Deleterious Mechanical Effects of The Hematoma

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Intracerebral hemorrhages is strongly associated with cerebral microvascular diseases (Xi et al., 2006).

The most frequent underlying disorder is hypertensive microangiopathy which predominantly manifests
in deep cerebral structures (basal ganglia, brain stem and cerebellum) (Fisher, 1971, 2003)

Predictors of poor clinical outcome are the initial hematoma volume, hematoma expansion during the
first day, location of the hematoma, extent of brain edema, age and neurological status on admission
(Hanley, 2009; Mendelow et al., 2011; Kuramatsu et al., 2013)

Deleterious mechanical effects of the hematoma


Primary brain injury after ICH is caused by the tissue disruption due to parenchymal blood accumulation
and the mechanical damage associated with the mass effect (Figure (Figure1).1). Besides treating
increased intracranial pressure (Helbok et al., 2011), surgical interventions to remove the blood clot and
release the pressure would appear a plausible approach in this phase (Gautschi and Schaller, 2013). In
about one third of patients (Kazui et al., 1996; Brott et al., 1997), re-bleeding and the expansion of the
hemorrhage within the first day after the ictus further exacerbates the mass effect and thus neurological
damage. Preventing this complication by aggressive antihypertensive therapy or by administration of
hemostatic factors may prevent secondary hematoma growth. (Sakamoto et al., 2013). However,
evidence for clinical efficacy is limited. The concept of brain damage resulting from peri-hematomal
ischemia induced by the increased intracranial pressure has not been confirmed in studies using
positron emission tomography in patients (Zazulia et al., 2001). However, a recent magnetic resonance
imaging (MRI) study found ischemic events in one third of ICH patients within 1 month after the ictus
(Menon et al., 2012).

Immediately after ICH, peri-hematomal edema develops which increases intracranial pressure and
contributes to the mass effect (Xi et al., 2006). Edema in ICH is associated with higher in-hospital
mortality (Staykov et al., 2011). In animal models, edema peaks already 3–4 days after ICH-induction (Xi
et al., 1998). In contrast, the edema expands in ICH patients until at least 10 days after the ictus (Staykov
et al., 2011). In the first hours after ICH, edema is mainly formed by plasma egress due to the increased
hydrostatic pressure and the damaged blood-brain barrier (BBB); edema also results from extruded
serum during clot retraction (Wagner et al., 1996). Later on, thrombin production, erythrocyte lysis and
the triggered inflammatory processes are responsible for edema formation (Xi et al., 2001a)

Mechanisms of secondary brain damage


Besides the mechanical tissue damage caused by the initial hematoma, injured brain cells and the
extravasated components of the blood clot trigger a complex sequence of parallel and sequential
deleterious mechanisms including inflammatory and oxidative stress pathways

Activation of hemostatic mechanisms is a physiological tissue response to hemorrhage to stop the


bleeding. Thrombin is essential for the blood coagulation processes and gets activated within the first
hour after ICH (Gong et al., 2008). Intracerebral injection of thrombin leads to early brain edema
formation by direct opening of the BBB (Lee et al., 1997) and to neuronal damage at days 1 and 3 after
ICH (Gong et al., 2008). High concentrations of thrombin induce neuronal damage in vitro, however, low
concentrations are neuroprotective against various insults including ischemia or oxidative stress
(Vaughan et al., 1995; Donovan et al., 1997; Striggow et al., 2000). Moreover, thrombin has an important
role in brain recovery after intracerebral hemorrhage (Hua et al., 2009) possibly via the initiation of
neurogenesis (Yang et al., 2008) and angiogenesis (Tarzami et al., 2006; Tsopanoglou and Maragoudakis,
2007). Therefore, the role of thrombin after ICH remains controversial

