Meyer J, Lentz C W, Stothert J C, Traber L D, Herndon D N, Traber D L
Department of Anesthesiology and Operative Intensive Care Medicine, Westfälische Wilhelms-Universität Münster, FRG.
Crit Care Med. 1994 Feb;22(2):306-12. doi: 10.1097/00003246-199402000-00023.
To investigate the effects of N omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, on hemodynamics, gas exchange and oxygen transport in an ovine model of hyperdynamic sepsis.
Prospective, nonrandomized, controlled study, with repeated measurements.
University research laboratory.
Twenty healthy adult sheep (weighing 20 to 45 kg) were divided into two groups of 12 treated sheep and eight control sheep and studied.
Twenty awake, chronically instrumented sheep received a continuous infusion of endotoxin (10 ng/kg/min) over 48 hrs. Twenty-four hours after the start of the endotoxin infusion, 12 sheep (treatment group) received a bolus of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (25 mg/kg), while the other eight animals (control group) received the carrier (0.9% NaCl).
Twenty-four hours after the start of the endotoxin infusion, both groups exhibited a hyperdynamic state with increased cardiac indices, decreased systemic vascular resistance indices, impaired oxygenation, and increased pulmonary shunt fractions. In both groups, oxygen delivery was significantly increased, while oxygen consumption remained virtually unchanged, resulting in a decreased oxygen extraction ratio. In the control group, the significant alterations in systemic hemodynamics, lung function and oxygen transport persisted for the remainder of the study. Administration of N omega-nitro-L-arginine methyl ester normalized cardiac index and systemic vascular resistance index, increased mean arterial blood pressure, and decreased heart rate. Although oxygen delivery significantly decreased after administration of N omega-nitro-L-arginine methyl ester, oxygen consumption did not change, resulting in a normalization of oxygen extraction ratio. Despite a significant reduction of pulmonary shunt fraction, oxygenation did not improve. Pulmonary arterial pressure and pulmonary vascular resistance index showed a peak 2 hrs after administration of the nitric oxide synthesis inhibitor and then tended to decrease. In contrast, the effects of N omega-nitro-L-arginine methyl ester on the systemic circulation persisted for the remainder of the study.
The data support the assumption that augmented nitric oxide production is a major cause of the hemodynamic alterations seen in hyperdynamic endotoxemia. Administration of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester normalized the endotoxin-induced hyperdynamic state, but did not impair oxygen consumption, indicating adequate tissue perfusion of metabolically active organs. Inhibition of nitric oxide synthesis may be a therapeutic option in the treatment of hyperdynamic septic patients when conventional therapy fails to maintain a minimum of cardiovascular performance.
研究一氧化氮合成抑制剂Nω-硝基-L-精氨酸甲酯对高动力型脓毒症绵羊模型的血流动力学、气体交换及氧输送的影响。
前瞻性、非随机、对照研究，重复测量。
大学研究实验室。
20只健康成年绵羊（体重20至45千克）分为两组，12只治疗组绵羊和8只对照组绵羊并进行研究。
20只清醒、长期植入仪器的绵羊在48小时内持续输注内毒素（10纳克/千克/分钟）。内毒素输注开始24小时后，12只绵羊（治疗组）静脉推注一氧化氮合成抑制剂Nω-硝基-L-精氨酸甲酯（25毫克/千克），而其他8只动物（对照组）输注载体（0.9%氯化钠）。
内毒素输注开始24小时后，两组均呈现高动力状态，心脏指数增加、全身血管阻力指数降低、氧合受损及肺分流分数增加。两组的氧输送均显著增加，而氧消耗基本不变，导致氧摄取率降低。在对照组中，全身血流动力学、肺功能及氧输送的显著改变在研究剩余时间持续存在。给予Nω-硝基-L-精氨酸甲酯可使心脏指数和全身血管阻力指数正常化，增加平均动脉血压并降低心率。尽管给予Nω-硝基-L-精氨酸甲酯后氧输送显著降低，但氧消耗未改变，导致氧摄取率正常化。尽管肺分流分数显著降低，但氧合并未改善。肺动脉压和肺血管阻力指数在给予一氧化氮合成抑制剂后2小时达到峰值，然后趋于下降。相比之下，Nω-硝基-L-精氨酸甲酯对全身循环的影响在研究剩余时间持续存在。
数据支持以下假设：一氧化氮生成增加是高动力型内毒素血症中血流动力学改变的主要原因。给予一氧化氮合成抑制剂Nω-硝基-L-精氨酸甲酯可使内毒素诱导的高动力状态正常化，但不损害氧消耗，表明代谢活跃器官有足够的组织灌注。当传统治疗无法维持最低心血管功能时，抑制一氧化氮合成可能是治疗高动力型脓毒症患者的一种治疗选择。
