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Glycemia in spontaneous intracerebral hemorrhage: 

clinical implications 

Hernando Alvis-Miranda1, Gabriel Alcala-Cerra2, Luis Rafael 

Moscote-Salazar2 

Universidad Cartagena, Colombia 
1Cartagena de Indias; 2Neurosurgeon 

 

Abstract 

Spontaneous cerebral hemorrhage or 

intracranial hemorrhage accounts for 10-15% 

of all strokes. Intracranial hemorrhage is much 

less common than ischemic stroke, but has 

higher mortality and morbidity, one of the 

leading causes of severe disability. Various 

alterations, among these the endocrine were 

identified when an intracerebral hemorrhage, 

these stress-mediated mechanisms exacerbate 

secondary injury. Deep knowledge of the 

injuries which are directly involved alterations 

of glucose, offers insight as cytotoxicity, 

neuronal death and metabolic dysregulations 

alter the prognosis of patients with 

spontaneous intracerebral hemorrhage. 

Key words: intracranial hemorrhage, 

Glycemia, stroke, neurosurgery 

Introduction 

Spontaneous intracerebral hemorrhage 

(sICH) is a devastating and disabling disease 

(1, 2). Is the second most common form of 

stroke, representing 10-30% of first-ever 

strokes (3). Overall incidence sICH worldwide 

is 24.6 per 100,000 person-years with 

approximately 40,000 to 67,000 cases per year 

in the United States (4-7), approximately half 

of this mortality occurs within the first 24 

hours, highlighting the critical importance of 

early and effective treatment in EDs (8). 

Deleterious effect of metabolic 

derangements like hyperglycemia has been 

studied since Claude Bernard described the 

relationship between hyperglycemia and 

cerebral injury (9).  The occurrence of 

hyperglycemia is a known phenomenon in 

various types of acute cerebral injury. When 

measured at arrival to ED, hyperglycemia is 

associated with worse outcome in both 

diabetic and nondiabetic patients (10-13). 

 A high proportion of patients (about 60%) 

might develop hyperglycemia even in the 

absence of a previous history of diabetes after 

sICH (14). Increased blood glucose in the 

acute setting of sICH is probably a response to 

stress and severity of sICH (15) and can persist 

for up to 72 h after sICH (14). Declining 

glucose values after sICH are associated with a 

decreased risk of hematoma expansion and 

poor outcome, suggesting that early glucose 



 

 

 

 

 
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control may improve outcomes (16). Many 

studies have shown that increased serum 

glucose on admission is associated with larger 

haematoma size, expantion, perihematomal 

oedema, cell death, intraventricular extention 

(17), and increased risk of poor outcome (10, 

11, 14, 18, 19), furthermore is a potent 

predictor of 30 day mortality in both diabetic 

and non-diabetic patients with sICH as well as 

an independent predictor of early mortality 

and worse functional outcome in non-diabetic 

patients with sICH (11, 19, 20). 

Glucose and brain physiology (21-48) 

The brain is an expensive energy organ. 

Brain function requires the 15% of the cardiac 

output, consumes 20% of the oxygen and the 

25% of the total organism glucose; has a high 

tolerance to the temporal fuel deficit, because 

it only consumes approximately 33% of the 

available oxygen and a 10% of the total glucose. 

The cerebral blood flow (CBF) is the supply of 

energetic sources, in a mean of 

50mL/100g/min, with a brain oxygen 

consumption of 50cm3/min, and a similar 

carbon dioxide production, with a respiratory 

quotient near to 1, indicating that 

carbohydrates are the main substrates for the 

brain oxidative metabolism (49). 

All the different cells types in the central 

nervous system (i.e., neurons, glia and vascular 

cells) show a different metabolic glucose 

consumption rate. Virtually, the only 

metabolic fuel of the brain is glucose; under 

aerobic conditions this molecule undergoes 

glycolysis to adenosine triphosphate (ATP) 

and pyruvate. Pyruvate is converted to acetyl-

CoA via the Kreb’s cycle to generate ATP and 

reducing equivalents, this is the aerobic way, 

renders 30 moles of ATP; exists another way to 

convert glucose to ATP, the anaerobic way, but 

it is inefficient, just renders 2 moles of ATP 

through production of lactic acid.  

Glucose entre to the brain through GLUT 

family of hexose transportes; astrocytes 

express GLUT1, GLUT2, and GLUT4, 

neurons express GLUT3, GLUT4, and GLUT8 

(50). If neurons, preferentially access to 

glucose directly from the brain interstitial fluid 

or if the metabolism of glucose to lactate by 

astrocytes is a required step, is still in debate 

(51, 52).  

Brain needs glucose, but also controls the 

glucose levels when integrating information 

from peripheral receptors (53). Has been 

established that brain insulin plays a crucial 

role in the regulation of the metabolism, 

enhancing glucose uptake by astrocytes (54). 

