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

Restricted access

✓ 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.

Article Information

Address reprint requests to: J. Paul Muizelaar, M.D., Ph.D., Division of Neurosurgery, Medical College of Virginia, Box 631, Richmond, Virginia 23298–0631.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Bar graph showing the average intracranial pressure (ICP) during the first 5 days following head injury (taken at 30-second intervals) in the placebo group and in three groups receiving polyethylene glycol-superoxide dismutase treated at the Medical College of Virginia. There were no statistically significant differences between results.

  • View in gallery

    Bar graph showing the mean percentage of time during which intracranial pressure was above 20 mm Hg in the placebo group and in three groups receiving polyethylene glycol-superoxide dismutase treated at the Medical College of Virginia. Statistical significance: p < 0.05 between the placebo group and the groups receiving 5000 U/kg and 10,000 U/kg on Days 1 and 4.

  • View in gallery

    Bar graph showing the mean percentage of patients in the combined outcome categories of good, moderate disability, and severe disability in the placebo group and in the group receiving 10,000 U/kg polyethylene glycol-superoxide dismutase (PEG-SOD) when considered separately by admission Glasgow Coma Scale (GCS) score (≤ 5 and ≥ 6).

References

  • 1.

    Beckman JSBeckman TWChen Jet al: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:162016241990Beckman JS Beckman TW Chen J et al: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624 1990

    • Search Google Scholar
    • Export Citation
  • 2.

    Bouma GJMuizelaar JPChoi SCet al: Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 75:6856931991Bouma GJ Muizelaar JP Choi SC et al: Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 75:685–693 1991

    • Search Google Scholar
    • Export Citation
  • 3.

    Bouma GJMuizelaar JPStringer WAet al: Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 77:3603681992Bouma GJ Muizelaar JP Stringer WA et al: Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 77:360–368 1992

    • Search Google Scholar
    • Export Citation
  • 4.

    Bracken MBShepard MJCollins WFet al: A randomized, controlled trial of methylprednisolone or Naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 322:140514111990Bracken MB Shepard MJ Collins WF et al: A randomized controlled trial of methylprednisolone or Naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 322:1405–1411 1990

    • Search Google Scholar
    • Export Citation
  • 5.

    Braughler JMHall ED: Current application of “high-dose” steroid therapy for CNS injury. A pharmacological perspective. J Neurosurg 62:8068101985Braughler JM Hall ED: Current application of “high-dose” steroid therapy for CNS injury. A pharmacological perspective. J Neurosurg 62:806–810 1985

    • Search Google Scholar
    • Export Citation
  • 6.

    Chan PHYurko MFishman RA: Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices. J Neurochem 38:5255311982Chan PH Yurko M Fishman RA: Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices. J Neurochem 38:525–531 1982

    • Search Google Scholar
    • Export Citation
  • 7.

    Choi SCMuizelaar JPBarnes TYet al: Prediction tree for severely head-injured patients. J Neurosurg 75:2512551991Choi SC Muizelaar JP Barnes TY et al: Prediction tree for severely head-injured patients. J Neurosurg 75:251–255 1991

    • Search Google Scholar
    • Export Citation
  • 8.

    Choi SCWard JDBecker DPet al: Chart for outcome prediction in severe head injury. J Neurosurg 59:2942971983Choi SC Ward JD Becker DP et al: Chart for outcome prediction in severe head injury. J Neurosurg 59:294–297 1983

    • Search Google Scholar
    • Export Citation
  • 9.

    Davis RJBulkley GBTraystman RJ: Role of oxygen free radicals in focal brain ischemia in Tomita MSaunda TNaritomi Het al (eds): Cerebral Hyperemia and Ischemia: From the Standpoint of Cerebral Blood Volume. Amsterdam: Excerpta Medica1988 pp 151156Davis RJ Bulkley GB Traystman RJ: Role of oxygen free radicals in focal brain ischemia in Tomita M Saunda T Naritomi H et al (eds): Cerebral Hyperemia and Ischemia: From the Standpoint of Cerebral Blood Volume. Amsterdam: Excerpta Medica 1988 pp 151–156

    • Search Google Scholar
    • Export Citation
  • 10.

    DeSalles AAFJenkins LWAnderson RLet al: Extracellular potassium activity following concussion. A microelectrode study in the cat. Soc Neurosci Abstr 12:9671986DeSalles AAF Jenkins LW Anderson RL et al: Extracellular potassium activity following concussion. A microelectrode study in the cat. Soc Neurosci Abstr 12:967 1986

    • Search Google Scholar
    • Export Citation
  • 11.

