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)