The lysis of erythrocytes within the first days after ICH leads to the release of hemoglobin which
is then converted by the heme oxygenase-1 enzyme (HO-1) into neurotoxic components such as
heme and iron which are major contributors to secondary brain injury (Wagner et al., 2003; Wu
et al., 2003; Keep et al., 2012). Intracerebral injection of lyzed erythrocytes or hemoglobin and
iron result in brain edema formation and neuronal damage (Xi et al., 1998; Huang et al., 2002).
The proposed mechanism of heme- and iron-induced neurotoxicity is the induction of oxidative
stress due to the activity of HO-1 (Koeppen et al., 2004; Wang and Doré, 2007a) and the iron-
mediated free radical production via the Fenton-reaction (Wu et al., 2003, 2011; Clark et al.,
2008).
The inflammatory reaction comprising both cellular and molecular components is a common
response of the central nervous system (CNS) to various stimuli. Neuroinflammation after ICH
involves the early activation of resident microglia, release of proinflammatory mediators and the
influx of peripheral leukocytes and has major role in the pathophysiology of secondary brain
damage (Wang and Doré, 2007b; Wang, 2010). Components of both innate and adaptive immune
system take part of ICH-induced neuroinflammation. At present, the involvement of antigen
specific immune processes remains unclear in both ischemic and hemorrhagic stroke.

Predictive factors of brain death in severe stroke


patients identified by organ procurement and
transplant coordination in Lorrain, France
Lisa Humbertjean
Gioia Mione
Renaud Fay
Laurent Durin
Sophie Planel
Jean‐Christophe Lacour
Ana‐Maria Enea
Sébastien Richard

There are no established predictive factors to identify patients at the acute phase of
severe stroke with a high probability of presenting brain death (BD). We
retrospectively collected clinical and paraclinical data of consecutive patients at the
acute phase of severe stroke with a potential progression to BD through the
hospital organ procurement and transplant coordination system in five centres in
Lorrain (France) between 1 January 2012 and 31 December 2013.

Patients with severe brain injuries are most likely to progress to brain death (BD) 1.
A French register conducted by the ‘Agence de la Biomédecine’ revealed that stroke
was the first cause of progression to BD and accounted for around 58% of organs
available for donation in France in 2013. Potential donors require intensive care
unit (ICU) management to preserve organs until possible BD. However, identifying
patients with severe stroke which could progress to BD is particularly difficult at the
acute phase because of a lack of clearly established predictive clinical or paraclinical
criteria. Previous studies have identified simple predictive clinical signs for BD in
comatose patients but only following haemorrhagic strokes or traumatic brain
injuries which are not representative of the population of patients in stroke units 2,
3. In practice, physicians do not have a reliable tool to predict BD which results in a
failure of screening potential organ donors among stroke patients and a risk of
inflicting invasive resuscitation measures to protect the organs in patients with a
low probability of BD. Determining the predictive factors of BD could help
physicians to better identify potential organ donors and to make the difficult choice
between management in ICU and a withholding and withdrawing decision. We
designed a study to determine predictive clinical and paraclinical factors of BD in
stroke victims at admission and to establish a simple score usable in clinical
practice.

Discussion
Stroke severity remains a subjective notion and is currently based on the
physician's experience taking into account all the clinical and radiological signs
which could predict a life‐threatening condition for the patient. Objective tools to
better define severity are required, all the more so in the case of a potential
progression to BD. We have identified several predictive factors which could form a
predictive score of BD in patients at the acute phase of severe stroke: GCS score ≤6
before sedation, stroke volume >65 ml, the presence of herniation and/or
hydrocephalus on brain imaging, initial SBP >150 mmHg and history of alcohol
abuse. These findings could form the basis of a simple score usable at the patient's
bedside to help physicians identify patients likely to progress to BD. Nearly, all the
patients in this study were identified by OPTC within 24 h following stroke onset,
that is the interval we consider as being the acute phase during which our score
would be applicable.

