McPherson R W, Koehler R C, Kirsch J R, Traystman R J
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Anesth Analg. 1997 Jan;84(1):139-47. doi: 10.1097/00000539-199701000-00026.
We tested the hypothesis that a centrally administered alpha 2-receptor agonist could alter the cerebrovascular response to hypoxia, without evidence of systemic absorption of the drug. Beagle dogs were anesthetized with 1.4% isoflurane and exposed to hypoxic hypoxia (Pao2 approximately 22 mm Hg) before and after ventricular-cisternal perfusion with mock cerebrospinal fluid (CSF group, n = 5) or dexmedetomidine (100 micrograms/mL; total dose 300 micrograms; DEX group, n = 6). Cerebral perfusion pressure, Paco2 and arterial oxygen content were controlled and regional cerebral blood flow (CBF; microspheres) and global cerebral metabolic rate for oxygen consumption (CMRO2) were measured. In another group (n = 5), drug distribution under the experimental conditions was assessed by 3H-clonidine administered by ventricular-cisternal perfusion. In the mock CSF group, flow to the cerebral hemispheres increased during hypoxia under baseline conditions and after CSF infusion: 66 +/- 8 to 170 +/- 15 mL.min-1.100 g-1 (265% +/- 24% of baseline value), 83 +/- 9 to 154 +/- 14 mL.min-1.100 g-1 (201% +/- 54% of post-CSF infusion value). DEX decreased normoxic flow in the cerebral hemispheres from 76 +/- 6 to 44 +/- 4 ml.min-1.100 g-1 with decreases in other regions of similar magnitude. After DEX, the absolute flow in all regions during hypoxia was 52%-55% of that prior to DEX (P < 0.05). However, because DEX also decreased normoxic CBF, the percent increase in flow during hypoxia was similar before and after DEX. CMRO2 was not affected by hypoxia prior to DEX. However, after DEX, hypoxia caused a marked reduction in cerebral oxygen delivery (5.2 +/- 1.0 vs 13.7 +/- 2.3 ml.min-1.100 g-1 for the CSF group) and CMRO2 (2.5 +/- 0.6 vs 3.9 +/- 0.6 ml.min-1.100 g-1). Regional accumulation of intraventricularly administered 3H-clonidine was greatest in periventricular brain structures (e.g., caudate nucleus, dorsal brainstem), and the concentration in the cerebral cortex was approximately 1% of the concentration in the ipsilateral caudate nucleus. We conclude that centrally administered DEX reduces CBF during normoxia and prevents adequate oxygen delivery during hypoxia. The mechanism of DEX-induced CBF reduction is not metabolically mediated, since CMRO2 is maintained at control values during normoxia despite the significant blood flow reduction. We believe that the reduction in CMRO2 during hypoxia in DEX-treated dogs is the result of a reduction of oxygen delivery rather than the underlying mechanism for the observed reduction in CBF during hypoxia.
经中枢给予α2受体激动剂可改变脑血管对缺氧的反应，且无药物全身吸收的证据。用1.4%异氟烷麻醉比格犬，在脑室 - 脑池灌注模拟脑脊液（脑脊液组，n = 5）或右美托咪定（100微克/毫升；总剂量300微克；DEX组，n = 6）前后，使其暴露于低氧性缺氧（动脉血氧分压约22毫米汞柱）环境。控制脑灌注压、动脉血二氧化碳分压和动脉血氧含量，并测量局部脑血流量（CBF；微球法）和全脑氧代谢率（CMRO2）。在另一组（n = 5）中，通过脑室 - 脑池灌注给予3H - 可乐定，评估实验条件下的药物分布。在模拟脑脊液组中，在基线条件下和输注脑脊液后，缺氧期间流向大脑半球的血流量增加：从66±8毫升·分钟-1·100克-1增至170±15毫升·分钟-1·100克-1（为基线值的265%±24%），从83±9毫升·分钟-1·100克-1增至154±14毫升·分钟-1·100克-1（为输注脑脊液后值的201%±54%）。DEX使大脑半球的常氧血流量从76±6毫升·分钟-1·100克-1降至44±4毫升·分钟-1·100克-1，其他区域也有类似程度的降低。给予DEX后，缺氧期间所有区域的绝对血流量为给予DEX前的52% - 55%（P < 0.05）。然而，由于DEX也降低了常氧CBF，缺氧期间血流量增加的百分比在给予DEX前后相似。在给予DEX之前缺氧对CMRO2没有影响。然而，给予DEX后，缺氧导致脑氧输送显著降低（脑脊液组为5.2±1.0毫升·分钟-1·100克-1 对比 13.7±2.3毫升·分钟-1·100克-1）以及CMRO2降低（2.5±0.6毫升·分钟-1·100克-1 对比 3.9±0.6毫升·分钟-1·100克-1）。脑室内给予的3H - 可乐定在脑室周围脑结构（如尾状核、背侧脑干）中的局部蓄积最大，大脑皮质中的浓度约为同侧尾状核浓度的1%。我们得出结论，经中枢给予DEX可降低常氧期间的CBF，并在缺氧期间阻止充足的氧输送。DEX诱导的CBF降低机制并非由代谢介导，因为尽管血流量显著减少，但常氧期间CMRO2维持在对照值。我们认为，DEX处理的犬在缺氧期间CMRO2的降低是氧输送减少的结果，而非缺氧期间观察到的CBF降低的潜在机制。