    Ellis EFWright KFWei EPet al: Cyclooxygenase products of arachidonic acid metabolism in cat cerebral cortex after experimental concussive brain injury. J Neurochem 37:8928961981Ellis EF Wright KF Wei EP et al: Cyclooxygenase products of arachidonic acid metabolism in cat cerebral cortex after experimental concussive brain injury. J Neurochem 37:892–896 1981

    • Search Google Scholar
    • Export Citation
  • 12.

    Faden AIDemediuk PPanter SSet al: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:7988001989Faden AI Demediuk P Panter SS et al: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800 1989

    • Search Google Scholar
    • Export Citation
  • 13.

    Foulkes MAEisenberg HMJane JAet al: The Traumatic Coma Data Bank: design, methods, and baseline characteristics. J Neurosurg 75:S8S131991Foulkes MA Eisenberg HM Jane JA et al: The Traumatic Coma Data Bank: design methods and baseline characteristics. J Neurosurg 75:S8–S13 1991

    • Search Google Scholar
    • Export Citation
  • 14.

    Fridovich I: The biology of oxygen radicals. The superoxide radical is an agent of oxygen toxicity; superoxide dismutases provide an important defense. Science 201:8758801978Fridovich I: The biology of oxygen radicals. The superoxide radical is an agent of oxygen toxicity; superoxide dismutases provide an important defense. Science 201:875–880 1978

    • Search Google Scholar
    • Export Citation
  • 15.

    Genneralli TAThibault LETipperman Ret al: Axonal injury in the optic nerve: a model simulating diffuse axonal injury in the brain. J Neurosurg 71:2442531989Genneralli TA Thibault LE Tipperman R et al: Axonal injury in the optic nerve: a model simulating diffuse axonal injury in the brain. J Neurosurg 71:244–253 1989

    • Search Google Scholar
    • Export Citation
  • 16.

    Haun SEKirsch JRHelfaer MAet al: Polyethylene glycol-conjugated superoxide dismutase fails to augment brain superoxide dismutase activity in piglets. Stroke 22:6556591991Haun SE Kirsch JR Helfaer MA et al: Polyethylene glycol-conjugated superoxide dismutase fails to augment brain superoxide dismutase activity in piglets. Stroke 22:655–659 1991

    • Search Google Scholar
    • Export Citation
  • 17.

    Imaizumi SWoolworth VFishman RAet al: Liposome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke 21:131213171990Imaizumi S Woolworth V Fishman RA et al: Liposome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke 21:1312–1317 1990

    • Search Google Scholar
    • Export Citation
  • 18.

    Jennett BBond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:4804841975Jennett B Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:480–484 1975

    • Search Google Scholar
    • Export Citation
  • 19.

    Jonsson G: Studies on the mechanisms of 6-hydroxy-dopamine cytotoxicity. Med Biol 54:4064201976Jonsson G: Studies on the mechanisms of 6-hydroxy-dopamine cytotoxicity. Med Biol 54:406–420 1976

    • Search Google Scholar
    • Export Citation
  • 20.

    Katayama YBecker DPTamura Tet al: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:8899001990Katayama Y Becker DP Tamura T et al: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900 1990

    • Search Google Scholar
    • Export Citation
  • 21.

    Katayama TCheung MKGorman Let al: Increase in extracellular glutamate and associated massive ionic fluxes following concussive brain injury. Soc Neurosci Abstr 14:11541988Katayama T Cheung MK Gorman L et al: Increase in extracellular glutamate and associated massive ionic fluxes following concussive brain injury. Soc Neurosci Abstr 14:1154 1988

    • Search Google Scholar
    • Export Citation
  • 22.

    Katusic ZSVanhoutte PM: Superoxide anion is an endothelium-derived contracting factor. Am J Physiol 257:H33H371989Katusic ZS Vanhoutte PM: Superoxide anion is an endothelium-derived contracting factor. Am J Physiol 257:H33–H37 1989

    • Search Google Scholar
    • Export Citation
  • 23.

