Intercenter variance in clinical trials of head trauma - Experience of the National Acute Brain Injury Study: Hypothermia

G. L. Clifton, S. C. Choi, E. R. Miller, H. S. Levin, Jr Smith K.R., Jan Paul Muizelaar, Jr Wagner F.C., D. W. Marion, T. G. Luerssen

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Object. In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences. Methods The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data. Conclusions. For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management; 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.

Original languageEnglish (US)
Pages (from-to)751-755
Number of pages5
JournalJournal of Neurosurgery
Volume95
Issue number5
StatePublished - 2001
Externally publishedYes

Fingerprint

Hypothermia
Craniocerebral Trauma
Brain Injuries
Clinical Trials
Cerebrovascular Circulation
Arterial Pressure
Intracranial Pressure
Guideline Adherence
Phase III Clinical Trials
Morphine
Incidence
Therapeutics

Keywords

  • Center variance
  • Clinical trial
  • Head injury
  • Hypothermia

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Clifton, G. L., Choi, S. C., Miller, E. R., Levin, H. S., Smith K.R., J., Muizelaar, J. P., ... Luerssen, T. G. (2001). Intercenter variance in clinical trials of head trauma - Experience of the National Acute Brain Injury Study: Hypothermia. Journal of Neurosurgery, 95(5), 751-755.

Intercenter variance in clinical trials of head trauma - Experience of the National Acute Brain Injury Study : Hypothermia. / Clifton, G. L.; Choi, S. C.; Miller, E. R.; Levin, H. S.; Smith K.R., Jr; Muizelaar, Jan Paul; Wagner F.C., Jr; Marion, D. W.; Luerssen, T. G.

In: Journal of Neurosurgery, Vol. 95, No. 5, 2001, p. 751-755.

Research output: Contribution to journalArticle

Clifton, GL, Choi, SC, Miller, ER, Levin, HS, Smith K.R., J, Muizelaar, JP, Wagner F.C., J, Marion, DW & Luerssen, TG 2001, 'Intercenter variance in clinical trials of head trauma - Experience of the National Acute Brain Injury Study: Hypothermia', Journal of Neurosurgery, vol. 95, no. 5, pp. 751-755.
Clifton, G. L. ; Choi, S. C. ; Miller, E. R. ; Levin, H. S. ; Smith K.R., Jr ; Muizelaar, Jan Paul ; Wagner F.C., Jr ; Marion, D. W. ; Luerssen, T. G. / Intercenter variance in clinical trials of head trauma - Experience of the National Acute Brain Injury Study : Hypothermia. In: Journal of Neurosurgery. 2001 ; Vol. 95, No. 5. pp. 751-755.
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abstract = "Object. In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences. Methods The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data. Conclusions. For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management; 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.",
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T1 - Intercenter variance in clinical trials of head trauma - Experience of the National Acute Brain Injury Study

T2 - Hypothermia

AU - Clifton, G. L.

AU - Choi, S. C.

AU - Miller, E. R.

AU - Levin, H. S.

AU - Smith K.R., Jr

AU - Muizelaar, Jan Paul

AU - Wagner F.C., Jr

AU - Marion, D. W.

AU - Luerssen, T. G.

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N2 - Object. In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences. Methods The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data. Conclusions. For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management; 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.

AB - Object. In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences. Methods The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data. Conclusions. For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management; 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.

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