Several criteria have already been used to predict BD in patients with serious post‐
traumatic cerebral injuries in neurosurgical centres but not for stroke patients.
Furthermore, while numerous studies describe criteria as factors of poor prognosis
(functional and vital) in stroke patients – primary coma, National Institute of Health
Stroke Score (NIHSS) >17 and stroke volume >60 cm – they do not specifically focus
3

on progression to BD 3. Clinical grading scales play an important role in evaluating


patients with acute neurological disorders and in their management. The impact of
a low initial GCS score has been reported as a predictive factor of poor outcome in
stroke patients and may reflect severe brain injury and hydrocephalus due to high
stroke volume and herniation 3. It should be systematically calculated at the first
medical examination to evaluate the patient's neurological status. The NIHSS does
not seem to be an appropriate indicator because of the quasi‐systematic presence
of coma on patient admission. In our study, high initial SBP is independently
associated with progression to BD. High blood pressure is a known predictive factor
of poor functional and vital outcomes, for both haemorrhagic and ischaemic
strokes, but has yet to be proved as a predictive factor of BD 7. The impact of stroke
volume on BD in our study was clear: we were able to define a cut‐off volume of
65 ml, a threshold above which patients are more likely to progress to BD. Earlier
studies have already described criteria to predict progression of fatal brain swelling
for anterior ischaemic strokes. They are in accordance with our study as stroke
volume was one of the strongest predictors. Kriger et  al. showed an independent
association with mortality for hypodensity in more than half of the middle cerebral
artery territory on CT scan, while Oppenheim et  al. determined a cut‐off of 145 ml
on diffusion weighted images for malignant progression with a sensitivity of 100%
8, 9. Our score used a lower cut‐point without reaching the same sensitivity.
However, previous studies were more focused on predicting death, while our 65 ml
cut‐off reflects progression to BD in a widespread population. It should be noted
that our volume was determined by combining PH and cerebral infarcts on CT scan
and MRI. For haemorrhagic stroke, several studies have established a link between
stroke volume and clinical outcome. A lower cut‐off between 20 and 30 ml is more
widely used to predict a high risk of short term mortality 10. Hydrocephalus and
herniation were also found associated with BD. This indirectly reflects a high stroke
volume associated with a compression of vital vegetative centres in the brain. One
study describes hydrocephalus as a predictor of early mortality in young patients
with nontraumatic intracerebral haemorrhage 4. Alcohol abuse has already been
described as an aggravating factor of stroke, especially for PH, as it can increase
SBP 11. Finally, it was found to be significantly associated with BD in our study.
Alcohol abuse was deduced from an interview with the patients’ relatives and was
retained if they considered the patient drank too much, too often or was unable to
control his/her alcohol consumption. Future prospective studies should assess this
factor with a more precise quantification of alcohol consumption, for example the
number of alcohol units consumed per week. No significant difference was
observed in progression to BD between ischaemic and haemorrhagic strokes. This
suggests that patients with cerebral infarctions can progress to BD, while physicians
are currently more likely to refer patients with PH or SAH to ICUs as potential
donors. The same observation can be made for location of ischaemic strokes:
physicians are less likely to consider patients with a posterior circulation stroke as
progressing to BD than those with anterior infarctions.

This retrospective study has some limitations that deserve to be mentioned and
which are mainly due to the study design and the difficulties in collecting data
because of the patients’ impaired consciousness. Some data about initial GCS score
and blood pressure was missing. Furthermore, it was not possible to collect some
important information such as the exact time between patient identification and
BD. Alcohol consumption could only be estimated from the family environment
with lacked precision. In addition, the presence of brain stem reflexes was not
observed directly, but their disappearance is almost always observed in ICU near
BD and less in stroke units at the initial phase of stroke. A better definition of
radiological criteria, such as differentiating between the types of herniation, may
also improve the accuracy of the scores. The OPTC unit was called after a decision
had been made to withhold therapy and depended on physician's opinion rather
than any specific criteria. This could lead to selection bias, as some physicians
consider, for instance, that patients with posterior stroke are not at high risk of
presenting BD, or that the organs of elderly patients are not suitable for
transplantation. All these limitations reinforce the need of a prospective study
including more precise selection and evaluation criteria.

