- Email: [email protected]
Spontaneous Intracerebral Hemorrhage in a Plateau Area: A Study Based on the Tibetan Population
Accepted Manuscript Spontaneous Intracerebral Hemorrhage in a Plateau Area: A Study Based on the Tibetan Population Ruiqi Chen, MD, Anqi Xiao, MD, Chao You, MD, Lu Ma, MD PII:
S1878-8750(18)31043-X
DOI:
10.1016/j.wneu.2018.05.090
Reference:
WNEU 8151
To appear in:
World Neurosurgery
Received Date: 23 March 2018 Revised Date:
11 May 2018
Accepted Date: 12 May 2018
Please cite this article as: Chen R, Xiao A, You C, Ma L, Spontaneous Intracerebral Hemorrhage in a Plateau Area: A Study Based on the Tibetan Population, World Neurosurgery (2018), doi: 10.1016/ j.wneu.2018.05.090. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Spontaneous Intracerebral Hemorrhage in a Plateau Area: A Study Based on the Tibetan Population
Authors: Ruiqi Chen1* MD, Anqi Xiao1* MD, Chao You1 MD and Lu Ma1 MD,
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*These authors contributed equally to the manuscript
1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu,
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Sichuan 610041, China;
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Corresponding author at all stages of refereeing and publication, also post-publication:
Lu Ma
No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, P.R. China
Tel: +86-028-85422972;
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Fax: +86-028-85422490;
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Email: [email protected]
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Corresponding author:
Key words: pediatric patients, pseudoaneurysms, head trauma, seizures, craniotomy surgery, endovascular
treatment
Abbreviation list:
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BMI: body mass index; CT: computed tomography; CTA: computed tomography angiography; CI: confidence
intervals; GCS: Glasgow Coma Scale; HIS: hospital information system; IRB: Institutional Review Board; mRS:
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Modified Rankin Scale; OR: odds ratio; SD: standard deviations; sICH: Spontaneous intracerebral hemorrhage;
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Objective: To reveal characteristics of spontaneous intracerebral hemorrhage (sICH) in a plateau area based on
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the Tibetan population.
Methods: Data of Tibetan and Han patients (control group) with sICH treated at our center from January 2013
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to April 2017 were retrospectively reviewed.
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Results: A total of 122 Tibetan and 927 Han patients were included. Compared with Han patients, Tibetan
patients were older (54.7±11.2 VS 50.9±18.3 years, P=0.027), exhibited higher ratios of males (73.8% VS
55.0%, P<0.001), overweight patients (22.1% VS 13.1%, P=0.007) and smokers (36.9% VS 20.5%, P<0.001),
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had a higher concentration of hemoglobin (163.7±17.6 VS 134.8±20.2 g/L, P<0.001) and included a higher
number of patients with hypertension (83.6% VS 60.5%, P<0.001), diabetes mellitus (19.2% VS 9.3%, P=0.002)
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and prior hemorrhagic stroke (9.0% VS 2.0%, P<0.001). Tibetan patients also experienced more brain stem
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hemorrhage (11.5% VS 5.1%, P=0.039) in the infratentorial region and had a higher risk of in-hospital
complications due to hematoma enlargement (20.5% VS 10.4%, P=0.002) and cerebral infarction (59.0% VS
9.7%, P<0.001). During a 6-month follow-up period, they had higher rates of unfavorable outcomes and case
mortality (P<0.05). A multivariable analysis adjusted for confounding factors revealed that the Tibetan race was
positively associated with unfavorable clinical outcomes in sICH patients (P<0.05).
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Conclusions: Tibetan sICH patients from the plateau area presented unique characteristics in their baseline
measurements, incidence of comorbidities, hematoma location, risk of in-hospital complications and clinical
outcomes in ICH patients.
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Key words: spontaneous intracerebral hemorrhage, Tibetan, Han, plateau area
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outcomes compared with Han patients. The Tibetan race was positively associated with unfavorable 6-month
Introduction
Spontaneous intracerebral hemorrhage (sICH) affects over 1 million people worldwide every year 1-3. It remains
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the most fatal and least treatable type of stroke. Although there have been many studies on sICH in different
populations, data from patients living in high-plateau areas remain absent. In China, the Tibetan minority is the
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typical population living in plateau areas. The so-called Tibetan plateau in West China (with an average
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elevation over 4500 m) is characterized by a special plateau atmosphere with low barometric pressure and
oxygen-thin air
4, 5
. The local high-salt and high-fat diet increases the risks of hypertension and hyperlipidemia
and, therefore, cerebral vascular diseases 6, 7. Little data on Tibetan sICH could be found until a Chinese national
survey revealed that ICH is the most frequent stroke subtype in the Tibetan population, with an incidence of
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450.4 per 100,000 individuals compared with an overall incidence of 135.6 per 100,000 individuals in Mainland
China 8. Due to a lack of related studies, the characteristics of Tibetan sICH remain unknown.
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As the largest and leading medical center in the western part of China, the West China Hospital of Sichuan
University (WCH) accepts a substantial number of patients from different regions covering the Tibetan
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plateau. In this study, we analyzed the medical data of Tibetan sICH patients recruited from our center from
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January 2013 to April 2017. By comparing them with contemporary Han patients (the majority of Chinese
Materials and methods
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population), we aimed to develop a better understanding of sICH in populations living in high-plateau areas.
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Study design and participants
This is a retrospective observational study approved by the Institutional Review Board (IRB) of WCH. The
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hospital information system (HIS) was used to search for consecutive sICH patients in our institute from
January 2013 to April 2017. Patients were filtered out by searching the discharge diagnosis in the HIS database
using the key words “Han”, “Tibetan” and “spontaneous intracerebral hemorrhage”. The exclusion criteria
were as follows: 1) patients with sICH due to head trauma, those who transferred from ischemic stroke, patients
with arteriovenous malformations or ruptured aneurysms, or patients with other secondary causes; 2) Tibetan
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patients living outside the Tibetan plateau region and Han patients from plateau area; and 3) patients with
incomplete medical or follow-up data.
