Perihematomal edema as predictor of outcome in spontaneous intracerebral hemorrhage

Introduction

Spontaneous intracerebral hemorrhage (SICH) (not related to trauma, thrombolysis, or anticoagulation) is a devastating form of cerebrovascular accident without any definite intervention to reduce the associated morbidity and mortality. There is a plethora of studies which have evaluated the predictors of outcome in SICH. Scoring systems utilizing the clinical and radiological parameters are in place to determine the prognosis. The acute mortality and morbidity in SICH have been linked to early hematoma expansion, cytotoxic and vasogenic perihematomal edema (PHE) formation, reduction in cerebral perfusion pressure, and raised intracranial pressure (ICP).[12] It is widely accepted that hematoma-induced neuronal damage is irreversible while that from PHE is reversible which makes the latter a potential therapeutic target. Hematoma volume is known to be a powerful predictor of outcome and also an independent predictor of absolute PHE volume.[3] PHE is visualized even when the imaging is performed within 3 h of onset. The major proportion of PHE is formed in initial 24 h and, after 72 h its growth occurs quite slowly for next 1 - 2 week. The pathogenesis of PHE is related primarily to three processes: Hematoma expansion and increased blood barrier permeability, clot retraction and activation of coagulation pathway and, finally, cytotoxic edema caused by erythrocyte lysis and hemoglobin breakdown products.[45] Factors which promote generation of PHE include hyperglycemia, hypertension, and ferritin level during the immediate postattack period.[67] The agents inhibiting N-methyl-D-aspartate receptor and desferroxamine which reduces the ferritin have been tried.[89] These studies underscore the increasingly recognized influence of PHE on the morbidity and mortality in patients of SICH. Studies determining contribution of absolute PHE volume and relative PHE (ratio of absolute PHE to hematoma volume) to morbidity and mortality are limited.[10] We undertook this study in our institution to determine the effect of PHE on the functional outcome in patients suffering from SICH.

Materials and Methods

This study was a prospective cohort study conducted from October 2010 to August 2012 in the Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India. Approval for the study was obtained from the Institutional Ethics Committee of the institution. Prior to enrollment an informed consent from the patients’ or their guardian was taken. Patients presenting with the clinical history suggestive of a cerebrovascular accident were subjected to screening with noncontrast computed tomography. The cases of SICH were evaluated.

Results

A total of 69 patients of SICH screened 25 patients had ≥1 features meeting the exclusion criteria. A total of 44 patients were enrolled in the study [Figure 2]. The baseline demographic, risk factors, and laboratory data of the patients are shown in Table 1. Mean hematoma volume for the primary patient population was 47.2 ± 13.07 mL; 86.4% of the hematomas were in deep anatomic locations. A mass effect (ventricular effacement/midline shift with line respect to pineal gland) was observed in 75% of the cases. The mean absolute PHE was 31.36 ± 10.32 mL, the minimum edema observed was 10.70 mL and the maximum was 58.0 mL. The mean relative edema in our study was 0.68 ± 024 ranging from 0.21 to 1.19.

Table 1 Historical, clinical, laboratory, disability status, and radiological characteristics of the patients

Predictors of outcome

On univariate analysis, none of the demographic characteristics of the patients, vascular risk factors, presenting complaints, blood pressure, Glasgow Coma Scale (GCS), and modified MRS score at admission, laboratory parameters were not significantly different in the two outcome groups. The location of hematoma (deep vs. superficial) also did not have influence on the outcome. The hematoma volume was significantly higher in the group with 12 week MRS ≥ 3 (P < 0.0001). The absolute PHE value did not seem to influence the outcome as it was insignificantly different in two groups. The relative edema was associated with a favorable outcome (MRS < 3) at 12 weeks (P < 0.0001) [Table 2].

Table 2 Predictive value of the characteristics on univariate analysis

Analyzing the all significant predictors together, the multivariate logistic regression revealed hematoma volume and the relative edema were found to affect the outcome significantly. The volume of hematoma correlated with a poor outcome [odds ratio (OR) =1.25, 95% confidence interval (CI) =1.02 - 1.53, P = 0.031] and relative edema correlated with a favorable outcome at 12 weeks (OR = 0.00, 95% CI = 0.00 - 0.08, P = 0.019) [Table 3]. We tested the effect of relative edema on survival by comparing the survival duration in the two groups with respect to the median relative edema volume (0.68 mL), the P value (0.126) was not significant [Figure 3].

