Lange Matthias, Szabo Csaba, Van Aken Hugo, Williams William, Traber Daniel L, Daudel Fritz, Bröking Katrin, Salzman Andrew L, Bone Hans-Georg, Westphal Martin
Department of Anesthesiology and Intensive Care, University of Muenster, 48161 Muenster, Germany.
Shock. 2006 Nov;26(5):516-21. doi: 10.1097/01.shk.0000228795.33421.45.
In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific K(ATP) channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to elucidate the short-term effects of glipizide, a specific K(ATP) channel inhibitor, on cardiopulmonary hemodynamics and global oxygen transport in healthy sheep and sheep with endotoxemia. Ten adult ewes were anesthetized and operatively instrumented with a pulmonary artery, a femoral artery, and a foley catheter. After 24 h of recovery, healthy sheep received glipizide as a bolus infusion (4 mg/kg over 15 min). After 24 h of recovery, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng.kg.(-1)min) was started in the same sheep and administered for the next 17 h. After 16 h of endotoxemia, glipizide was given as described above. Administration of glipizide was followed by a transient, but significant, increase in mean arterial pressure in both healthy controls (95 +/- 3 mmHg vs. 101 +/- 2 mmHg, P < 0.05) and sheep with endotoxemia (86 +/- 3 mmHg vs. 93 +/- 3 mmHg, P < 0.05). However, the increase in mean arterial pressure was longer lasting in ewes with endotoxemia. Cardiac index, oxygen delivery index, arterial lactate concentrations, and arterial pH were not significantly affected by glipizide. Therefore, administration of glipizide may represent a beneficial therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome. Additional studies are required to determine the effects of continuous infusion of glipizide in the presence of systemic inflammation.
在严重脓毒症和脓毒性休克中，血流动力学支持常因对外源性儿茶酚胺产生快速耐受而变得复杂。由于三磷酸腺苷（ATP）敏感性钾（K(ATP)）通道的激活在高动力性血管舒张性休克的发病机制中起关键作用，我们推测给予一种特异性K(ATP)通道抑制剂可能有助于预防或至少减轻脓毒症时的血流动力学功能障碍。本研究设计为一项前瞻性对照实验室实验，以阐明特异性K(ATP)通道抑制剂格列吡嗪对健康绵羊和内毒素血症绵羊心肺血流动力学及整体氧输送的短期影响。十只成年母羊麻醉后通过手术植入肺动脉、股动脉和弗利氏导管。恢复24小时后，健康绵羊接受格列吡嗪静脉推注（15分钟内4毫克/千克）。恢复24小时后，对同组绵羊开始持续输注内毒素（伤寒沙门菌，10纳克·千克⁻¹·分钟⁻¹），并持续输注17小时。内毒素血症16小时后，按上述方法给予格列吡嗪。给予格列吡嗪后，健康对照组（95±3毫米汞柱对101±2毫米汞柱，P<0.05）和内毒素血症绵羊（86±3毫米汞柱对93±3毫米汞柱，P<0.05）的平均动脉压均出现短暂但显著的升高。然而，内毒素血症母羊平均动脉压的升高持续时间更长。心脏指数、氧输送指数、动脉乳酸浓度和动脉pH值未受到格列吡嗪的显著影响。因此，给予格列吡嗪可能是治疗脓毒症和全身炎症反应综合征所致动脉低血压有益的治疗选择。需要进一步研究以确定在存在全身炎症时持续输注格列吡嗪的效果。
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