Dr Mauro Oddo Service de Médecine Intensive Adulte
CHUV-Lausanne
DIU Neuroréanimation Lyon 13 mars 2013
Contrôle glycémique chez le cérébro-lésé
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
• Experimental evidence – Hyperglycemia (blood glucose > 15 mmol/l) worsens neuronal damage
• ↓ pH, acidosis Rehncrona S et al. Acta Physiol Scand 1980
• ↑ excitotoxicity Li PA et al. Stroke 2000
• ↑ oxidative stress Tsuruta R et al. Brain Res 2009
• ↑ lesion size 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 Rovlias A et al. Neurosurgery 2000; Jeremitsky E et al. J Trauma 2005
• SAH Frontera JA et al. Stroke 2006; Badjatia N et al. Crit Care Med 2005
• Stroke Bruno A, Neurology 1999; Baird TA, Stroke 2003
Hyperglycémie et LCA
Cryer PE et al. J Clin Invest 2007
Barros LF et al. Glia 2007
Hypoglycémie et cerveau
Suh SW 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 »
Pellerin L, Magistretti PJ Glia 2007
Systemic glucose concentration
Astrocyte and Neuronal Glucose Transporters
limited glycogen stores
Métabolisme cérébral du glucose
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
Qutub AA Brain Res Rev 2005
Altération du transport du glucose au niveau cérébral après LCA
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
• Mechanisms
– Cerebral ischemia, impaired autoregulation
• reduced CPP
– Brain edema
• increased ICP, reduced CPP
– Excitotoxicity
• non-convulsive seizures
• cortical spreading depolarizations
↑↑ des besoins en glucose après LCA
Hillered L et al. J Neurotrauma, 2005;22:3-41
microdialyse cérébrale
↓ glucose cérébral en rapport avec les « cortical spreading depressions »
Parkin M J Cereb Blood Flow Metabol 2005
↓ 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 » ?
Hopwood S et al. J Cereb Blood Flow Metabol 2005
• 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
Cat, ischemic stroke
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
Cryer PE et al. J Clin Invest 2007
Barros LF et al. Glia 2007
Neuroglucopénie après LCA
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 0.79-1.75; 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)