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Data collection
The medical data collected contained the following baseline information: demographics including age, sex,
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body mass index (BMI; patients with BMI ≥25 were considered overweight), hemoglobin concentration, current
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smoking, current drinking and length of hospitalization; comorbidities, including history of hypertension,
diabetes mellitus, hypercholesterolemia, prior hemorrhagic stroke and coronary artery disease; clinical features,
including the Glasgow Coma Scale (GCS) upon admission; volume and location of hematoma, middle-line shift
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on the first computed tomography (CT) scan; treatment methods, as such as craniotomy surgery or conservative
treatment; in-hospital complications, such as hematoma enlargement, cerebral infarction, hydrocephalus,
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seizures, infectious diseases and gastrointestinal bleeding; and clinical outcomes, including in-hospital mortality,
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case mortality and neurological functional outcomes measured by the Modified Rankin Scale (mRS) at 1, 3 and
6 months after discharge. A favorable outcome was defined as an mRS score between 0 and 2 points, and an
unfavorable outcome was defined as an mRS score between 3 and 6 points.
Standard treatment
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Patients were quickly sent to the stroke unit to start the standard medical treatment and care. CT and CT
angiography (CTA) scans, routine blood work, biochemical examinations (hepatic and renal function,
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electrolytes and other tests) and routine coagulation studies were performed immediately. The medical history
and physical examination were also simultaneously recorded once the patients were admitted to the stroke unit.
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All patients had their vital signs monitored and were simultaneously given supportive treatment. All patients
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received standard medical treatments for sICH, including reducing intracranial pressure, controlling blood
pressure, preventing complications and other individualized treatments. Mannitol or glycerol/fructose was
administered at an appropriate dose for each individual. A craniotomy for ICH evacuation was performed for
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cortical/cerebellar locations, for large hemorrhage volumes associated with midline shift, for deteriorating
neurological status or for increased intracranial pressure. All medical procedures followed the recommendations
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Outcomes
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of the latest guidelines and clinical experience 9, 10.
The primary outcome was the risk factors for unfavorable neurological functional outcomes for ICH patients at
6 months after discharge. The secondary outcomes were the differences in the baseline information, incidence of
comorbidities, clinical features, risk of in-hospital complications and clinical outcomes between the Tibetan and
Han sICH patients.
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SPSS statistical software (version 22.0; SPSS Inc., Chicago, Illinois, USA) and Prism software (version 7.0;
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GraphPad Software Inc., San Diego, California, USA) were used for all statistical analyses. The means ±
standard deviations (SD) are reported for quantitative data. Categorical data are expressed as frequencies and
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percentages. Univariable analyses were conducted using Chi-square test or Fisher exact tests, Student t tests and
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Mann–Whitney U tests as appropriate to compare the medical data between “Tibetan” and “Han” sICH
patients. Kaplan-Meier curves were used to show and compare the survival curves between the two groups.
The Multiple logistic regression analysis was performed to adjust for confounding factors. If the odds ratio (OR)
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of a test was larger than 1, it was considered a risk factor; if the OR was less than 1, it was considered a
protective factor. Significance was defined as P<0.05, and 95% confidence intervals (CI) were calculated for
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each variable.
Results
Characteristics of Tibetan plateau ICH
A total of 122 Tibetan patients and 927 Han patients were retrospectively reviewed. A comparison of the
Tibetan and Han ICH patients is shown in Table 1. Compared with the Han patients, the Tibetan patients were
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older (54.7±11.2 VS 50.9±18.3 years, P=0.027), with higher constitutional ratios of male patients (73.8%,
n=90 VS 55.0%, n=510, P<0.001), overweight patients (22.1%, n=27 VS 13.1%, n=121, P=0.007) and smokers
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(36.9%, n=45 VS 20.5%, n=190, P<0.001) and had more patients with a history of hypertension (83.6%, n=102
VS 60.5%, n=561, P<0.001), diabetes mellitus (19.2%, n=23 VS 9.3%, n=86, P=0.002) and prior hemorrhagic
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stroke (9.0%, n=11 VS 2.0%, n=19, P<0.001). Tibetan patients also had a significantly higher hemoglobin
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concentration (163.7±17.6 VS 134.8±20.2 g/L, P<0.001). For the location of the hematomas in the
infratentorial region, the Tibetan patients had a significantly higher incidence of brain stem hemorrhage than the
Han patients (11.5%, n=14 VS 5.1%, n=56, P=0.039), while the Han patients had a higher incidence of
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cerebellum hematoma than the Tibetan patients (12.9%, n=120 VS 4.1%, n=6, P=0.016). Regarding the
in-hospital complications, the Tibetan group presented significantly higher risks of hematoma enlargement
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(20.5%, n=25 VS 10.4%, n=96, P=0.002) and cerebral infarction (59%, n=72 VS 9.7%, n=90, P<0.001) than the
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Han patients. Regarding the clinical outcomes, the Tibetan patients had a significantly higher rate of in-hospital
mortality (28.7%, n=38 VS 18.4%, n=171, P=0.011) than the Han patients. At the end of the 6-month follow-up
period, the Han patients had a significantly higher rate of favorable outcomes (38.5%, n=357 VS 28.7%, n=35,
P=0.045) and a lower mortality rate (23.3%, n=216 VS 35.2%, n=43, P=0.006) than the Tibetan patients.