Conclusions
To the best of our knowledge, this is the first study to highlight predictive clinical
and paraclinical factors of BD in patients at the acute phase of severe stroke and to
establish a predictive score. Initial GCS score, stroke volume, herniation,
hydrocephalus, initial high SBP and a history of alcohol abuse represent predictive
factors of progression to BD for patients in this setting. Taken together, these
factors can form the basis of a simple score system to help physicians make a
difficult decision: it could contribute to identify more accurately if a patient with
severe stroke could be a potential organ donor, and improve selection of these
cases to propose ICU management to preserve organs in patients with a high
probability of progression to BD. This could facilitate the delicate discussions with
family members to request permission for organ donation, as many find
uncertainty about the patient's outcome unbearable. The findings of this study
have to be confirmed by other prospective multicentre studies with a higher
number of patients and including other clinical data like brain stem reflexes.

Effects of Aging

Advanced age is associated with worse clinical outcomes in many conditions. In the case
of ICH, this association may be independent or directly related to the pathology of
multiple risk factors of stroke, such as hypertension. There are numerous effects of
aging on the body, and most significant in the case of ICH, are age related changes of the
cerebrovascular system and the aging brain.

The effect of aging on the brain’s microvasculature is well-recognized, and includes


decreased vascular density, micro embolic brain injury, vessel basement membrane
thickening, endothelial dysfunction, and increased blood brain barrier permeability. In
addition, cerebral white matter lesions known as leukoaraiosis— characterized by
spongiosis, gliosis, demyelination, and capillary degeneration [6]—are seen in the
elderly population with vascular risk factors and/or vascular dementia, and are thought
to be related to cerebrovascular disease in this population. Systemic conditions such as
hypertension and diabetes mellitus may also contribute to these changes of the
cerebrovasculature. These structural changes to the brain’s vasculature make the
parenchyma that it supplies more susceptible to injury, which increases the risk of
stroke. Pathology involving further endothelial damage, changes in vessel elasticity, or
fluctuations in blood flow and pressure, implicate chronic diseases such as
hypertension, atherosclerosis, diabetes, and atrial fibrillation in worsening risks of
neurologic injury.

Age-related changes of gross brain volume are also well documented, with an annual
loss of volume ranging from 0.2-0.5% [4], especially in regions such as the prefrontal
cortex [3], and are thought to be the result of neuronal atrophy. In a study by Gottesman
et al., the authors suggested that since the elderly tend to have anatomically smaller
brains than their younger counterparts, a given stroke volume in the elderly would affect
a greater proportion of brain parenchyma, which may be a factor in the poorer
neurological outcome [7]. Older populations also have a higher probability of having a
history of prior strokes, which could impair their ability to recover from and make them
more susceptible to additional injuries [8]. Additionally, several animal studies have
shown that white matter vulnerability increases with age and could explain why post-
ictus cognitive decline is higher in older populations

Aging and Other Issues

The weakened physiologic reserve, higher mortality rates, worse healing, worse long-
term functional outcomes, and more debilitation with less insult is often seen in
comparison to younger cohorts [33]. This reduction in physiologic reserve, the extra
capacity of the body’s organ systems to overcome challenges, increases the susceptibility
of older patients to injury, disease, and loss of function. In Pisani’s review article, many
of the physiological changes associated with treating elderly populations are elucidated
[34]. For instance, as individuals age, their ability to respond to sympathetic stimulation
declines, leading to failure of compensatory mechanisms such as increased maximal
heart rate, ejection fraction and cardiac output. This puts them at an increased risk for
vascular complications. A decrease in pulmonary function up to 50% can also be seen
with older patients. Likewise, the kidneys also experience declining function due to the
fact that approximately 40% of the nephrons become sclerotic between the ages of 25
and 85. Furthermore, renal blood flow decreases by half and the glomerular filtration
rate declines to about 45% by the time an individual reaches 80 years of age.
Medications will also have a different physiological effect. Hepatic blood flow
diminishes by 30% between the ages of 30 and 75, and this alters the absorption,
distribution, metabolism and excretion of medication. These factors culminate in age-
related decline of organ system functions that cause an increased vulnerability to sepsis,
changes in pharmodynamics, and cognitive decline [34], all of which are contributing to
disproportionate rates of complications, extended inpatient hospitalizations, and
intensive care unit admissions in older cohorts compared to their younger counterparts.
While a determined age at which these changes occur most frequently is still uncertain,
the literature suggests that age does impact certain complication rates during inpatient
hospitalizations after stroke.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772257/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772257/

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