Table 3 Modified rankin scale and Neuroimaging parameters

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Figure 3

Kaplan Meier Survival curve comparing survival in the two outcome groups with respect to mean relative edema

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Discussion

SICH is a devastating form of cerebrovascular accident associated with severe morbidity and mortality. The impact of SICH has been correlated with the patient's characteristics including, demographic profile, vascular risk factors, baseline sensorium, blood pressure and glycemic control, coagulation parameters and imaging findings, particularly the hematoma volume and the PHE. The infratentorial SICH is different from the supratentorial by virtue of being enclosed in a smaller space and a high likelihood of damaging the vasomotor and respiratory centers which can lead to immediate mortality. Similarly, the intraventicular extension of the hematoma also has poor prognostic implications for SICH. The infratentorial location and intraventricular extension have been found to be independent predictors of poor prognosis.[12] Moreover, the intraventricular extension can lead to extravasation of cerebrospinal fluid into PHE and leading to overestimation of the latter. In the supratentorial SICH without intraventricular extension hematoma volume has been established outcome across multiple studies as the strongest independent marker for a poorer prognosis. However, there have been conflicting observations regarding the importance of the patient's demographic characteristics, the baseline clinical and laboratory parameters. Recently, interest has been generated regarding the effect of the PHE on prognosis as the measures modifying it may serve to improve the patient's functional status. Since the maximum PHE formation occurs in the initial 24 h and grows slowly after 72 h, we chose to correlate the PHE in the window period of 24-72 h with the outcome. We had excluded infratentorial SICH and those with intraventricular extension. The absolute PHE has not been found to be an independent predictor for 30 day mortality as it has been correlated with hematoma expansion which in turn independently predicts 30 day mortality. The effect of relative edema is variable depending on the time from the onset of symptoms at which it is determined.

In our study, none of the demographic characteristics the age, gender, and the vascular risk factors including diabetes mellitus, hypertension, tobacco, and alcohol consumption was correlated with 12-week functional status. The presenting complaints and the baseline parameters such as the blood pressure (systolic, diastolic, and mean arterial), GCS, glycemic status, coagulation, and bleeding parameters were also of no significant difference among the two outcome groups. Castellanos et al.,[13] in a study evaluating the predictors of outcome in SICH had found that male gender and preexisting arterial hypertension predicted a poor prognosis. Claude et al.,[14] had established a scoring system for prognosis in SICH which comprised of age, GCS at presentation, location of hemorrhage, presence/absence of intraventricular hemorrhage, and the volume of hematoma. In their study GCS < 5 predicted a 97.1% mortality and age >80 years was correlated with a higher 30 day mortality rate compared with the younger patients. However, another recent study by Gebel et al., did not draw similar conclusions. In their study the patients’ characteristics, baseline clinical and laboratory parameters were no different in patients with favorable and unfavorable outcome.[13] It is hypothesized that high arterial blood pressure at the time of admission would promote initial hematoma expansion.[15] An elevated blood pressure at admission (MAP ≥ 145) had been correlated with worse morbidity and mortality by Dandapani BK et al.[15] The subsequent studies have not showed similar effect of blood pressure on outcome.[1617]. Melamed[18] was the first to demonstrate that reactive hyperglycemia is associated with poor outcome. A meta-analysis included the studies which have evaluated the glycemic status within 24 h of onset in relation to short term prognosis (up to one month).[19] It concluded that acute hyperglycemia predicts a poor short-term outcome; however, a prospective randomized control trial was deemed necessary in this regard.

Among the radiological characteristics the frequency of location of hematoma (deep vs. lobar) was no different in two groups of outcome. Claude et al., had demonstrated that deep location hematoma were significantly more in the patients with poor prognosis. However, once again Gebel et al., did not find such correlation in their study. A larger hematoma volume was found to be significantly and independently associated with a poor outcome in our subjects. In various studies, hematoma volume has been found to be an independent risk factor for 30 day mortality. Castellano et al., found a higher median hematoma volume 78.2 mL in patients with poor outcome compared with 58.2 mL in patients with favorable outcome. Claude et al., had defined hematoma volume greater than 30 mL in supratentorial SICH as a marker of high 30 day mortality. Gebel et al., found in their study a poor functional outcome at 12 weeks when the hematoma volume was high. The volume of absolute PHE was not different in the two outcome groups in our study. The PHE is primarily related to the hematoma volume and is not an independent predictor of outcome. The majority of the edema formation occurs during initial 24 h and its pathogenesis is considered to be secondary to hematoma expansion which disrupts the blood brain barrier leading to transudation of plasma into interstitium along the oncotic gradient. Hence, this is probably why the absolute edema does not hold significance in prediction of prognosis. Relative PHE was significantly different in the two groups in our study. A larger ratio of edema to hematoma volume was noticed in the group with favorable outcome (MRS < 3) at 12 weeks. This was contrary to the hypothesis that a higher edema would be associated with unfavorable functional outcome.[20] Our observation is in agreement with Gebel et al., they too had found that a higher relative edema was associated with a better function status at 12 weeks. The one plausible explanation to this phenomenon could be that the hematoma edema in initial hours may obliterate the shell of edema surrounding it. Since hematoma volume is directly related to morbidity and mortality, edema higher in relation to hematoma would probably signify lesser hematoma expansion and indirectly a better functional status.[15] The relative edema did not seem to affect the survival function in our patient as assessed by Kaplan-Meier survival curve.

Conclusion

In our study, the demographic features, vascular risk factors, disability and GCS at admission, and laboratory parameters did not exert any influence on the functional outcome. The hematoma volume predicted a poor outcome, while a relative edema was associated with a good functional status at 12 weeks.