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Furthermore, the Kaplan-Meier 6-month survival curves confirmed the significant higher trend of survival rates
in the Han group than in the Tibetan group (P=0.008). (Figure 1)
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Multivariable analysis
To evaluate the relationship between the Tibetans and poor clinical outcomes in ICH, we performed a multiple
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logistic regression analysis adjusted for confounding factors. After adjustment for age, sex, overweight,
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hemoglobin concentration, smoking, history of hypertension, diabetes mellitus and previous hemorrhagic stroke,
brain stem hemorrhage, complications of hematoma enlargement and cerebral infarction, the Tibetan group was
Discussion
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still associated with unfavorable outcomes among ICH patients. (Table 2)
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Tibet is located on the high Qinghai-Tibetan plateau and is known as the ‘third pole’ of the world. Its average
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altitude is approximately 4500 m above sea level. Thus far, limited data regarding sICH in the Tibetan
high-plateau population has been previously reported. Based on this present retrospective study, upon
comparing the clinical data for Tibetans with contemporary Han patients, Tibetan sICH patients tended to be
older, were predominantly male and had higher hemoglobin concentrations and higher ratios of overweight
patients, smokers and patients with a history of hypertension, diabetes mellitus or prior hemorrhagic stroke. In
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the infratentorial region, Tibetan patients had more hematoma in the brain stem rather than in the cerebellum.
They had higher risks of complications, including hematoma enlargement and cerebral infarction. They
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presented a poor clinical prognosis at the 6-month follow-up period with regard to mortality and neurological
functional status. Multivariable analysis revealed that Tibetan race was positively associated with the
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unfavorable clinical outcomes among sICH patients. The results of our study could help obtain a better
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understanding of sICH in the Tibetan people as a representative high-plateau population.
Tibetans are a race well known for their high-altitude adaptations. Based on our study, several differences were
observed between Tibetan and Han sICH patients. The typical plateau atmosphere, cultural background, social
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economic status and unique lifestyle of the Tibetan population may contribute to these discrepancies to some
extent. One of the most representative examples lies in the compensatory increase in blood hemoglobin
. In our study, the hemoglobin concentration was confirmed to be significantly higher in the Tibetan group
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concentration due to the reduced oxygen levels in the plateau area, also known as high-altitude polycythemia 11,
than in the Han group. Similarly, the significantly higher rate of hypertension among patients in the Tibetan
group may be due to their high-sodium, low-potassium diet habit in the plateau area, factors that have been
reported to be the risk factors of hypertension in related studies
13, 14
. The results were also consistent with
several observational studies reporting that a higher prevalence of hypertension was observed in Tibet than in
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15, 16
. In addition, poverty, insufficient medical resources and facilities might explain the high
rates of comorbidities, and the high risk of recurrent hemorrhagic stroke might be the consequence of an
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inadequate system for stroke rehabilitation 17. Further, unhealthy lifestyle habits, such as smoking addiction and
lack of weight control, further increased the risk of cardiovascular disease and its related mortality rate and
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morbidities 18, 19. Compared with females, males were more likely to engage in these unhealthy habits, possibly
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explaining the male predominance in the Tibetan group. Together, these results indicate that we still have a long
way to go regarding to the prevention, treatment and rehabilitation of hemorrhagic stroke in the Tibetan plateau
area. However, a decrease in ICH incidence and a better clinical prognosis could be expected with economic
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development, improvements in the medical system, education in ways to change unhealthy lifestyle habits and,
most importantly, as an adequate preventative measure, the timely diagnosis and proper treatment of
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hypertension.
In our study, a significantly greater number of patients with unfavorable neurological functional outcomes and
higher case mortality were observed in the Tibetan group during the 6-month follow-up. Based on the multiple
logistic regression analysis adjusted for potential confounding factors, the Tibetan race itself was still positively
associated with unfavorable outcomes in ICH patients. In addition, other risk factors for poor prognosis,
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including older age, the male sex, increased hemoglobin concentration and brain stem hemorrhage, were all
noted and showed significant differences between the Tibetan and Han groups. The results were consistent with
20-22
. In addition,
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previous studies that report the above risk factors for poor clinical prognosis in sICH patients
location of the hematoma in the infratentorial region showed a significant difference between the Tibetan and
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Han groups. The Tibetan group had more patients with brain stem hemorrhage, while cerebellum hemorrhage
predictor for a better clinical outcome
prognosis
25, 26
23, 24
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was more commonly seen in the Han group. According to previous studies, hematoma in the cerebellum was a
; in contrast, patients with brain stem hemorrhage had a worse
. This result was confirmed in our multivariable analysis of the location of the hematoma in the
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brain stem as a risk factor of unfavorable outcome among sICH patients. Together, these results indicate that
Tibetan race itself is an independent risk factor for an unfavorable outcome in sICH. However, the distinctive
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clinical outcomes between the Tibetan and Han groups might be caused by a combination of all of the risk
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factors mentioned above.
Notably, our study also found significantly higher risks of in-hospital complications, including hematoma
enlargement and cerebral infarction, among the Tibetan sICH patients. Based on our multivariable regression
analysis, the presence of these complications was also confirmed to be positively correlated with unfavorable
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outcomes in sICH patients. In addition to the increased risk of hemorrhage, greater concern should be placed on
the risk of cerebral infarction in the Tibetan group. Acute cerebral infarction is considered to be one of the major
30
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causes of unfavorable clinical outcome 27, 28 and manifests in approximately 3.7-22.9% of patients with sICH 29,
. Notably, 59% of patients in the Tibetan group presented cerebral infarction, which is significantly higher
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than the percentage of patients reported in previous studies. Given the significantly higher concentration of
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hemoglobin levels in Tibetan patients, we proposed the “hemoglobin, blood viscosity, tiny thrombosis-based
cerebral infarction” hypothesis as a possible mechanism of the high cerebral infarction risk in Tibetan sICH
cases. Specifically, the compensatory high hemoglobin concentration due to the oxygen-thin atmosphere of the
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Tibetan plateau area functions as the initial step in the transduction axis and then causes increased blood
viscosity. High blood viscosity subsequently leads to the development of tiny thromboses inside the cerebral
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vascular system, and finally, a cerebral infarction is formed. Several previous studies have reported increased
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blood viscosity caused by high hemoglobin levels
31, 32
. Moreover, some other studies have reported a
relationship between high blood viscosity and ischemic stroke in which the formation of tiny thromboses in the
cerebral vascular system may play an important role
33, 34
. Although supported by the studies mentioned above,
additional research is still needed to confirm our hypothesis.
