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Three Part Question

In [adults with traumatic brain injury] is there any role for [combination treatment with progesterone and vitamin. D] in [improving clinical outcomes].

Clinical Scenario

You are the emergency department consultant who attends an adult who has been brought in by HEMS following a high speed RTC. He suffered loss of consciousness and was intubated at scene with a GCS 6. He has a sustained a severe closed head injury.

You consider if there is any benefit for this patient in receiving combination progesterone and vitamin. D therapy for potential neuroprotection post- traumatic brain injury. Would this therapy improve clinical outcomes for the patient? You resolve to search the literature.

Search Strategy

Medline 1966-11/04 using the OVID interface
[exp adults with traumatic brain injury] AND [combination therapy] AND [progesterone and vitamin. D therapy] OR exp clinical outcomes. LIMIT to human adults only AND English language.

Search Outcome

Seven papers were identified. Out of a total of seven papers 3 identified were suitable. Non-English and irrelevant papers were excluded.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Aminmansour et al. 2012 Iran	60 adult patients with brain trauma and diffuse axonal injury all with GCS < 8. 3 groups of 20 patients each assigned either placebo, progesterone or combination therapy with PROG & VDH.	RCT	Rate of improvement in GCS	Those treated with combination therapy had lower mortality rates at 10 % compared to 40% in placebo. They also had higher rates of functional recovery.
			Improvement of Glasgow outcome scale. (GOS)	Statistically significant difference in GOS between treatment groups.
cekic et al, 2010	Retrospective review of both pre-clinical and clinical trials related to combination therapy in TBI and also disease specific neurodegeneration.	RR	Neuroprotection post-TBI	Significantly better compared to placebo
			Potential mechanism of action	Acts to reduce post-inflammatory damage associated with TBI.
			Rationale for combination therapy compared to Monotherapy PROG.	Targets two separate pathways known to be affected in TBI. Augmenting the pleiotropic effects of PROG.
			Delay in diagnosis	No diagnostic delay in any group
			Sensitivity and specificity of ultrasound diagnoses	NS
			Appropriateness of the decision to operate	NS
Cekic et al. 2009 USA	Systemic review of various studies involving combination therapy of PROG & VDH in TBI.	RR	Functional recovery	Significantly improved recovery with combined therapy post-TBI.
			Neuroprotection demonstrated by reduced inflammatory markers.	Several studies with animal models showed reduced inflammatory markers with combination therapy. There has yet to been quantative human studies showing this picture.
			PROG Monotherapy compared to combined therapy.	Combination therapy is significantly better at reducing mortality & morbidity compared to Monotherapy. This is particularly seen in those patients who are already vitamin. D deficient prior to insult.

Comment(s)

PROG has been shown have numerous pleiotropic effects and specifically be neuroprotective in those with TBI. 4, 5,6 The primary TBI insult initiates a complex cascade of neuroinflammatory responses affecting glial cells, astrocytes and inflammatory mediators. Furthermore, VDH is seen as a steroid hormone that can modulate neuroinflammation, oxidative stress and play a role in neuronal apoptosis. 7 There is emerging evidence from both pre-clinical and clinical studies, that combination therapy of both PROG and VDH is neuroprotective in this setting. A targeted combined therapy, addresses separate pathways affected in TBI mediating a neuroprotective effect and positive effects on clinical outcomes. Current, multi-centre phase III clinical trials are underway to further support the additional benefits of combination therapy in human studies but results from current studies prove promising. This is a promising area of research for those with TBI in the emergency department. Further, questions in regards to dosing regimens, optimal time of delivery still remain.

Clinical Bottom Line

There is yet to be firm clinical evidence from the few clinical trials adopting combination PROG & VDH therapy. However, current trials look to further evaluate the potential benefit for combination therapy in those with TBI. These should be randomized, properly controlled, clearly reported and blinded where possible. The limited available evidence is promising for this therapy but a majority of this evidence is in animal models.

References

1. O.A. Khan, J. Dunning, A.C. Parvaiz, R et al. Towards evidence-based medicine in surgical practice: best BETs. Int J Surg 2011, pp. 585–588.
2. Aminmansour B, Nikbakht H, Ghorbani A et al. Comparison of the administration of progesterone versus progesterone and vitamin D in improvement of outcomes in patients with traumatic brain injury: A randomized clinical trial with placebo group. Adv Biomed Res. 2012;1:58.
3. Cekic M, Stein DG. Traumatic brain injury and aging: is a combination of progesterone and vitamin D hormone a simple solution to a complex problem? Neurotherapeutics. 2010 Jan;7(1):81-90.
4. Cekic M, Sayeed I, Stein DG. Combination treatment with progesterone and vitamin D hormone may be more effective than monotherapy for nervous system injury and disease. Front Neuroendocrinol. 2009;30(2):158-72
5. Stein DG, Cekic MM. Progesterone and vitamin d hormone as a biologic treatment of traumatic brain injury in the aged. PM R. 2011 Jun;3(6 Suppl 1):S100-10.
6. Wei J, Xiao GM. The neuroprotective effects of progesterone on traumatic brain injury: current status and future prospects. Acta Pharmacol Sin. 2013;34(12): 1485–1490.
7. Radosevich JJ, Patanwala AE, Erstad BL. Emerging pharmacological agents to improve survival from traumatic brain injury. Brain Inj. 2013;27(13-14):1492-9.
8. Cekic M, Cutler SM, VanLandingham JW et al. Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats. Neurobiol Aging. 2011;32(5):864–874.