluation index because it is not easily affected by eating or body position [12,13].In addition, NC is related to oropharyngeal fat in ltration, narrowing the upper respiratory tract [14].However, little is known about the role of NC in patients with ICH.The purpose of this study was to explore the relationship between the NC and the prognosis of ICH.

Study design
This is a single-centre prospective study.We identi ed all the patients with ICH visited to West China hospital from January 2018 to November 2019.Informed consent was obtained from all patients or family members.All procedures in the study were approved by the Ethics Committee of the West China Hospital of Sichuan University (Sichaun, China).

Patients
We de ned inclusion criteria as follows: 1) A diagnosis of intracranial hemorrhage by computed tomography (CT); 2) Blood routine examination and laboratorial tests were conducted within 24 hours after admission; 3) ≥ 18 years.Patients who met the following criteria were excluded: 1) that ICH was attributable to aneurysm, arteriovenous malformation or moyamoya disease; 2) that ICH was attributable to acute cerebral infarction, thrombolysis of cerebral or myocardial infarction; 3) patients with prior systemic diseases such as immunological disease, neurological disease, recent infectious disease, severe hepatic, renal dysfunction and coagulation dysfunction.4) patients with isolated intraventricular hemorrhage; 5) patients with a history of neck surgery.
Clinical and laboratory parameters.
Baseline clinical and demographic parameters were collected at hospital arrival, including NC, BMI, HNR (height-to-NC ratio), age, sex, medical history, Glasgow Coma Scale (GCS) score on admission, blood pressure, cigarette consumption and alcohol use, history of stroke, medical history of hypertension, diabetes mellitus, and history of endotracheal intubation and tracheotomy.
Laboratorial variables were also recorded including white blood cells (WBC), platelet, blood glucose, cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C).The NC (cm) was taken to the nearest 1 mm, using plastic tape measure.It was taken in a plane as horizontal as possible, at a point just below the larynx (thyroid cartilage) and perpendicular to the long axis of the neck (the tape line in front of the neck at the same height as the tape line in the back of the neck).Two reviewers independently estimated the values of NC.Any disagreement between the two reviewers was solved by the consensus.Height (m) and weight (kg) were measured at the bed side by trained staff on admission using a measure and a digital weight scale, respectively, and BMI (kg/m 2 ) was calculated as standard.Admission HNR was calculated as the ratio of the height to the NC.
Radiological results collected from head CT within 24 h after admission to hospital included hematoma location, hematoma size, presence of Intraventricular hemorrhage (IVH).Hematoma volume was measured by ABC/2 method as described previously [15].Two reviewers independently estimated all the head CT scans.Any disagreement between the two reviewers was solved by the consensus.
The functional outcome was assessed by 180-day MRS score by telephone or outpatient visiting.MRS score ≥ 3 was de ned as unfavorable outcome including severe disability, persistent vegetative state, as well as death.

Statistical analysis.
All the baseline characteristics including clinical variables, laboratorial parameters and radiological data were compared between patients with poor outcome and with favorable outcome.Continuous variables were expressed as mean ± standard deviation or median with interquartile range (IQR) for normal distribution and non-normal distribution, respectively, whereas categorical variables were expressed as frequency and percentage.Univariate analyses were conducted by independent t test or Mann-Whitney U test or Chi-square (χ 2 ) test or Fisher's exact test.Independent t test or Mann-Whitney U test were applied to compare continuous variables.Chi-square (χ 2 ) test or Fisher's exact test were conducted to compare categorical data.Variables signi cant at p < 0.20 level in the univariate analysis were retained in the multivariate model.For interpretation purposes, some variables were classed as follows: GCS score as "13-15 points", "9-12 points" and "3-8 points"; and hematoma location as "lobe", "basal ganglia", "thalamus", "cerebellum" and "brainstem".Receiver operating characteristic (ROC) analysis was performed to indicate the predictive value of NC for the functional outcome of ICH patients.The cut-off value of NC was decided by Youden index from the ROC curve.A value of p < 0.05 was considered as statistical signi cant.All the above-mentioned statistical analyses were performed by SPSS version 21.0 (SPSS, Chicago, IL, USA).

Results
From January 2018 to November 2019, 312 consecutive patients (229 males and 83 females) with spontaneous ICH who met the inclusive criteria were enrolled in this prospective study, the lost rate of follow up was 2% (7/367, Fig. 1).