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Our study also has some limitations. First, the study design was a retrospective, nonrandomized, observational
study performed only at a single center. Thus, the findings may not be generalizable to patients in other plateau
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areas with different conditions. Second, all of the data collected were based on inpatient records and short-term
follow-up periods; thus, the long-term prognoses remain uncertain. Third, as a minority population, the number
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of Tibetan patients in our study was much smaller than the number of Han patients. Meanwhile, our
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“hemoglobin, blood viscosity, tiny thrombosis-based cerebral infarction” hypothesis was based on speculation
by reviewing related studies and has not been directly reported in other scientific research. Therefore, additional
well-designed studies at multiple centers in high-plateau areas are required to provide more robust evidence to
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Conclusions
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verify the results of this study.
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Tibetan patients with sICH from a plateau area presented several unique characteristics in their baseline
measurements, incidence of comorbidities, hematoma location, risk of in-hospital complications and clinical
outcomes compared with Han patients. The Tibetan race was positively associated with unfavorable outcomes
in ICH patients.
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ACCEPTED MANUSCRIPT Acknowledgement: None
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Funding: This work was supported by the Fundamental Research Funds for Central Universities
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(2012017yjsy200).
the findings described in this paper.
1.
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ACCEPTED MANUSCRIPT Table 1: Comparison of Tibetan and Han ICH patients Tibetan
Han
(n=122)
(n=927)
54.7 (11.2)
50.9 (18.3)
0.027
90:32
510:417
<0.001
27 (22.1)
121 (13.1)
0.007
163.7 (17.6)
134.8 (20.2)
<0.001
Current smoker, n (%)*
45 (36.9)
190 (20.5)
<0.001
Current alcohol consumption, n (%)
32 (26.2)
258 (27.8)
0.972
12.8 (13.9)
0.122
P value
Sex ratio (male:female)* Overweight, n (%)* Mean hemoglobin, g/L (SD)*
Hospitalization, days (SD)
14.9 (15.5)
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Comorbidities, n (%)
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Mean age, years (SD)*
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Baseline information
102 (83.6)
561 (60.5)
<0.001
23 (19.2)
86 (9.3)
0.002
6 (4.9)
33 (3.6)
0.624
11 (9.0)
19 (2.0)
<0.001
20 (16.4)
109 (11.8)
0.187
9.5 (3.8)
9.9 (3.9)
0.286
36.03 (17.1)
34.9 (21.9)
0.955
32 (26.2)
234 (25.2)
0.901
70 (57.4)
517 (55.8)
0.811
Brain stem*
14 (11.5)
56 (6.0)
0.039
Cerebellum*
6 (4.1)
120 (12.9)
0.016
With IVH, n (%)
38 (31.1)
333 (35.9)
0.349
Midline shift, n (%)
45 (36.9)
301 (32.5)
0.383
Hypertension* Diabetes mellitus* Coronary artery disease Prior hemorrhagic stroke* Hypercholesterolemia
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Clinical features
GCS on admission, mean (SD) Hematoma volume, mL (SD)
Supratentorial
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Lobe
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Hematoma location, n (%)
Deep
Subtentorial
0.849
Treatment, n (%) Craniotomy
38 (31.1)
301 (32.5)
---
Conservative
84 (68.9)
626 (67.5)
---
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96 (10.4)
0.002
Infarction*
72 (59.0)
90 (9.7)
<0.001
Hydrocephalus
13 (10.7)
67 (7.2)
0.246
6 (4.9)
43 (4.6)
0.928
20 (16.4)
128 (13.8)
0.527
5 (4.1)
31 (3.3)
0.868
35 (28.7)
171 (18.4)
0.011
Pulmonary infection Gastrointestinal bleeding Clinical outcomes In-hospital mortality, n (%)* 6-month follow-up, n (%)
35 (28.7)
Mortality*
43 (35.2)
357 (38.5)
0.045
216 (23.3)
0.006
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Favorable outcome*
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Seizures
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Hematoma enlargement*
Tibetan indicates Tibetan spontaneous intracerebral hemorrhage (sICH) patients; Han indicates Han sICH patients; SD indicates standard deviation; overweight was defined as a body mass index (BMI) ≥25; GCS indicates Glasgow Coma Scale; NIHSS indicates National Institutes of Health Stroke Scale; IVH indicates intraventricular hemorrhage; Favorable outcome was defined as a Modified Rankin
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Scale (mRS) rating of 0-2; *P<0.05.
ACCEPTED MANUSCRIPT Table 2: Multivariable analysis of factors associated with unfavorable outcome in ICH patients
Risk ratio
Lower 95% CI
Age
1.10*
1.01
Male
2.71*
1.28
Tibetan
2.45*
1.39
Overweight
1.10
Hemoglobin concentration
3.04*
Upper 95% CI
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Characteristics
1.20
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6.42
4.33
2.84
1.01
5.57
0.68
2.17
1.70
0.45
3.61
Diabetes mellitus
1.83
0.13
5.42
Prior hemorrhagic stroke
1.31
0.42
2.17
Brain stem hemorrhage
1.16*
1.02
2.26
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0.58
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Hypertension
1.71
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Smoking
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1.03
1.12
Cerebral infarction
1.50*
1.17
1.93
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Hematoma enlargement
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CI indicates confidence interval; *P<0.05.
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ACCEPTED MANUSCRIPT 1049 sICH patients over a 4-year interval
2.
