Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a Phase II trial

Abstract

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.

Superoxide Generation Links Protein Kinase C Activation to Impaired ATP-Sensitive K + Channel Function After Brain Injury

“…21 Recently, a trial with SOD in humans with severe head injuries showed that death and vegetative state were increased in patients receiving a placebo compared with those receiving polyethylene glycol and SOD. 22 Intracellular generation of superoxide or other species could alter structures and/or production of nucleotides, second messengers, receptors, and membranes, and the movement of superoxide out of the cell through anion channels could result in high concentrations of activated oxygen species at cell surfaces, including endothelium. Such oxygen species are thought to antagonize NO function and to contribute to altered cerebral hemodynamics after FPI in the piglet because free radical scavengers partially restored decreased CSF cGMP concentration and decreased responses to NO-dependent dilator stimuli such as opioids.…”

Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

“…A phase II clinical trial in which PEG-SOD was administered intravenously to adults within twelve hours after severe head injury demonstrated an improvement in three-and six-month mortality and functional outcome (as measured by the Glasgow Outcome Scale) in patients receiving the highest dose of PEG-SOD (10,000U/kg). 112 However, when further tested in a phase III randomized controlled trial, no statistical difference in mortality or outcome at three months post-injury was found between controls and patients receiving either 10,000U/kg or 20,000U/kg of PEG-SOD. 113 The free radical scavenger tirilazad mesylate also failed to show any benefit over placebo in a randomized controlled trial of adults with severe and moderate TBI with the exception of males presenting with a subarachnoid hemorrhage.…”

Neuroprotection from Delayed Postischemic Administration of a Metalloporphyrin Catalytic Antioxidant

“…production in the pathogenesis and evolution of acute brain injury has not been resolved. Numerous studies have investigated the therapeutic efficacy of antioxidant compounds in both animal models and humans (Forsman et al, 1988;Matsumiya et al, 1991;Uyama et al, 1992;Muizelaar et al, 1993). Results have been mixed, and issues of bioavailability of the various compounds have not been resolved (Haun et al, 1991).…”