Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial

Guomin Xiao, Jing Wei, Weiqi Yan, Weimin Wang, Zhenhui Lu, Guomin Xiao, Jing Wei, Weiqi Yan, Weimin Wang, Zhenhui Lu

Abstract

Background: Severe traumatic brain injury (TBI) has been increasing with greater incidence of injuries from traffic or sporting accidents. Although there are a number of animal models of TBI using progesterone for head injury, the effects of progesterone on neurologic outcome of acute TBI patients remain unclear. The aim of the present clinical study was to assess the longer-term efficacy of progesterone on the improvement in neurologic outcome of patients with acute severe TBI.

Methods: A total of 159 patients who arrived within 8 hours of injury with a Glasgow Coma Score </= 8 were enrolled in the study. A prospective, randomized, placebo-controlled trial of progesterone was conducted in the Neurotrauma Center of our teaching hospital. The patients were randomized to receive either progesterone or placebo. The primary endpoint was the Glasgow Outcome Scale score 3 months after brain injury. Secondary efficacy endpoints included the modified Functional Independence Measure score and mortality. In a follow-up protocol at 6 months, the Glasgow Outcome Scale and the modified Functional Independence Measure scores were again determined.

Results: Of the 159 patients randomized, 82 received progesterone and 77 received placebo. The demographic characteristics, the mechanism of injury, and the time of treatment were compared for the two groups. After 3 months and 6 months of treatment, the dichotomized Glasgow Outcome Scale score analysis exhibited more favorable outcomes among the patients who were given progesterone compared with the control individuals (P = 0.034 and P = 0.048, respectively). The modified Functional Independence Measure scores in the progesterone group were higher than those in the placebo group at both 3-month and 6-month follow-up (P < 0.05 and P < 0.01). The mortality rate of the progesterone group was significantly lower than that of the placebo group at 6-month follow-up (P < 0.05). The mean intracranial pressure values 72 hours and 7 days after injury were lower in the progesterone group than in the placebo group, but there was no statistical significance between the two groups (P > 0.05). Instances of complications and adverse events associated with the administration of progesterone were not found.

Conclusion: Our data suggest that acute severe TBI patients with administration of progesterone hold improved neurologic outcomes for up to 6 months. These results provide information important for further large and multicenter clinical trials on progesterone as a promising neuroprotective drug.

Trial registration: ACTRN12607000545460.

Figures

Figure 1
Figure 1
Trial profile.
Figure 2
Figure 2
Dichotomized Glasgow Outcome Scale scores for patients receiving either progesterone or placebo. There was a remarkably more favorable outcome among patients who were given progesterone compared with patients receiving placebo (P = 0.034) 3 months postinjury. At 6-month follow-up, the significant difference in the dichotomization of Glasgow Outcome Scale scores between the progesterone and placebo groups was similar to that after three-month injury (P = 0.048).
Figure 3
Figure 3
Modified Functional Independence Measure scores for patients receiving either progesterone or placebo. Modified Functional Independence Measure (FIM) scores at 3-month and 6-month follow-up from patients receiving either progesterone or placebo show that the scores in the progesterone group were significantly higher than those in the placebo group at both 3-month and 6-month follow-up. Data expressed as the mean ± standard deviation. Different from the placebo group: *P < 0.05, **P < 0.01.
Figure 4
Figure 4
Comparison of intracranial pressure between patients receiving either progesterone or placebo. The mean intracranial pressure between the progesterone and placebo group patients shows no significant differences 24 hours, 72 hours and 7 days after injury between the two groups (P > 0.05). Data expressed as the mean ± standard deviation.