Characteristics of sICH in plateau area were reported based on the Tibetan population.
3.
Tibetan race was positively associated with unfavorable outcomes in ICH patients
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1.
S1878-8750(18)31043-X
DOI:
10.1016/j.wneu.2018.05.090
Reference:
WNEU 8151
To appear in:
World Neurosurgery
Received Date: 23 March 2018 Revised Date:
11 May 2018
Accepted Date: 12 May 2018
Please cite this article as: Chen R, Xiao A, You C, Ma L, Spontaneous Intracerebral Hemorrhage in a Plateau Area: A Study Based on the Tibetan Population, World Neurosurgery (2018), doi: 10.1016/ j.wneu.2018.05.090. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Spontaneous Intracerebral Hemorrhage in a Plateau Area: A Study Based on the Tibetan Population
Authors: Ruiqi Chen1* MD, Anqi Xiao1* MD, Chao You1 MD and Lu Ma1 MD,
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*These authors contributed equally to the manuscript
1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu,
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Sichuan 610041, China;
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Corresponding author at all stages of refereeing and publication, also post-publication:
Lu Ma
No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, P.R. China
Tel: +86-028-85422972;
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Fax: +86-028-85422490;
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Email: [email protected]
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Corresponding author:
Key words: pediatric patients, pseudoaneurysms, head trauma, seizures, craniotomy surgery, endovascular
treatment
Abbreviation list:
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BMI: body mass index; CT: computed tomography; CTA: computed tomography angiography; CI: confidence
intervals; GCS: Glasgow Coma Scale; HIS: hospital information system; IRB: Institutional Review Board; mRS:
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Modified Rankin Scale; OR: odds ratio; SD: standard deviations; sICH: Spontaneous intracerebral hemorrhage;
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Objective: To reveal characteristics of spontaneous intracerebral hemorrhage (sICH) in a plateau area based on
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the Tibetan population.
Methods: Data of Tibetan and Han patients (control group) with sICH treated at our center from January 2013
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to April 2017 were retrospectively reviewed.
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Results: A total of 122 Tibetan and 927 Han patients were included. Compared with Han patients, Tibetan
patients were older (54.7±11.2 VS 50.9±18.3 years, P=0.027), exhibited higher ratios of males (73.8% VS
55.0%, P<0.001), overweight patients (22.1% VS 13.1%, P=0.007) and smokers (36.9% VS 20.5%, P<0.001),
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had a higher concentration of hemoglobin (163.7±17.6 VS 134.8±20.2 g/L, P<0.001) and included a higher
number of patients with hypertension (83.6% VS 60.5%, P<0.001), diabetes mellitus (19.2% VS 9.3%, P=0.002)
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and prior hemorrhagic stroke (9.0% VS 2.0%, P<0.001). Tibetan patients also experienced more brain stem
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hemorrhage (11.5% VS 5.1%, P=0.039) in the infratentorial region and had a higher risk of in-hospital
complications due to hematoma enlargement (20.5% VS 10.4%, P=0.002) and cerebral infarction (59.0% VS
9.7%, P<0.001). During a 6-month follow-up period, they had higher rates of unfavorable outcomes and case
mortality (P<0.05). A multivariable analysis adjusted for confounding factors revealed that the Tibetan race was
positively associated with unfavorable clinical outcomes in sICH patients (P<0.05).
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Conclusions: Tibetan sICH patients from the plateau area presented unique characteristics in their baseline
measurements, incidence of comorbidities, hematoma location, risk of in-hospital complications and clinical
outcomes in ICH patients.
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Key words: spontaneous intracerebral hemorrhage, Tibetan, Han, plateau area
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outcomes compared with Han patients. The Tibetan race was positively associated with unfavorable 6-month
Introduction
Spontaneous intracerebral hemorrhage (sICH) affects over 1 million people worldwide every year 1-3. It remains
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the most fatal and least treatable type of stroke. Although there have been many studies on sICH in different
populations, data from patients living in high-plateau areas remain absent. In China, the Tibetan minority is the
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typical population living in plateau areas. The so-called Tibetan plateau in West China (with an average
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elevation over 4500 m) is characterized by a special plateau atmosphere with low barometric pressure and
oxygen-thin air
4, 5
. The local high-salt and high-fat diet increases the risks of hypertension and hyperlipidemia
and, therefore, cerebral vascular diseases 6, 7. Little data on Tibetan sICH could be found until a Chinese national
survey revealed that ICH is the most frequent stroke subtype in the Tibetan population, with an incidence of
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450.4 per 100,000 individuals compared with an overall incidence of 135.6 per 100,000 individuals in Mainland
China 8. Due to a lack of related studies, the characteristics of Tibetan sICH remain unknown.
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As the largest and leading medical center in the western part of China, the West China Hospital of Sichuan
University (WCH) accepts a substantial number of patients from different regions covering the Tibetan
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plateau. In this study, we analyzed the medical data of Tibetan sICH patients recruited from our center from
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January 2013 to April 2017. By comparing them with contemporary Han patients (the majority of Chinese
Materials and methods
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population), we aimed to develop a better understanding of sICH in populations living in high-plateau areas.
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Study design and participants
This is a retrospective observational study approved by the Institutional Review Board (IRB) of WCH. The
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hospital information system (HIS) was used to search for consecutive sICH patients in our institute from
January 2013 to April 2017. Patients were filtered out by searching the discharge diagnosis in the HIS database
using the key words “Han”, “Tibetan” and “spontaneous intracerebral hemorrhage”. The exclusion criteria
were as follows: 1) patients with sICH due to head trauma, those who transferred from ischemic stroke, patients
with arteriovenous malformations or ruptured aneurysms, or patients with other secondary causes; 2) Tibetan
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patients living outside the Tibetan plateau region and Han patients from plateau area; and 3) patients with
incomplete medical or follow-up data.
