Coma aux Soins Intensifs

Contrôle glycémique
chez le cérébro-lésé
Dr Mauro Oddo
Service de Médecine Intensive Adulte
CHUV-Lausanne
DIU Neuroréanimation Lyon 13 mars 2013
Plan
• Hyperglycémie et LCA
• Hypoglycémie et LCA
• Métabolisme du glucose
– Normal
– LCA
• Contrôle glycémique après LCA
• Études cliniques
• Recommandations
ACSOS
Agresseurs Cérébraux
Secondaires d’Origine
Systémique
Hyperglycémie et LCA
Kruyt ND et al. Nat Rev Neurol 2010
Hyperglycémie et LCA
• Experimental evidence
– Hyperglycemia (blood glucose > 15 mmol/l) worsens neuronal damage
•
•
•
•
↓ pH, acidosis
↑ excitotoxicity
↑ oxidative stress
↑ lesion size
Rehncrona S et al. Acta Physiol Scand 1980
Li PA et al. Stroke 2000
Tsuruta R et al. Brain Res 2009
Chew W et al. Am J Neuroradiol
• Clinical evidence
– Admission hyperglycemia (blood glucose > 10-11 mmol/l) is a strong
risk factor of increased mortality and poor neurological recovery
• TBI
• SAH
• Stroke
Rovlias A et al. Neurosurgery 2000; Jeremitsky E et al. J Trauma 2005
Frontera JA et al. Stroke 2006; Badjatia N et al. Crit Care Med 2005
Bruno A, Neurology 1999; Baird TA, Stroke 2003
Hypoglycémie et cerveau
Barros LF et al. Glia 2007
Cryer PE et al. J Clin Invest 2007
•
•
•
Glucose Deprivation (GD) increases neuronal cell death
GD followed by administration of i.v. glucose bolus (GD/GR) further increases neuronal cell death
Compared to hypoglycemia alone (HG), HG followed by i.v. glucose (HG/GR) to reach blood glucose
of 5-10 mM and 10-15 mM increases the number of degenerating neurons
 The treatment of inadvertent hypoglycemia with the administration of i.v glucose
↑↑ neuronal injury
– « glucose reperfusion injury »
Suh SW J Clin Invest 2007
Métabolisme cérébral du glucose
Systemic glucose concentration
limited glycogen stores
Astrocyte and Neuronal
Glucose Transporters
Pellerin L, Magistretti PJ Glia 2007
la concentration de glucose cérébral est dépendante
de la concentration de glucose systémique
Choi IY et al. J Cereb Blood Flow Metab 2001
Chez le sujet cérébro-lésé
Bouzat P et al. Annals Intensive Care 2013; in press
Altération du transport du glucose au niveau
cérébral après LCA
Qutub AA Brain Res Rev 2005
Le cerveau lésé a une plus grande « avidité » de glucose
- Cerebral hyperglycolysis
-
Oxidative stress
Mitochondrial dysfunction
-- In the absence of cerebral ischemia
Bergsneider M et al. J Neurosurg 1997 ; Glenn TC et al. J Cerebr Blood Flow Metab 2003; Vespa P et al. J Cerebr Blood Flow
Metab 2005
↑↑ des besoins en glucose après LCA
• Mechanisms
– Cerebral ischemia, impaired autoregulation
• reduced CPP
– Brain edema
• increased ICP, reduced CPP
– Excitotoxicity
• non-convulsive seizures
• cortical spreading depolarizations
microdialyse cérébrale
Hillered L et al. J Neurotrauma, 2005;22:3-41
Parkin M J Cereb Blood Flow Metabol 2005
 ↓ glucose cérébral en rapport avec les « cortical spreading
depressions »
↓ brain glucose correlates with worse outcome
Oddo M et al. Crit Care Med 2008
Contrôle glycémique chez le cérébro-lésé
• Traitement de l’hyperglycémie
– Insuline iv.
• Quelle cible « optimale » ?
