Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase

A Phase II trial

Jan Paul Muizelaar, A. Marmarou, H. F. Young, S. C. Choi, A. Wolf, R. L. Schneider, H. A. Kontos

Research output: Contribution to journalArticle

174 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)375-382
Number of pages8
JournalJournal of Neurosurgery
Volume78
Issue number3
StatePublished - 1993
Externally publishedYes

Fingerprint

Craniocerebral Trauma
Reactive Oxygen Species
Placebos
Intracranial Pressure
Superoxides
Glasgow Outcome Scale
Glasgow Coma Scale
Wounds and Injuries
Mannitol
Metabolic Networks and Pathways
polyethylene glycol-superoxide dismutase
Brain Injuries
Superoxide Dismutase
Age Groups
Logistic Models
Head
Safety
Control Groups

Keywords

  • Glasgow Outcome Scale
  • oxygen radical scavenger
  • Phase II trial
  • polyethylene glycol
  • severe head injury
  • superoxide dismutase

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase : A Phase II trial. / Muizelaar, Jan Paul; Marmarou, A.; Young, H. F.; Choi, S. C.; Wolf, A.; Schneider, R. L.; Kontos, H. A.

In: Journal of Neurosurgery, Vol. 78, No. 3, 1993, p. 375-382.

Research output: Contribution to journalArticle

Muizelaar, Jan Paul ; Marmarou, A. ; Young, H. F. ; Choi, S. C. ; Wolf, A. ; Schneider, R. L. ; Kontos, H. A. / Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase : A Phase II trial. In: Journal of Neurosurgery. 1993 ; Vol. 78, No. 3. pp. 375-382.
@article{c1bfc75fca724a6280aa7240f40ae378,
title = "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.",
keywords = "Glasgow Outcome Scale, oxygen radical scavenger, Phase II trial, polyethylene glycol, severe head injury, superoxide dismutase",
author = "Muizelaar, {Jan Paul} and A. Marmarou and Young, {H. F.} and Choi, {S. C.} and A. Wolf and Schneider, {R. L.} and Kontos, {H. A.}",
year = "1993",
language = "English (US)",
volume = "78",
pages = "375--382",
journal = "Journal of Neurosurgery",
issn = "0022-3085",
publisher = "American Association of Neurological Surgeons",
number = "3",

}

TY - JOUR

T1 - Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase

T2 - A Phase II trial

AU - Muizelaar, Jan Paul

AU - Marmarou, A.

AU - Young, H. F.

AU - Choi, S. C.

AU - Wolf, A.

AU - Schneider, R. L.

AU - Kontos, H. A.

PY - 1993

Y1 - 1993

N2 - 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.

AB - 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.

KW - Glasgow Outcome Scale

KW - oxygen radical scavenger

KW - Phase II trial

KW - polyethylene glycol

KW - severe head injury

KW - superoxide dismutase

UR - http://www.scopus.com/inward/record.url?scp=0027414276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027414276&partnerID=8YFLogxK

M3 - Article

VL - 78

SP - 375

EP - 382

JO - Journal of Neurosurgery

JF - Journal of Neurosurgery

SN - 0022-3085

IS - 3

ER -