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Data collection
The medical data collected contained the following baseline information: demographics including age, sex,
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body mass index (BMI; patients with BMI ≥25 were considered overweight), hemoglobin concentration, current
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smoking, current drinking and length of hospitalization; comorbidities, including history of hypertension,
diabetes mellitus, hypercholesterolemia, prior hemorrhagic stroke and coronary artery disease; clinical features,
including the Glasgow Coma Scale (GCS) upon admission; volume and location of hematoma, middle-line shift
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on the first computed tomography (CT) scan; treatment methods, as such as craniotomy surgery or conservative
treatment; in-hospital complications, such as hematoma enlargement, cerebral infarction, hydrocephalus,
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seizures, infectious diseases and gastrointestinal bleeding; and clinical outcomes, including in-hospital mortality,
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case mortality and neurological functional outcomes measured by the Modified Rankin Scale (mRS) at 1, 3 and
6 months after discharge. A favorable outcome was defined as an mRS score between 0 and 2 points, and an
unfavorable outcome was defined as an mRS score between 3 and 6 points.
Standard treatment
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Patients were quickly sent to the stroke unit to start the standard medical treatment and care. CT and CT
angiography (CTA) scans, routine blood work, biochemical examinations (hepatic and renal function,
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electrolytes and other tests) and routine coagulation studies were performed immediately. The medical history
and physical examination were also simultaneously recorded once the patients were admitted to the stroke unit.
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All patients had their vital signs monitored and were simultaneously given supportive treatment. All patients
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received standard medical treatments for sICH, including reducing intracranial pressure, controlling blood
pressure, preventing complications and other individualized treatments. Mannitol or glycerol/fructose was
administered at an appropriate dose for each individual. A craniotomy for ICH evacuation was performed for
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cortical/cerebellar locations, for large hemorrhage volumes associated with midline shift, for deteriorating
neurological status or for increased intracranial pressure. All medical procedures followed the recommendations
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Outcomes
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of the latest guidelines and clinical experience 9, 10.
The primary outcome was the risk factors for unfavorable neurological functional outcomes for ICH patients at
6 months after discharge. The secondary outcomes were the differences in the baseline information, incidence of
comorbidities, clinical features, risk of in-hospital complications and clinical outcomes between the Tibetan and
Han sICH patients.
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SPSS statistical software (version 22.0; SPSS Inc., Chicago, Illinois, USA) and Prism software (version 7.0;
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GraphPad Software Inc., San Diego, California, USA) were used for all statistical analyses. The means ±
standard deviations (SD) are reported for quantitative data. Categorical data are expressed as frequencies and
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percentages. Univariable analyses were conducted using Chi-square test or Fisher exact tests, Student t tests and
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Mann–Whitney U tests as appropriate to compare the medical data between “Tibetan” and “Han” sICH
patients. Kaplan-Meier curves were used to show and compare the survival curves between the two groups.
The Multiple logistic regression analysis was performed to adjust for confounding factors. If the odds ratio (OR)
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of a test was larger than 1, it was considered a risk factor; if the OR was less than 1, it was considered a
protective factor. Significance was defined as P<0.05, and 95% confidence intervals (CI) were calculated for
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each variable.
Results
Characteristics of Tibetan plateau ICH
A total of 122 Tibetan patients and 927 Han patients were retrospectively reviewed. A comparison of the
Tibetan and Han ICH patients is shown in Table 1. Compared with the Han patients, the Tibetan patients were
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older (54.7±11.2 VS 50.9±18.3 years, P=0.027), with higher constitutional ratios of male patients (73.8%,
n=90 VS 55.0%, n=510, P<0.001), overweight patients (22.1%, n=27 VS 13.1%, n=121, P=0.007) and smokers
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(36.9%, n=45 VS 20.5%, n=190, P<0.001) and had more patients with a history of hypertension (83.6%, n=102
VS 60.5%, n=561, P<0.001), diabetes mellitus (19.2%, n=23 VS 9.3%, n=86, P=0.002) and prior hemorrhagic
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stroke (9.0%, n=11 VS 2.0%, n=19, P<0.001). Tibetan patients also had a significantly higher hemoglobin
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concentration (163.7±17.6 VS 134.8±20.2 g/L, P<0.001). For the location of the hematomas in the
infratentorial region, the Tibetan patients had a significantly higher incidence of brain stem hemorrhage than the
Han patients (11.5%, n=14 VS 5.1%, n=56, P=0.039), while the Han patients had a higher incidence of
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cerebellum hematoma than the Tibetan patients (12.9%, n=120 VS 4.1%, n=6, P=0.016). Regarding the
in-hospital complications, the Tibetan group presented significantly higher risks of hematoma enlargement
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(20.5%, n=25 VS 10.4%, n=96, P=0.002) and cerebral infarction (59%, n=72 VS 9.7%, n=90, P<0.001) than the
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Han patients. Regarding the clinical outcomes, the Tibetan patients had a significantly higher rate of in-hospital
mortality (28.7%, n=38 VS 18.4%, n=171, P=0.011) than the Han patients. At the end of the 6-month follow-up
period, the Han patients had a significantly higher rate of favorable outcomes (38.5%, n=357 VS 28.7%, n=35,
P=0.045) and a lower mortality rate (23.3%, n=216 VS 35.2%, n=43, P=0.006) than the Tibetan patients.