    Kontos HA: Oxygen radicals in experimental brain injury in Hoff JTBetz AL (eds): Intracranial Pressure VII. Berlin: Springer-Verlag1989 pp 787798Kontos HA: Oxygen radicals in experimental brain injury in Hoff JT Betz AL (eds): Intracranial Pressure VII. Berlin: Springer-Verlag 1989 pp 787–798

    • Search Google Scholar
    • Export Citation
  • 24.

    Kontos HAPovlishock JT: Oxygen radicals in brain injury. Cent Nerv Syst Trauma 3:2572631986Kontos HA Povlishock JT: Oxygen radicals in brain injury. Cent Nerv Syst Trauma 3:257–263 1986

    • Search Google Scholar
    • Export Citation
  • 25.

    Kontos HAWei EP: Superoxide production in experimental brain injury. J Neurosurg 64:8038071986Kontos HA Wei EP: Superoxide production in experimental brain injury. J Neurosurg 64:803–807 1986

    • Search Google Scholar
    • Export Citation
  • 26.

    Levasseur JEPatterson JL JrGhatak NRet al: Combined effect of respirator-induced ventilation and superoxide dismutase in experimental brain injury. J Neurosurg 71:5735771989Levasseur JE Patterson JL Jr Ghatak NR et al: Combined effect of respirator-induced ventilation and superoxide dismutase in experimental brain injury. J Neurosurg 71:573–577 1989

    • Search Google Scholar
    • Export Citation
  • 27.

    Liu THBeckman JSFreeman BAet al: Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am J Physiol 256:H589H5931989Liu TH Beckman JS Freeman BA et al: Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am J Physiol 256:H589–H593 1989

    • Search Google Scholar
    • Export Citation
  • 28.

    Marmarou AAnderson RLWard JDet al: Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg 75:S59S661991Marmarou A Anderson RL Ward JD et al: Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg 75:S59–S66 1991

    • Search Google Scholar
    • Export Citation
  • 29.

    Marshall JJWei EPKontos HA: Independent blockade of cerebral vasodilation from acetylcholine and nitric oxide. Am J Physiol 255:H847H8541988Marshall JJ Wei EP Kontos HA: Independent blockade of cerebral vasodilation from acetylcholine and nitric oxide. Am J Physiol 255:H847–H854 1988

    • Search Google Scholar
    • Export Citation
  • 30.

    Matsumiya NKoehler RCKirsch JRet al: Conjugated superoxide dismutase reduces extent of caudate injury after transient focal ischemia in cats. Stroke 22:119312001991Matsumiya N Koehler RC Kirsch JR et al: Conjugated superoxide dismutase reduces extent of caudate injury after transient focal ischemia in cats. Stroke 22:1193–1200 1991

    • Search Google Scholar
    • Export Citation
  • 31.

    Mayer MLWestbrook GL: Cellular mechanisms underlying excitotoxicity. Trends Neurosci 10:59611987Mayer ML Westbrook GL: Cellular mechanisms underlying excitotoxicity. Trends Neurosci 10:59–61 1987

    • Search Google Scholar
    • Export Citation
  • 32.

    Misra HPFridovich I: The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:317031751972Misra HP Fridovich I: The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175 1972

    • Search Google Scholar
    • Export Citation
  • 33.

    Muizelaar JPBouma GJ: Cerebral blood flow and cerebral blood volume after severe head injury. J Neurotrauma (In press)Muizelaar JP Bouma GJ: Cerebral blood flow and cerebral blood volume after severe head injury. J Neurotrauma (In press)

    • Search Google Scholar
    • Export Citation
  • 34.

    Muizelaar JPMarmarou AWard JDet al: Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 75:7317391991Muizelaar JP Marmarou A Ward JD et al: Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial. J Neurosurg 75:731–739 1991

    • Search Google Scholar
    • Export Citation
  • 35.

    Povlishock JT: Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol 2:1121992Povlishock JT: Traumatically induced axonal injury: pathogenesis and pathobiological implications. Brain Pathol 2:1–12 1992

    • Search Google Scholar
    • Export Citation
  • 36.

    Povlishock JTBecker DPCheng CLYet al: Axonal change in minor head injury. J Neuropathol Exp Neurol 42:2252421983Povlishock JT Becker DP Cheng CLY et al: Axonal change in minor head injury. J Neuropathol Exp Neurol 42:225–242 1983

    • Search Google Scholar
    • Export Citation
  • 37.

    Rubanyi GMVanhoutte PM: Superoxide anions and hvperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 250:H822H8271986Rubanyi GM Vanhoutte PM: Superoxide anions and hvperoxia inactivate endothelium-derived relaxing factor. Am J Physiol 250:H822–H827 1986

    • Search Google Scholar
    • Export Citation
  • 38.