Studies using SPECT technology have 

suggested that glucose transport and 

metabolism in human brain are dependent of 

blood supply. Has been demonstrated insulin-

mediated increases in mean global rate of 

brain glucose utilization, suggesting that 

insulin may play some role in the regulation of 

cerebral glucose, especially in the cortex (55). 

Alterations of the insulin actions in the 

brain are involved in metabolic diseases. The 

mechanisms by which glucose sensitive 

neurons detect changes in glycemia and alter 

their firing pattern are still being investigated. 

In the glucose sensing process participate the 

same proteins that control glucose signaling in 

pancreatic beta-cells (56), i.e., the GLUT2, the 

enzyme glucokinase and the ATP sensitive 

potassium channel. In the response to 



 

 

 

 

 
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hypoglycemia participate the AMP-activated 

protein kinase (57).  

When an injury impaired the oxidative 

phosphorylation, either lower arterial oxygen 

tension, mitochondrial dysfunction or brain 

lesions, the glycolysis is deviated to the 

anaerobic way, producing lactic acid and 

hydrogen ions, generating tissue acidosis and 

reactive species of oxygen, respectively. When 

this takes place, trigger deleterious effects in 

the neuronal cells, product of the activation of 

calcium entry to the cells, the release of 

cytotoxic free fatty acids and excitotoxic 

neurotransmitters like glutamate. Although 

the intermediate metabolites of glucose 

breakdown, pyruvate and lactate, in some 

circumstances can sustain the energy demand 

of the neuronal activity, both lack the ability to 

cross the blood-brain barrier. In pathological 

states, also are used as metabolic substrates the 

ketonic bodies. 

Brain glycogen is primarily located in the 

astrocytes (58). And its stores finishes in about 

5 minutes, when needed. In an animal model 

of type 2 diabetes mellitus, glycogen 

metabolism has been demonstrated to be 

important for supporting glutamatergic and 

GABAergic homeostasis, maintaining a 

proper ratio between excitatory and inhibitory 

neurotransmitters (59).  Different animal and 

human studies evidence a significantly 

compromised altered glucose metabolism in 

the setting of traumatic brain injury, cerebral 

ischemia and hemorrhages. Due to the 

mitochondrial membrane dysfunction during 

hypoxic and hyperglycemic insults, the cells in 

the perihemorrhagic area are unable to 

metabolise the excess of glucose, this happens 

specifically in intracerebral hemorrhage, and 

are the main phenomena to comprehend why 

hypo/hyperglycemia are so deleterious in the 

setting of an acute brain lesion. 

Hyperglycemia and the sICH 

The hyperglycemic state results from 

metabolic derangements in the glucose 

metabolism (60). In the acute phase of sICH 

develops an unspecific, programmed and 

adaptive response to the stress that induce 

activation of the hypothalamic-hypophysis-

adrenal axis and the subsequent releasing of 

hyperglycemic hormones (61-64), activation 

of the autonomous nervous system and 

changes in the behavior, everything as a part of 

the well described metabolic–hormonal 

response to stress and to the systemic 

inflammatory response syndrome (SIRS). 

In the context of a lesion, irrespective of the 

nature, the mechanism that drives to a stress 

hyperglycemia are the increased 

gluconeogenesis and insulin resistance, the 

later, may be result from impaired insulin 

receptor binding and signal transduction, 

increased hepatic glucose production, and 

decreased peripheral glucose uptake (65). 

The big final effect, a stress-induced 

hyperglycemic state, constitutes an 

aggravating factor of the lesion. Also has been 

demonstrated an independent relationship 

between the kind and the severity of the 

neurologic injury (66, 67). The surgical 

procedures also contribute to activate a 

neuroendocrine response that predispose the 

patient to develop hyperglycemia and 

ketoacidosis because its antagonizing action 

on the insulin activity (60, 63). Other well 

documented effects of stress-induced 



 

 

 

 

 
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hyperglycemia are the endothelial cell 

dysfunction, increased oxidative stress, 

cardiovascular effects and lesion in other 

specific brain areas (68-70). 

When the hyperglycemic state is 

stablished, it plays a range of deleterious 

mechanisms on the injured brain, through the 

increase of oxidative stress, inflammatory 

cytokines, induction of excitotoxicity [e.g., 

stimulation of the N-methyl-Daspartate 

(NMDA) receptor] potentiating the calcium 

entry to the cells, alters the brain metabolism 

and therefore the perfusion (71-73). Due to the 

above, glucose neurotoxicity   

The excessive glucose concentration in the 

lesions microenvironment induces lipid 

peroxidation, protein carbonilation, and DNA 

damage. As the superoxyde is been 

neutralizing the nitric oxide, the vasodilation 

is impaired (74, 75). As result of the 

productions of reactive species of oxygen 

(RSO), then is activated an inflammatory 

response that leads to immune cells attraction, 

and then increasing the production of EROs. 