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Furthermore, the Kaplan-Meier 6-month survival curves confirmed the significant higher trend of survival rates
in the Han group than in the Tibetan group (P=0.008). (Figure 1)
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Multivariable analysis
To evaluate the relationship between the Tibetans and poor clinical outcomes in ICH, we performed a multiple
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logistic regression analysis adjusted for confounding factors. After adjustment for age, sex, overweight,
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hemoglobin concentration, smoking, history of hypertension, diabetes mellitus and previous hemorrhagic stroke,
brain stem hemorrhage, complications of hematoma enlargement and cerebral infarction, the Tibetan group was
Discussion
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still associated with unfavorable outcomes among ICH patients. (Table 2)
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Tibet is located on the high Qinghai-Tibetan plateau and is known as the ‘third pole’ of the world. Its average
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altitude is approximately 4500 m above sea level. Thus far, limited data regarding sICH in the Tibetan
high-plateau population has been previously reported. Based on this present retrospective study, upon
comparing the clinical data for Tibetans with contemporary Han patients, Tibetan sICH patients tended to be
older, were predominantly male and had higher hemoglobin concentrations and higher ratios of overweight
patients, smokers and patients with a history of hypertension, diabetes mellitus or prior hemorrhagic stroke. In
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the infratentorial region, Tibetan patients had more hematoma in the brain stem rather than in the cerebellum.
They had higher risks of complications, including hematoma enlargement and cerebral infarction. They
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presented a poor clinical prognosis at the 6-month follow-up period with regard to mortality and neurological
functional status. Multivariable analysis revealed that Tibetan race was positively associated with the
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unfavorable clinical outcomes among sICH patients. The results of our study could help obtain a better
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understanding of sICH in the Tibetan people as a representative high-plateau population.
Tibetans are a race well known for their high-altitude adaptations. Based on our study, several differences were
observed between Tibetan and Han sICH patients. The typical plateau atmosphere, cultural background, social
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economic status and unique lifestyle of the Tibetan population may contribute to these discrepancies to some
extent. One of the most representative examples lies in the compensatory increase in blood hemoglobin
. In our study, the hemoglobin concentration was confirmed to be significantly higher in the Tibetan group
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concentration due to the reduced oxygen levels in the plateau area, also known as high-altitude polycythemia 11,
than in the Han group. Similarly, the significantly higher rate of hypertension among patients in the Tibetan
group may be due to their high-sodium, low-potassium diet habit in the plateau area, factors that have been
reported to be the risk factors of hypertension in related studies
13, 14
. The results were also consistent with
several observational studies reporting that a higher prevalence of hypertension was observed in Tibet than in
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15, 16
. In addition, poverty, insufficient medical resources and facilities might explain the high
rates of comorbidities, and the high risk of recurrent hemorrhagic stroke might be the consequence of an
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inadequate system for stroke rehabilitation 17. Further, unhealthy lifestyle habits, such as smoking addiction and
lack of weight control, further increased the risk of cardiovascular disease and its related mortality rate and
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morbidities 18, 19. Compared with females, males were more likely to engage in these unhealthy habits, possibly
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explaining the male predominance in the Tibetan group. Together, these results indicate that we still have a long
way to go regarding to the prevention, treatment and rehabilitation of hemorrhagic stroke in the Tibetan plateau
area. However, a decrease in ICH incidence and a better clinical prognosis could be expected with economic
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development, improvements in the medical system, education in ways to change unhealthy lifestyle habits and,
most importantly, as an adequate preventative measure, the timely diagnosis and proper treatment of
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hypertension.
In our study, a significantly greater number of patients with unfavorable neurological functional outcomes and
higher case mortality were observed in the Tibetan group during the 6-month follow-up. Based on the multiple
logistic regression analysis adjusted for potential confounding factors, the Tibetan race itself was still positively
associated with unfavorable outcomes in ICH patients. In addition, other risk factors for poor prognosis,
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including older age, the male sex, increased hemoglobin concentration and brain stem hemorrhage, were all
noted and showed significant differences between the Tibetan and Han groups. The results were consistent with
20-22
. In addition,
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previous studies that report the above risk factors for poor clinical prognosis in sICH patients
location of the hematoma in the infratentorial region showed a significant difference between the Tibetan and
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Han groups. The Tibetan group had more patients with brain stem hemorrhage, while cerebellum hemorrhage
predictor for a better clinical outcome
prognosis
25, 26
23, 24
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was more commonly seen in the Han group. According to previous studies, hematoma in the cerebellum was a
; in contrast, patients with brain stem hemorrhage had a worse
. This result was confirmed in our multivariable analysis of the location of the hematoma in the
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brain stem as a risk factor of unfavorable outcome among sICH patients. Together, these results indicate that
Tibetan race itself is an independent risk factor for an unfavorable outcome in sICH. However, the distinctive
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clinical outcomes between the Tibetan and Han groups might be caused by a combination of all of the risk
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factors mentioned above.
Notably, our study also found significantly higher risks of in-hospital complications, including hematoma
enlargement and cerebral infarction, among the Tibetan sICH patients. Based on our multivariable regression
analysis, the presence of these complications was also confirmed to be positively correlated with unfavorable
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outcomes in sICH patients. In addition to the increased risk of hemorrhage, greater concern should be placed on
the risk of cerebral infarction in the Tibetan group. Acute cerebral infarction is considered to be one of the major
30
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causes of unfavorable clinical outcome 27, 28 and manifests in approximately 3.7-22.9% of patients with sICH 29,
. Notably, 59% of patients in the Tibetan group presented cerebral infarction, which is significantly higher
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than the percentage of patients reported in previous studies. Given the significantly higher concentration of
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hemoglobin levels in Tibetan patients, we proposed the “hemoglobin, blood viscosity, tiny thrombosis-based
cerebral infarction” hypothesis as a possible mechanism of the high cerebral infarction risk in Tibetan sICH
cases. Specifically, the compensatory high hemoglobin concentration due to the oxygen-thin atmosphere of the
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Tibetan plateau area functions as the initial step in the transduction axis and then causes increased blood
viscosity. High blood viscosity subsequently leads to the development of tiny thromboses inside the cerebral
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vascular system, and finally, a cerebral infarction is formed. Several previous studies have reported increased
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blood viscosity caused by high hemoglobin levels
31, 32
. Moreover, some other studies have reported a
relationship between high blood viscosity and ischemic stroke in which the formation of tiny thromboses in the
cerebral vascular system may play an important role
33, 34
. Although supported by the studies mentioned above,
additional research is still needed to confirm our hypothesis.