    Schettini ALippman HRWalsh EK: Attenuation of decompressive hypoperfusion and cerebral edema by superoxide dismutase. J Neurosurg 71:5785871989Schettini A Lippman HR Walsh EK: Attenuation of decompressive hypoperfusion and cerebral edema by superoxide dismutase. J Neurosurg 71:578–587 1989

    • Search Google Scholar
    • Export Citation
  • 39.

    Schlaepfer WWZimmerman VJPet al: Neurofilament proteolysis in rat peripheral nerve. Homologies with calcium-activated proteolysis of other tissues. Cell Calcium 2:2352501980Schlaepfer WW Zimmerman VJP et al: Neurofilament proteolysis in rat peripheral nerve. Homologies with calcium-activated proteolysis of other tissues. Cell Calcium 2:235–250 1980

    • Search Google Scholar
    • Export Citation
  • 40.

    Schwartz DLellouch J: Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 20:6376481967Schwartz D Lellouch J: Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 20:637–648 1967

    • Search Google Scholar
    • Export Citation
  • 41.

    Snelling LKAckerman ADDean JMet al: The effects of superoxide dismutase on neurologic recovery (cerebral blood flow and evoked potentials) following global cerebral ischemia. Anesthesiology 67:A1531987 (Abstract)Snelling LK Ackerman AD Dean JM et al: The effects of superoxide dismutase on neurologic recovery (cerebral blood flow and evoked potentials) following global cerebral ischemia. Anesthesiology 67:A153 1987 (Abstract)

    • Search Google Scholar
    • Export Citation
  • 42.

    Takahashi HManaka SSano K: Changes in extracellular potassium concentration in cortex and brain stem during the acute phase of experimental closed head injurv. J Neurosurg 55:7087171981Takahashi H Manaka S Sano K: Changes in extracellular potassium concentration in cortex and brain stem during the acute phase of experimental closed head injurv. J Neurosurg 55:708–717 1981

    • Search Google Scholar
    • Export Citation
  • 43.

    Teasdale GJennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81841974Teasdale G Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84 1974

    • Search Google Scholar
    • Export Citation
  • 44.

    Wei EPKontos HADietrich WDet al: Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res 48:951031981Wei EP Kontos HA Dietrich WD et al: Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats. Circ Res 48:95–103 1981

    • Search Google Scholar
    • Export Citation
  • 45.

    Wei EPLamb RGKontos HA: Increased phospholipase C activity after experimental brain injury. J Neurosurg 56:6956981982Wei EP Lamb RG Kontos HA: Increased phospholipase C activity after experimental brain injury. J Neurosurg 56:695–698 1982

    • Search Google Scholar
    • Export Citation
  • 46.

    Yoshida KBurton GFMcKinney JSet al: Brain and tissue distribution of polyethylene glycol-conjugated superoxide dismutase in rats. Stroke 23:8658691992Yoshida K Burton GF McKinney JS et al: Brain and tissue distribution of polyethylene glycol-conjugated superoxide dismutase in rats. Stroke 23:865–869 1992

    • Search Google Scholar
    • Export Citation
  • 47.

    Yoshida KBurton GFYoung HFet al: Brain levels of polyethylene glycol-conjugated superoxide dismutase following fluid percussion brain injury in rats. J Neurotrauma 9:85921992Yoshida K Burton GF Young HF et al: Brain levels of polyethylene glycol-conjugated superoxide dismutase following fluid percussion brain injury in rats. J Neurotrauma 9:85–92 1992

    • Search Google Scholar
    • Export Citation
  • 48.

    Zimmerman RSMuizelaar JPWei EPet al: Reduction of intracranial hypertension with free radical scavengers in Hoff JTBetz AL (eds): Intracranial Pressure VII. Berlin: Springer-Verlag1989 pp 804809Zimmerman RS Muizelaar JP Wei EP et al: Reduction of intracranial hypertension with free radical scavengers in Hoff JT Betz AL (eds): Intracranial Pressure VII. Berlin: Springer-Verlag 1989 pp 804–809

    • Search Google Scholar
    • Export Citation

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 116 116 9
Full Text Views 174 174 1
PDF Downloads 101 101 1
EPUB Downloads 0 0 0

PubMed

Google Scholar