Lactic acid is also concentrated, so is an easy 

way to turn acidotic the neuron cells, this 

acidosis alters mitochondrial function (76, 77). 

In rat models of intracerebral hemorrhage 

(78-80) have been demonstrated the 

mentioned physiopathological events, and 

higher size of hemorrhage in the 

hyperglycemic rat groups. In a recent 

experiment was observed that in response to 

the intracerebral hemorrhage lesion, 

significant increase of albumin was 

ubiquitously observed in the brains of 

normoglycemic rats but not in the brains of 

hyperglycemic rats. In the last group, more 

significant neuronal apoptosis were found in 

the perihematomal regions of hyperglycemic 

rats, suggesting a protection role of albumin in 

acute stage of intracerebral hemorrhage, 

which may be dependent on different blood 

sugar levels (81). 

Hypoglucemia and the sCHI 

Defined as glucose plasma level <50mg/dL 

(<2.8mmol/L) with/without symptoms (49). 

Currently, there is a paucity of data on cerebral 

glucose metabolism in human subjects with 

spontaneous intracerebral hemorrhage, but 

have been demonstrated that hypoglycemia, 

the other side of the coin, also worsens the 

outcome of patients with critical illness. In the 

acute injured brain, hypoglycemia could be 

particularly harmful. 

The “neurological injury glucose 

threshold” varies with some patient’s factors, 

i.e., history of diabetes mellitus, the speed of 

the glucose level drop, the duration of the 

hypoglycemia event and the cerebral blood 

flow, etc. In patients with poor-grade 

subarachnoid hemorrhage the acute 

reductions in serum glucose, even to levels 

within the normal range, could generate brain 

energy metabolic crisis and lactate/pyruvate 

ratio elevation (82). When the brain’s 

metabolism autoregulation is altered, there 

ares parts of them specially more susceptible 

than others (83-86), when could be thoughtful 

glucose level as “sufficient” in a patient whith 

acute brain lesion this might be insuffient and 

even deleterious. The brain’s compensation 

systems (release of conter-regulatory 

hormones, increase the cerebral blood flow, 

use of the glycogen storages) to the glycopenia 

are limited (87-89). The big problem with a 



 

 

 

 

 
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hypoglycemia state is that is associated with 

aberrant depolarization in the perilesional 

tissue that drives to a perpetuating glucose 

depletion, as has been demonstrated in 

traumatic brain injury (32, 90) 

Mortality and other Outcomes 

As stated in other items of this review, the 

hyperglycemia measured in peripheral blood 

is both a marker of injury severity and of poor 

outcome, a relationship that has captured the 

attention of clinicians over the past few years. 

Studies evaluating the association of glycemia 

derangements and sICH are scarce (10, 14), in 

comparison with other types of stroke, where 

later researches utilize multimodal 

neuromonitoring with intracerebral 

microdialysis catheters, brain oxygen 

monitors and measurements of both, 

peripheral and cerebral blood glucose. 

Kimura and colleagues with a prospective 

observational study design and 100 patients 

with acute supratentorial Intracerebral 

hemorrhage, assessing clinical characteristics 

and plasma glucose. ICH volume was 

measured on admission CT (b24 h) and 

follow-up CT (b48 h) scans. Patients were 

divided into two groups: the death group, who 

died within 14 days of onset, and the survival 

group. Using receiver operating characteristic 

(ROC) curve, founded that cut-off values that 

predicted early death were 150 mg/dl for the 

glucose level and N20 ml for the initial IVH 

volume, they conclude that admission 

hyperglycemia may independently increase 

the risk of early death in acute spontaneous 

intracerebral hemorrhage (10).  

Godoy and collegues in a prospective study 

with 250 patients with a well-defined diagnosis 

of sICH admitted into 24 h in three primary 

referred centers. Patients had extensive 

monitoring of BG values and those with BG 

values >8.29 mmol/l (150 mg/dl) received a 

variable intravenous insulin dose to maintain 

BG concentrations during the first 72 h after 

sICH between 3.32 and8.29 mmol/l (60–150 

mg/dl) using pre-specified insulin dosing 

schedule protocol, and using a cutoff value of 

>164mg/dL, they conclude that hyperglycemia 

is a common condition after sICH that could 

worsen prognosis and the very early insulin 

therapy does not improve prognosis, also show 

an increased risk of poor outcomes and death. 

