The risk factors and prognosis of delayed perihematomal edema in patients with spontaneous intracerebral hemorrhage

Abstract Purpose We hypothesize delayed perihematomal edema (DHE) leads to secondary injury after spontaneous intracerebral hemorrhage (sICH) with a poor prognosis. Hence, we need to investigate the risk factors of DHE and identify whether DHE will predict the poor outcome of sICH. Methods We retrospectively recruited 121 patients with sICH admitted to the Department of Neurology from January 2014 to August 2018. After dividing all these patients into DHE group and non‐DHE group, we analyzed the potential risk factors and outcome of DHE using a multivariate logistic regression model. Results We conclude DHE after sICH associates with age, hospitalization time, hematoma shape, blood pressure upon admission, alcohol consumption, blood sodium level, and baseline hematoma volume within 24 hours after symptom onset, among which differences were statistically significant (P < .05). Logistic regression analysis finally identified that age (OR = 0.958, 95% CI = 0.923‐0.995) and the baseline hematoma volume (OR = 1.161, 95% CI = 1.089‐1.238) were the most significant risk factors for DHE, and moreover, the DHE (OR = 3.062, 95% CI = 1.196‐7.839) was also a risk factor for poor prognosis in sICH patients. Conclusion We suggest DHE is a clinical predictor of secondary injury following sICH and poor prognosis. In addition, age and baseline hematoma volume are considered significant high‐risk factors for DHE in patients with sICH.

mortality rate. However unfortunately, in addition to the hematoma itself, the secondary hematoma expansion and perihematomal edema (PHE) greatly affect the prognosis. It is currently understood that the development of PHE is a responsible factor for secondary injury after sICH, which usually leads to high cranial pressure, neurological deterioration, and even hernia leading to the extremely high mortality and disability rate, significantly relating to the course of disease. 3 A recent review article summarized that the PHE formation after sICH is complex and still quite controversial. It is known to occur hours, days, and even weeks following sICH onset, 4 and it is associated with direct hematoma compression on the surrounding tissues, hematoma toxicity, oxidative stress, and inflammation. 5,6 It is generally recognized that the disruption of vessels will rapidly cause a hematoma and vasogenic edema in the super-acute stage of ICH.
Except the hematoma occupying effect, the production of thrombin and activation of blood coagulation cascade contributes to a slow progressive edema growth, approximately peaking on the seventh day after ICH. 5,[7][8][9] On the other hand, the breakdown of the blood brain barrier, inflammatory cascades, heme, and iron load secondary to red cell dissolution as well as hemoglobin degradation will give rise to or accelerate PHE, but PHE will ameliorate or disappear with the alleviation of hematoma. [9][10][11] In our clinical work, we founded there are some patients admitted on hospital due to headache, vomiting, visual disturbance, or other symptoms caused by increased intracranial pressure, which is ascribed to the massive PHE happening on the convalescence after sICH. Many studies only mentioned the possible formation of delayed perihematomal edema, but did not give us a explicit definition of DHE. According to our research, we temporally defined the phenomenon, and the hematoma was significantly absorbed after the occurrence of sICH in closet 14th day after onset, but the PHE apparently aggravated, as delayed perihematomal edema (DHE). 4 Many studies focus on the hyperacute stage or acute stage after the ictus of sICH, and few recent studies describe DHE. Therefore, our study aims to investigate the risk factors and prognosis of DHE following the sICH and try to demonstrate whether DHE could be a clinical marker of sICH.