References

    1. Roberts I, Schierhout G, Alderson P. Absence of evidence for the effectiveness of five interventions routinely used in the intensive care management of severe head injury: a systematic review. Neurol Neurosurg Psychiatry. 1998;65:729–733.
    1. Muzelaar JP, Mararon A, Young HF. Improving the outcome of severe head injury with oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase trial. J Neurosury. 1993;78:375–382.
    1. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005;22:106–118. doi: 10.1089/neu.2005.22.106.
    1. Roof RL, Duvdevani R, Stein DG. Gender influences outcome of brain injury: progesterone play a protective role. Brain Res. 1993;607:333–336. doi: 10.1016/0006-8993(93)91526-X.
    1. Roof RL, Zhang Q, Glasier MM, Stein DG. Gender-specific impairment on Morris water maze task after entorhinal cortex lesion. Behav Brain Res. 1993;57:41–51. doi: 10.1016/0166-4328(93)90060-4.
    1. Roof RL, Hall ED. Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma. 2000;17:367–388.
    1. Roof RL, Duvdevani R, Braswell L, Stein DG. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp Neurol. 1994;129:64–69. doi: 10.1006/exnr.1994.1147.
    1. Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol. 1997;31:1–11. doi: 10.1007/BF02815156.
    1. Roof RL, Duvdevani R, Stein DG. Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor Neurol Neurosci. 1992;4:425–427.
    1. Ransohoff RM, Tani M. Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci. 1998;21:154–159. doi: 10.1016/S0166-2236(97)01198-3.
    1. Cervantes M, Gonzalez-vdal MD, Ruelas R, Escobar A, Moralí G. Neuroprotective effects of progesterone on damage elicited by acute global cerebral ischemia in neurons of the caudate mucleus. Arch Med Res. 2002;33:6–14. doi: 10.1016/S0188-4409(01)00347-2.
    1. Asbury ET, Fritts ME, Horton JE, Isaac WL. Progesterone facilitates the acquisition of avoidance learning and protects against subcortical neuronal death following prefrontal cortex ablation in the rat. Behav Brain Res. 1998;97:99–106. doi: 10.1016/S0166-4328(98)00031-X.
    1. Shear DA, Galani R, Hoffman SW, Stein DG. Progesterone protects against necrotic damage and behavioral abnormalities caused by traumatic brain injury. Exp Neurol. 2002;178:59–67. doi: 10.1006/exnr.2002.8020.
    1. Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005;1049:112–119. doi: 10.1016/j.brainres.2005.05.004.
    1. Chen J, Chopp M, Li Y. Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat. Neurol Sci. 1999;171:24–30. doi: 10.1016/S0022-510X(99)00247-6.
    1. Jiang N, Chopp M, Stein D, Feit H. Progesterone is neuroprotective after transient middle cerebral artery occlusion in male rat. Brain Res. 1996;735:101–107. doi: 10.1016/0006-8993(96)00605-1.
    1. Kumon Y, Kim SC, Tompkins P, Stevens A, Sakaki S, Loftus CM. Neuroprotective effects of postischemic administration of progesterone in spontaneously hypertensive rats with focal cerebral ischemia. J Neurosurg. 2000;92:848–852.
    1. Thomas AJ, Nockels RP, Pan HQ, Shaffrey CI, Chopp M. Progesterone is neuroprotective after acute experimental spinal cord trauma in rats. Spine. 1999;24:2134–2138. doi: 10.1097/00007632-199910150-00013.
    1. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med. 2007;49:391–402. doi: 10.1016/j.annemergmed.2006.07.932.
    1. Palmer S, Bader MK, Qureshi A, Palmer J, Shaver T, Borzatta M, Stalcup C. The impact on outcomes in a community hospital setting of using the AANS traumatic brain injury guidelines. American Association of Neurologic Surgeons. J Trauma. 2001;50:657–664.
    1. O'dell MW, Barr K, Spanier D, Warnick RE. Functional outcome of inpatient rehabilitation in persons with brain tumors. Arch Phys Med Rehabil. 1998;79:1530–1534. doi: 10.1016/S0003-9993(98)90414-2.
    1. Mosenthal AC, Livingston DH, Lavery RF, Knudson MM, Lee S, Morabito D, Manley GT, Nathens A, Jurkovich G, Hoyt DB, Coimbra R. The effect of age on functional outcome in mild traumatic brain injury: 6-month report of a prospective multicenter trial. J Trauma. 2004;56:1042–1048.
    1. Leker RR, Shohami E. Cerebral ischemia and trauma – different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Rev. 2002;39:55–73. doi: 10.1016/S0165-0173(02)00157-1.
    1. Sobrado M, López MG, Carceller F, García AG, Roda JM. Combined nimodipine and citicoline reduce infrarct size, attenuate apoptosis and increase BCL-2 expression after focal cerebral ischemia. Neuroscience. 2003;118:107–113. doi: 10.1016/S0306-4522(02)00912-0.
    1. Allolio B, Oremus M, Reincke M, Schaeffer HJ, Winkelmann W, Heck G, Schulte HM. High-dose progesterone infusion in healthy males: evidence against antiglucocorticoid activity of progesterone. Eur J Endocrinol. 1995;133:696–700.
    1. Goldfien A. The gonadal hormones and inhibitors. In: Katzung BG, editor. Basic and Clinical Pharmacology. 4. Norwalk, CT: Appleton and Lange; 1989. pp. 493–516.
    1. Bullock MR, Lyeth BG, Muizelaar JP. Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. J Neurosurgery. 1999;45:207–220. doi: 10.1097/00006123-199908000-00001.
    1. Lancel M, Faulhaber J, Holsboer F, Rupprecht R. Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators. Am J Physiol. 1996;271:763–772.
    1. Wright DW, Ritchie JC, Mullins RE, Kellermann AL, Denson DD. Steady-state serum concentrations of progesterone following continuous intravenous infusion in patients with acute moderate to severe traumatic brain injury. J Clin Pharmacol. 2005;45:640–648. doi: 10.1177/0091270005276201.
    1. Goss CW, Hoffman SW, Stein DG. Behavioral effects and anatomic correlates after brain injury: a progesterone dose–response study. Pharmacol Biochem Behav. 2003;76:231–242. doi: 10.1016/j.pbb.2003.07.003.
    1. Wright DW, Bauer ME, Hoffman SW, Stein DG. Serum progesterone levels correlate with decreased cerebral edema after traumatic brain injury in male rats. J Neurotrauma. 2001;18:901–909. doi: 10.1089/089771501750451820.

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