Muizelaar J P, Marmarou A, Young H F, Choi S C, Wolf A, Schneider R L, Kontos H A
Division of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond.
J Neurosurg. 1993 Mar;78(3):375-82. doi: 10.3171/jns.1993.78.3.0375.
Formation of the oxygen radical superoxide anion is one of the final events of several metabolic pathways in the cascade that leads to delayed neuronal death after traumatic or ischemic brain injury. In the laboratory, scavenging of the superoxide anion with native superoxide dismutase (SOD) or polyethylene glycol (PEG)-conjugated SOD (PEG-SOD) has been shown to be beneficial in several types of traumatic and ischemic injury. Accordingly, PEG-SOD was utilized in a randomized controlled Phase II trial to evaluate its safety and efficacy in severely head-injured patients with a Glasgow Coma Scale score of 8 or less. At two institutions, 104 patients were randomly assigned to receive either placebo or PEG-SOD (2000, 5000, or 10,000 U/kg) intravenously as a bolus, an average of 4 hours after injury. Prognostic factors were evenly distributed in the four groups, except for mean age which was significantly higher in the group receiving 10,000 U/kg than in the placebo group (mean age 34 years vs. 25 years). No complications attributed to the study medication were noted. The average intracranial pressure (ICP) was similar in the four groups, but the percentage of time during which ICP was above 20 mm Hg was less in the groups receiving 5000 or 10,000 U/kg of PEG-SOD. Patients in the group receiving 10,000 U/kg also required less mannitol for ICP control than the placebo group. Outcome was assessed using the Glasgow Outcome Scale at 3 and 6 months postinjury in 91 and 93 patients, respectively, by blinded observers not involved in the clinical management of the patients. At 3 months, 44% of patients in the placebo group were vegetative or had died, while only 20% of patients in the group receiving 10,000 U/kg of PEG-SOD were in these outcome categories (p < 0.03, multiple logistic regression test); at 6 months, these figures were 36% and 21%, respectively (p = 0.04). Differences in outcome between the placebo group and either of the other two dosage groups were not statistically significant. It is concluded that PEG-SOD was generally well tolerated and appears promising in improving outcome after severe head injury. A larger, multicenter, Phase III trial, using a higher dose (20,000 U/kg) compared to placebo and to 10,000 U/kg of PEG-SOD is planned.
氧自由基超氧阴离子的形成是创伤性或缺血性脑损伤后导致迟发性神经元死亡的级联反应中几种代谢途径的最终事件之一。在实验室中，用天然超氧化物歧化酶（SOD）或聚乙二醇（PEG）共轭超氧化物歧化酶（PEG-SOD）清除超氧阴离子已被证明对几种类型的创伤性和缺血性损伤有益。因此，PEG-SOD被用于一项随机对照II期试验，以评估其在格拉斯哥昏迷量表评分为8分或更低的重度颅脑损伤患者中的安全性和有效性。在两家机构，104例患者被随机分配接受安慰剂或PEG-SOD（2000、5000或10000 U/kg）静脉推注，平均在受伤后4小时给药。除了接受10000 U/kg的组的平均年龄显著高于安慰剂组（平均年龄34岁对25岁）外，预后因素在四组中分布均匀。未观察到归因于研究药物的并发症。四组的平均颅内压（ICP）相似，但接受5000或10000 U/kg PEG-SOD的组中ICP高于20 mmHg的时间百分比更低。接受10000 U/kg的组的患者在控制ICP方面也比安慰剂组需要更少的甘露醇。分别由未参与患者临床管理的盲法观察者在受伤后3个月和6个月使用格拉斯哥预后量表对91例和93例患者的预后进行评估。在3个月时，安慰剂组中44%的患者处于植物状态或已死亡，而接受10000 U/kg PEG-SOD的组中只有20%的患者属于这些预后类别（p<0.03，多重逻辑回归检验）；在6个月时，这些数字分别为36%和21%（p = 0.04）。安慰剂组与其他两个剂量组之一之间的预后差异无统计学意义。得出的结论是，PEG-SOD总体耐受性良好，在改善重度颅脑损伤后的预后方面似乎很有前景。计划进行一项更大规模的多中心III期试验，将与安慰剂和10000 U/kg PEG-SOD相比使用更高剂量（20000 U/kg）。