Discussion
To the best of our knowledge, this is the rst study that focused on the NC in patients with ICH.We found that NC was an independent risk factor for poor prognosis of ICH, and BMI was independently inversely associated with poor outcome in ICH patients.NC is an indicator of obesity that re ects human health [16][17][18][19][20][21].Previous studies have shown that NC is associated with an increased risk of hypertension [18], diabetes [17,21] and metabolic syndrome [19].NC is also found to be associated with congestive heart failure incidence and coronary heart disease mortality [20].However, researches regarding the association between NC and ICH were limited.
According to the "obesity paradox", obese and overweight stroke patients had favorable prognosis than those with a normal or lower BMI [22][23][24].Consistent with these ndings, we found that BMI was independently inversely associated with poor outcome in ICH patients.Interestingly, we also found a contradictory relationship between BMI and NC in predicting the prognosis of ICH.One possible explanation for the paradoxical phenomenon may be that the two obesity indicators are different in fat distribution.BMI only re ects the total body obesity and NC represents an alternative method for measuring upper body subcutaneous fat [25].Moreover, it had been demonstrated that NC was associated with oropharyngeal fatty in ltration, which narrows the upper airway, resulting in obstructive sleep apnea (OSA) [14].
A retrospective study found that the larger the NC (≥ 43.2 cm in men and ≥ 36.8 cm in women), the higher the incidence of obstructive sleep apnea was 2.52 times in men and 3.13 times in women [26].And, it was reported that compared with BMI, NC better explained the change in apnea-hypopnea index in morbidity obese women (n = 115) in the predictive model [27].OSA had been reported to be associated with ICH.The hypoxia and hemodynamic responses associated with OSA may predispose to stroke [28].Moreover, OSA was associated with the development of perihematoma edema [29], which may cause poor outcome after ICH [30][31][32].Several mechanisms may have in uence on the development of encephaledema after ICH.The early stage of cerebral edema occurs in the rst few hours after ICH, which involves hydrostatic pressure induced by formation of hematoma and retraction of clot, the second phase, caused by production of thrombin and activation of the coagulation cascade, occurs within the rst 24 hours, and the delayed stage involves in red blood cells hemolysis and hemoglobin-induced toxicity [33,34].The sizes of perihematoma edema have also been related to several factors such as the level of serum ferritin and increased matrix metalloproteinase-9 activity, which is an important enzyme for the blood brain barrier remodeling and perihematoma edema development [35][36][37][38].
Due to a momentary cessation of breathing, OSA patients with this disorder have repeated episodes of hypoxia/reoxygenation, promoting systemic oxidative stress, clotting cascade activation, in ammation, and damaged repair competence of the vascular endothelium [39].Thus, through the above several pathways, OSA may have a role in the generation of perihematoma edema.Moreover, OSA has also been demonstrated to be associated with the enhanced activity of matrix metalloproteinase-9.Therefore, it is reasonable to believe that the association between OSA and perihematoma edema is biologically plausible.
Mechanical ventilation after tracheotomy or endotracheal intubation may prevent OSA-related hypoxia.However, a previous study have reported that in acute spontaneous ICH patients, endotracheal intubation and mechanical ventilation were associated with increased risk of hospital-acquired pneumonia and inhospital mortality [40].Consistently, in the present study, we found that the proportions of patients with tracheotomy and endotracheal intubation were higher in the poor outcome group.The reason may be that the hematoma volume in ICH patients with tracheotomy or endotracheal intubation was larger than patients without tracheotomy or endotracheal intubation, which suggested more severe condition and poorer prognosis.
In addition, previous studies have shown that NC was associated with an increased risk of hypertension [18], diabetes [17,21] and metabolic syndrome [19], which also played a role in the occurrence and development of ICH [41][42][43].Furthermore, Pezzini et al. found that obesity, mainly through its indirect effect on hypertension and obesity-related complication, played a role in ICH [44].Taken together, NC should not be overlooked in evaluating ICH patients.However, our study still has several limitations.First, this study collected data from one hospital, with a limited sample size, which may lead to selection bias.Second, NC is one of the factors causing upper respiratory tract stenosis, and the presence of other unmeasured factors will still in uence our nal conclusion.Third, OSA was not accurately assessed in our study.At last, all the ICH patients were only from West China Hospital, recruiting poor clinical conditions patients usually because of the medical referral system.

Conclusions
NC is an independent predictor of unfavorable functional outcome at 6 months.Further experiments are necessary to explore the speci c mechanism.

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Figure 1 Flow
Figure 1