Damage Control Resuscitation, US Army Institute of Surgical Research, JBSA Fort Sam Houston, Texas.
Shock. 2017 Nov;48(5):583-589. doi: 10.1097/SHK.0000000000000895.
There is interest in the small-volume therapeutic use of adjunct drugs for treating hemorrhagic shock (HS). However, critical information is only partially available on mechanisms of action of promising compounds such as adenosine-lidocaine-magnesium (ALM), beta-hydroxybutyrate plus melatonin (BHB/M), and poloxamer 188 (P-188). Therefore, we tested the hypothesis that these adjuncts would reverse HS-induced damage to microvascular endothelial glycocalyx and hemodynamics.
After baseline, 40% of total blood volume was removed from 44 anesthetized Sprague-Dawley male rats. One hour after hemorrhage, animals were resuscitated using ALM, BHB/M, or P-188 followed by lactated Ringer's (LR, 15 mL/kg). Control animals were not treated (SHAM) or received LR alone. Sampled blood was used to quantify shed syndecan-1 in plasma; multiple systemic physiological parameters were recorded. In vivo glycocalyx thickness, microvascular permeability, and microhemodynamics were evaluated in >200 cremaster venules using intravital videomicroscopy.
Compared with baseline, resuscitation using adjuncts was associated with glycocalyx restoration of 97 ± 9% (ALM), 75 ± 8% (BHB/M), and 85 ± 5% (P-188): significantly higher than LR-only (56 ± 4%). Significantly better permeability, similar to SHAM values, was measured after ALM and P-188, and low plasma syndecan-1 levels were measured after resuscitation with all adjuncts. Microhemodynamic changes were relatively small while systemic parameters such as mean arterial pressure and lactate improved but remained below or above the baseline, respectively, as expected from this hypotensive resuscitation model.
The drugs ALM, BHB/M, and P-188 provide beneficial effects as adjuncts to hypotensive resuscitation in this HS model by mechanisms involving changes at the microvascular level including the glycocalyx.
人们对小剂量辅助药物治疗失血性休克（HS）的治疗作用很感兴趣。然而，关于腺苷-利多卡因-镁（ALM）、β-羟基丁酸加褪黑素（BHB/M）和泊洛沙姆 188（P-188）等有前途的化合物的作用机制的关键信息仅部分可用。因此，我们测试了以下假设，即这些辅助药物将逆转 HS 引起的微血管内皮糖萼和血液动力学损伤。
在麻醉的 Sprague-Dawley 雄性大鼠中，40%的总血量被抽提，然后在 44 只大鼠中进行基线测量。出血后 1 小时，用 ALM、BHB/M 或 P-188 进行复苏，然后给予乳酸林格氏液（LR，15mL/kg）。对照组（SHAM）未进行治疗或单独给予 LR。采集血液样本以检测血浆中脱落的硫酸乙酰肝素蛋白聚糖 1（syndecan-1）；记录多个系统生理参数。通过活体视频显微镜评估超过 200 个提睾肌静脉的糖萼厚度、微血管通透性和微血流动力学。
与基线相比，用辅助药物复苏后，糖萼的恢复率为 97±9%（ALM）、75±8%（BHB/M）和 85±5%（P-188）：明显高于 LR 单独使用（56±4%）。ALM 和 P-188 后测量的通透性显著更好，与 SHAM 值相似，所有辅助药物复苏后测量的血浆硫酸乙酰肝素蛋白聚糖 1 水平均较低。微血流动力学变化相对较小，而系统参数（如平均动脉压和乳酸）有所改善，但分别仍低于或高于基线，这与这种低血压复苏模型的预期相符。
在这种 HS 模型中，ALM、BHB/M 和 P-188 作为低血压复苏的辅助药物，通过涉及微血管水平变化的机制，包括糖萼，提供了有益的效果。
