hypothermia against stroke
DESCRIPTION
This is a slide presented in 24th annual meeting of the Japanese society of cerebral blood flow and metabolim.TRANSCRIPT
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内在性神経細胞保護機構を活用した虚血脳保護戦略の展望
脳梗塞に対する脳低温療法の作用機序と臨床応用
新潟大学脳研究所神経内科下畑享良,西澤正豊
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脳低温療法の適応
動物モデルから見た作用機序
ヒト脳梗塞に有効か?
概 略
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概 略
脳低温療法の適応
1. 脳低温療法の対象疾患
2. 脳虚血に対するエビデンス
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28 29 30 31 32 33 34 35 36 37℃
28-32℃
Moderate
33-36℃
Mild
脳低温療法の分類
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全脳虚血局所虚血(脳梗塞)
脳低温療法の対象疾患
×
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全脳虚血局所虚血(脳梗塞)
脳低温療法の対象疾患
RCT; 心停止後 NEJM 2002
新生児仮死 Lancet 2005
NEJM2005
なし
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脳梗塞で行われない理由
安全性
副作用感染症,不整脈血小板減少等
利便性
大掛かり全身麻酔
人工呼吸器管理
Protocol ?
至適温度Time window持続時間
↓動物モデル
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小括1
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脳低温療法の適応
動物モデルから見た作用機序
ヒト脳梗塞に有効か?
概 略
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Prof. Gary K Steinberg
Prof. Zhao Heng
Stanford university 2004~2006
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動物モデルとヒト脳梗塞の違い
虚血・再灌流モデル
100% 再開通
実際の臨床では・・・
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動物モデルとヒト脳梗塞の違い
Suture modelは適切か?
Neurology 71, 1304–1312, 2008.
再開通 再開通せず
部分的再開通
tPA静注後転帰38%
29%
32%
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ヒト脳梗塞に似た動物モデル
部分的再開通モデル
総頸動脈閉塞CCAo 1h
24 h 48 h
中大脳動脈遠位閉塞distal MCAo
Zhao H et al. J Neurosci 25; 9794-9806, 2005
30℃
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強力な脳低温療法( 24h後)
30℃37℃Zhao H et al. J Neurosci 25; 9794-9806, 2005
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強力な脳低温療法( 24h後)
80%減
Zhao H et al. J Neurosci 25; 9794-9806, 2005
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Zhao H et al. J Neurosci 25; 9794-9806, 2005
長期的効果(2週後)
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Intraischemic hypothemiaのメカニズム
PI3K/Akt活性化
PKC活性化
PKC抑制
生存シグナル抗アポトーシス作用
アポトーシス促進
Zhao H et al. J Neurosci 25; 9794-9806, 2005Shimohata T et al. Stroke 38; 375-380, 2007Shimohata T et al. JCBFM 27; 1463-1475, 2007
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多彩な内在性脳保護機構
Yenari M et al. Nat Rev Neurosci 13; 267-278, 2012
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小括2
30℃ Intra-ischemic!
総頸動脈閉塞CCAo 1h
24 h 48 h
中大脳動脈遠位閉塞distal MCAo
脳低温療法は部分再開通モデルでも有効
実際の臨床でありえない!
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動物モデルから見た作用機序
概 略
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臨床応用のため検討すべきこと
至適温度 持続時間 Time window
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Intra-ischemic 30℃(Moderate)
Intra-ischemic 33℃(Mild)
Post-ischemic 30℃(Moderate)
至適温度と開始時間
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33℃に上げるとどうか?
Zhao H et al. J Neurosurg 107; 636-641, 2007
4h
2h CCAo 48h
1. 37℃
2. 33℃3. 30℃
distal MCAo
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Zhao H et al. J Neurosurg 107; 636-641, 2007
至適温度
37℃ 33℃ 30℃
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Zhao H et al. J Neurosurg 107; 636-641, 2007
至適温度
80
60
40
20
037/37 33/33 30/30
P<0.01 P<0.05
P<0.001
梗塞サイズ(
半
球%)
33℃有効!
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至適温度
Zhao H et al. J Neurosurg 107; 636-641, 2007
2h 2h
2h CCAo 48h
2. 33 373. 37 33
5. 30 37
distal MCAo
1. 37 37
4. 33 33
6. 30 30
Intra-ischemicPost-ischemic
持続時間( 2h vs 4h)
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Zhao H et al. J Neurosurg 107; 636-641, 2007
至適温度
80
60
40
20
037/37 33/37 37/33 33/33 30/37 30/30
33℃では 4時間行わないと無効
30℃では上乗せ効果なし延長効果も限度あり
Intra 2hPost 2h
4h
Intra 2h 4h
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開始時間( Time window)
Lee SM et al. JCBFM 29; 1589-1600, 2009
Delayed hypothermia
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開始時間( Time window)
Normo Intra Immediate Delayed
梗塞サイ
ズ
(cm3)
35
30
25
20
15
10
5
0
わずか 30分の 違いで効果消失
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開始時間( Time window)
• Time windowは非常に短い• 持続時間をさらに伸ばせばどうか?• Time windowは非常に短い• 持続時間をさらに伸ばせばどうか?
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持続時間 (1)
90 m
1h
33℃, 24h 35℃, 24h
1ヶ月
90 m 1ヶ月
Colbourne F et al. JCBFM 20; 1702-1708, 2000
虚血・再灌流モデル
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持続時間 (1)
梗塞サイ
ズ
(mm3)
normothermia hypothermia
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1h12h
24h
48h
Clark DL et al. Exp Neurol 212; 386-392, 2008
持続時間 (2)
永久閉塞モデル
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持続時間 (2)
Clark DL et al. Exp Neurol 212; 386-392, 2008
Normo 12h 24h 48h
200
150
100
50
0
梗塞サイ
ズ
(mm3)
* *
長時間望ましい(上限は不明)
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基礎研究から臨床へ
至適温度 持続時間Time window
33℃でも有効持続時間に依存
非常に狭い持続時間に依存
長時間が望ましい合併症を考慮
再灌流の有無を考慮する再灌流の有無を考慮する
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結 論
脳梗塞に対する脳低温療法は有効かもしれない
動物モデルを参考にしたプロトコール
利便性・安全性の追求