Stress hyperglycaemia is a common finding 

in patients presenting with intracerebral 

haemorrhage. It is a marker of poor outcomes 

and higher mortality, more so in patients with 

no known history of diabetes (91). Over the 

years ICH has been reported to have a 

mortality rate between 35–52% and poor 

functional outcome of survivors, with only 10–

20% living independently at 30 days (92-96) 

Literature has reported Glasgow Coma Scale 

(GCS) on arrival, blood pressure on 

presentation, volume of hemorrhage, 

concomitant intraventricular hemorrhage, 

previous ischemic stroke, and National 

Institutes of Health Stroke Scale (NIHSS) 

score as predictors of early mortality in 

patients with ICH (11). 

For evaluating glycaemia derangements in 

unspecific medical conditions but in critically 

ill patients a study look for evaluate the 

compared risk adjusted mortality when those 

patients were admitted to a surgical intensive 

care over 4 years.  Patients were divided into 

glycemic groups: HYPER (≥1 episode > 180 



 

 

 

 

 
318          Alvis-Miranda et al          Glycemia in spontaneous intracerebral hemorrhage 

 

 

 

 

 

 

 

mg/dL, any <60), HYPO (≥1 episode < 60 

mg/dL, any >180), BOTH (≥1 episode < 60 and 

≥1 episode > 180 mg/dL), NORMO (all 

episodes 60-180 mg/dL), HYPER-Only (≥1 

episode > 180, none <60 mg/dL), and HYPO-

Only (≥ episode < 60, none >180 mg/dL). The  

mortality ratios (O/E) were studied using the 

expected Acute Physiology and Chronic 

Health Evaluation (APACHE) III. Number of 

adverse glycemic events was compared with 

mortality. Hypoglycemia and hyperglycemia 

occurred in 18 per cent and 50 per cent of 

patients. Mortality was 12.4 per cent (O/E = 

0.88). BOTH had the highest O/E ratio (1.43) 

with HYPO the second highest (1.30). Groups 

excluding hypoglycemia (NORMO and 

HYPER-only) had the lowest O/E ratios: 0.56 

and 0.88. Increasing number of hypoglycemic 

events were associated with increasing O/E 

ratio: 0.69 O/E for no events, 1.19 for 1-3 

events, 1.35 for 4-6 events, 1.9 for 7-9 events, 

and 3.13 for >/= 10 events. As result was 

observed that, ten or more hyperglycemic 

events were needed to significantly associate 

with worse mortality (O/E 1.53); and 

hyper/hypoglycemia increase mortality 

compared with APACHE III expected 

mortality, with highest mortality risk if both 

are present. In this study hypoglycemia was 

associated with worse risk, so the authors 

recommend that glucose control may need to 

be loosened to prevent hypoglycemia and 

reduce glucose variability (97). 

In a study evaluating the prognosis and 

outcome of acute stroke in an Universitary 

hospital in Nigeria, founded that age above 39 

years, male gender, systemic hypertension, 

early onset of coma after stroke, and presence 

of co-morbidities were associated with poor 

stroke outcome, the 78.8% of all stroke 

subtypes corresponded to intracerebral 

hemorrhage (98). 

The effects of parameters as elevation of 

white blood cell count (WBC), C-reactive 

protein (CRP), and blood glucose (BG) 

concentration at presentation prognosticate 

poor outcome in sICH patients were 

investigated for Di Napoli and colleagues 

conclude that higher WBC, CRP, and BG are 

associated with increased mortality in sICH 

patients, and also founded that only CRP 

elevation portends higher risk of death 

independently of other indicators of sICH 

severity (99). 

In the Acute Brain Bleeding Analysis 

Study, a korean study for evaluate the effects of 

glucose level on early and long-term mortality 

after intracerebral haemorrhage was observed 

a long-term mortality rate of 21.1% after a 

mean follow-up of 434.3 +/- 223.2 days and 

was found to increase significantly with 

glucose quartile (p < 0.001). The admission 

glucose level was an independent risk factor 

for early mortality (adjusted HR 1.10 [95% CI 

1.01-1.19]), but not for long-term mortality. 

Moreover, when analysis was restricted to 

patients without diabetes, glucose level was 

found to be an independent risk factor for 

post-ICH mortality (n = 1,119; adjusted HR 

1.10 [95% CI 1.03-1.17]) and had marginal 

significance for early (p = 0.053) and long-

term mortality (p = 0.09). From the above is 

conclusive that admission glucose levels are 

associated with early mortality after 

intracerebral hemorrhage. In patients without 

diabetes, admission glucose levels were 



 

 

 

 

 
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associated with long-term mortality (19).  

Kimura and colleagues have founded an 

association between hyperglycemia at 

admission to EDs and an increased risk of 

early death (10). Other worry about the 

assessment of mortality in sICH is that in 

comparison with other cerebrovascular 

diseases, there are no grading prognostic scales 

routinely used in sICH around the world. 

 

Correspondence 

Dr. Luis Rafael Moscote-Salazar, Universidad de 

Cartagena, Cartagena de Indias, Colombia. E-mail: 

mineurocirujano@aol.com 

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