Cat, ischemic stroke
•
insulin-induced ↓ of blood glucose

is associated with an ↑ of peri-ischemic depolarizations, particularly when blood glucose
concetration falls < 6 mmol/l
 neuroglucopenic injury appears at higher blood glucose thresholds than in
normal conditions
Hopwood S et al. J Cereb Blood Flow Metabol 2005
Crit Care Med 2008
neuroglucopenia
cerebral metabolic distress
Crit Care Med 2008
 Tight glucose control is associated with reduced brain tissue glucose and increased
episodes of cerebral metabolic crisis (LP ratio >40)
• Independently from CPP and ICP levels
Additional clinical evidence
• Tight (4-6 mmol/l) vs. moderate (7-9 mmol/l) blood
glucose control with the use of insulin:
– ↑ LP ratio, glutamate and glycerol in the cerebral microdialysis fluid
• Vespa P et al. Crit Care Med 2006
• Schlenk F et al. Int Care Med 2008
• Meierhans R et al. Crit Care 2010
 Intensive insulin therapy may aggravate secondary neuronal injury
 Moderate insulin therapy is more protective
Neuroglucopénie après LCA
Barros LF et al. Glia 2007
Cryer PE et al. J Clin Invest 2007
INSULINOTHÉRAPIE CHEZ LE
CÉRÉBRO-LÉSÉ
Intensive vs. Conventional insulin therapy in the Neuro-ICU
effect on outcome
Ref.
N
Study
type
Population
IIT
Conventional
Effect on outcome
BG target (mmol/l)
Vespa
(2006)
44
R
TBI
4.5-6
sc insulin if >10
none
Bilotta
(2007)
78
P
SAH
4.4-6.7
sc insulin if >11
none
Bilotta
(2008)
96
P
TBI
4.4-6.7
sc insulin if >11
none
Meier
(2008)
228
R
TBI
4-5
6-8
none
Bruno
(2008)
46
P
Stroke
5-7
sc insulin if >11
none
Latorre
(2009)
498
R
SAH
4.5-7
sc insulin if >11
better with IIT
(p<0.01)
Green
(2010)
81
P
All NICU
4.4-6
<8
none
Coester
(2010)
88
P
TBI
4.4-6
sc insulin if >10
none
• Randomised study
 Neuro-ICU patients
• Pas d’effet sur le pronostic
 Effect of Intensive Insulin Therapy (BG 4.5-6 mmol/l) vs.
Moderate Insulin Therapy (BG 6-10 mmol/l) on TBI
patients
 9 RCTs with a total of 1160 patients for analysis
 IIT did not decrease the risk of in-hospital or late mortality
and had no protective effect on long-term neurological
outcomes
mortality
Kramer A Crit Care 2012 –meta-analysis
functional recovery
Kramer A Crit Care 2012 –meta-analysis
hypoglycemia
Kramer A Crit Care 2012 –meta-analysis
Conclusions
•
Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but
did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04)
•
However, improved outcomes were only observed when glucose levels in the conventional
glycemic control group were permitted to be relatively high [threshold for insulin
administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic
targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]
•
Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p =
0.002), but there was a large degree of heterogeneity in the results of individual trials (Q =
47.9; p<0.0001; I2 = 75%)
•
Mortality was non-significantly higher with intensive insulin in studies where the
proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.791.75; p = 0.44)
Kramer A Crit Care 2012 –meta-analysis
 Recommandations
 L’insulino-thérapie intensive (cible glycémique 80-110 g/dl ou 4.4-6 mmol/l)
augmente le risque d’hypoglycémie, de neuroglucopénie et de stress métabolique
cérébral chez le patient cérébro-lésé et ne diminue pas la mortalité
 L’hyperglycémie (glycémie > 200 mg/dl ou 10 mmol/L) est associée à un moins bonne
récupération neurologique et doit être évitée
 Chez le sujet cérébro-lésé, la cible glycémique optimale se situe entre 140-150 et
180 mg/dl ou 6-6.5 et 9 mmol/l (insulino-thérapie modérée)