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Our study also has some limitations. First, the study design was a retrospective, nonrandomized, observational
study performed only at a single center. Thus, the findings may not be generalizable to patients in other plateau
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areas with different conditions. Second, all of the data collected were based on inpatient records and short-term
follow-up periods; thus, the long-term prognoses remain uncertain. Third, as a minority population, the number
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of Tibetan patients in our study was much smaller than the number of Han patients. Meanwhile, our
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“hemoglobin, blood viscosity, tiny thrombosis-based cerebral infarction” hypothesis was based on speculation
by reviewing related studies and has not been directly reported in other scientific research. Therefore, additional
well-designed studies at multiple centers in high-plateau areas are required to provide more robust evidence to
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Conclusions
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verify the results of this study.
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Tibetan patients with sICH from a plateau area presented several unique characteristics in their baseline
measurements, incidence of comorbidities, hematoma location, risk of in-hospital complications and clinical
outcomes compared with Han patients. The Tibetan race was positively associated with unfavorable outcomes
in ICH patients.
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Funding: This work was supported by the Fundamental Research Funds for Central Universities
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(2012017yjsy200).
the findings described in this paper.
1.
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ACCEPTED MANUSCRIPT Table 1: Comparison of Tibetan and Han ICH patients Tibetan
Han
(n=122)
(n=927)
54.7 (11.2)
50.9 (18.3)
0.027
90:32
510:417
<0.001
27 (22.1)
121 (13.1)
0.007
163.7 (17.6)
134.8 (20.2)
<0.001
Current smoker, n (%)*
45 (36.9)
190 (20.5)
<0.001
Current alcohol consumption, n (%)
32 (26.2)
258 (27.8)
0.972
12.8 (13.9)
0.122
P value
Sex ratio (male:female)* Overweight, n (%)* Mean hemoglobin, g/L (SD)*
Hospitalization, days (SD)
14.9 (15.5)
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Comorbidities, n (%)
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Mean age, years (SD)*
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Baseline information
102 (83.6)
561 (60.5)
<0.001
23 (19.2)
86 (9.3)
0.002
6 (4.9)
33 (3.6)
0.624
11 (9.0)
19 (2.0)
<0.001
20 (16.4)
109 (11.8)
0.187
9.5 (3.8)
9.9 (3.9)
0.286
36.03 (17.1)
34.9 (21.9)
0.955
32 (26.2)
234 (25.2)
0.901
70 (57.4)
517 (55.8)
0.811
Brain stem*
14 (11.5)
56 (6.0)
0.039
Cerebellum*
6 (4.1)
120 (12.9)
0.016
With IVH, n (%)
38 (31.1)
333 (35.9)
0.349
Midline shift, n (%)
45 (36.9)
301 (32.5)
0.383
Hypertension* Diabetes mellitus* Coronary artery disease Prior hemorrhagic stroke* Hypercholesterolemia
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Clinical features
GCS on admission, mean (SD) Hematoma volume, mL (SD)
Supratentorial
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Lobe
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Hematoma location, n (%)
Deep
Subtentorial
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Treatment, n (%) Craniotomy
38 (31.1)
301 (32.5)
---
Conservative
84 (68.9)
626 (67.5)
---
ACCEPTED MANUSCRIPT Complications, n (%) 25 (20.5)
96 (10.4)
0.002
Infarction*
72 (59.0)
90 (9.7)
<0.001
Hydrocephalus
13 (10.7)
67 (7.2)
0.246
6 (4.9)
43 (4.6)
0.928
20 (16.4)
128 (13.8)
0.527
5 (4.1)
31 (3.3)
0.868
35 (28.7)
171 (18.4)
0.011
Pulmonary infection Gastrointestinal bleeding Clinical outcomes In-hospital mortality, n (%)* 6-month follow-up, n (%)
35 (28.7)
Mortality*
43 (35.2)
357 (38.5)
0.045
216 (23.3)
0.006
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Favorable outcome*
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Seizures
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Hematoma enlargement*
Tibetan indicates Tibetan spontaneous intracerebral hemorrhage (sICH) patients; Han indicates Han sICH patients; SD indicates standard deviation; overweight was defined as a body mass index (BMI) ≥25; GCS indicates Glasgow Coma Scale; NIHSS indicates National Institutes of Health Stroke Scale; IVH indicates intraventricular hemorrhage; Favorable outcome was defined as a Modified Rankin
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Scale (mRS) rating of 0-2; *P<0.05.
ACCEPTED MANUSCRIPT Table 2: Multivariable analysis of factors associated with unfavorable outcome in ICH patients
Risk ratio
Lower 95% CI
Age
1.10*
1.01
Male
2.71*
1.28
Tibetan
2.45*
1.39
Overweight
1.10
Hemoglobin concentration
3.04*
Upper 95% CI
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Characteristics
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6.42
4.33
2.84
1.01
5.57
0.68
2.17
1.70
0.45
3.61
Diabetes mellitus
1.83
0.13
5.42
Prior hemorrhagic stroke
1.31
0.42
2.17
Brain stem hemorrhage
1.16*
1.02
2.26
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0.58
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Hypertension
1.71
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Smoking
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1.03
1.12
Cerebral infarction
1.50*
1.17
1.93
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Hematoma enlargement
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CI indicates confidence interval; *P<0.05.
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ACCEPTED MANUSCRIPT 1049 sICH patients over a 4-year interval
2.
Characteristics of sICH in plateau area were reported based on the Tibetan population.
3.
Tibetan race was positively associated with unfavorable outcomes in ICH patients
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1.