| Clinical data
The retrospective baseline data of 121 patients with sICH (Table 1) who were admitted to the Department of Neurology of the First Affiliated Hospital of Chongqing Medical University from January 2014 to August 2018 were recruited, of whom 38 patients were males and 83 were females, aged from 18 to 86, the median age being 59. All the included 121 patients were diagnosed with sICH in accordance with American Heart Association guidelines by a head computed tomography(CT) examination 2 within 24 hours after the known time of symptom onset in our hospital, and at least, three more head CT's performed within 24 hours, 5-9 days, and 12-20 days after the onset of sICH, retrospectively. All the patients were treated by controlling blood pressure and with conventional dehydration treatment.
We divided these patients into the DHE group and non-DHE group. The selection criteria of DHE were as follows: head CT obtained within 24 hours, 5-9 days, 12-20 days after the onset of sICH. We roughly calculated the volume of HE and PHE based on the CT thresholds. Moreover, the CT value of HE is varying from 44 to 100 Hounsfield units and the PHE is ranging from 5 to 33 Hounsfield units in the head CT. We use the area of every slice on CT multiply the slice thickness and then got the volume of HE and PHE by adding up all results. 2,12 The volume was blindly calculated by two physicians, and these measurements were used to obtain a volume average which was finally used in the analysis. The volume of PHE minus the volume of hematoma is the volume of absolute PHE. If the volume of absolute PHE in 12-20 days is 3 mL obviously larger than the volume of absolute PHE in 5-9 days, this could be defined as DHE in our study ( Figure 1

| Methods
Basic, clinically relevant data were collected from sICH patients: gender, age, blood pressure on admission, hospitalization time, hematoma shape, past medical history, the level of blood sodium, baseline hematoma volume within 24 hours after symptom onset, prothrombin time, fibrinogen level, albumin level, the location of hemorrhage, and modified Rankin Scale score (MRS score). As described previously, these factors were used to assess the association with the prognosis of ICH and DHE.

| Statistical analysis
Continuous variables that did not satisfy the normal distribution were expressed as median with interquartile range (IQR), and the Mann-Whitney U test was used for comparison between groups.
The categorical variables were reported as numbers (n) and percentages of the total (%), and the chi-square test was used to test the difference between groups. The multivariate logistic regression model was used to screen risk factors of DHE using a stepwise method. The data analysis for this study was generated using SAS 9.4 software (Copyright © 2016 SAS Institute Inc). Significant difference was determined at the α level of .05.

| General information
The Table 1 shows us a series of characteristics of basic data between the DHE group and the non-DHE group of sICH patients. The results of the single factor analysis on each variable determined the differences of age, hospitalization time, the regularity of hematoma border, blood pressure on admission, alcohol consumption, blood sodium levels, and baseline hematoma volume in the two groups were statistically significant (P < .05). The other characteristics made no difference between two groups.

| Multiple logistic analysis
Variables in which the P value < .05 in Table 1

| The prognosis of sICH patients
Whether the variables in Table 1

| D ISCUSS I ON
Our study demonstrates that the logistic analysis of all possible factors in Table 1  the continuous decrease in cerebral blood flow and cerebral perfusion pressure around the hematoma creates an ischemic area around the hematoma, resulting in the damage of the blood brain barrier and the increase in vasogenic edema, which supports our conclusion. 10,20 In addition, our study demonstrated that increased age de- especially regarding its role in late-onset brain edema.

| CON CLUS ION
Our data define the DHE and conclude that the occurrence of DHE is closely related to the poor prognosis of sICH patients. We suggest that clinicians be aware and alert of these factors. It is necessary for clinicians to repeat the head CT scan in 2 weeks or even a few weeks after the onset of sICH, especially those with symptoms like vomiting and headache. Otherwise, our research also suggests that the baseline hematoma volume and age are risk factors of DHE.
Considering the impacts of DHE, we propose with larger initial hematoma volume, the early operation should be more aggressive, and the dehydration treatment should be strengthened in clinical work to minimize the risk of DHE and improve the prognosis of DHE. For younger sICH patients, observation of their condition should also be closely and timely, so as to timely adjust the targeting treatment and reduce the incidence of DHE.

ACK N OWLED G M ENTS
The authors are grateful for the assistance from The First Affiliated Hospital of Chongqing Medical University for assistance with neuronal culture techniques.

CO N FLI C T S O F I NTE R E S T
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Informed Consent: Informed consent was obtained from all individual participants included in the study.

E TH I C A L A PPROVA L
This retrospective and single-center cohort study did not violate the