Neuroprotective agents use for traumatic brain injury - modified for thesis defense session

2. Neuroprotective agents use for
Traumatic Brain Injury:
A Systematic Review & Meta-Analyses
A Presentation submitted for MD Thesis
Presented by: Mohammad Meshkini
Supervised by: Dr. Ali Meshkini
Dr. Homayoun Sadeghi-Bazargani
Tabriz University of Medical Sciences(Bio-Medicine)

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OurPleasureAcknowledgmentsbelongsto: Mrs Fathifar | Mr Saeidi | Mr Ahadi
Dr. David B. Arciniegas | Dr. Lisa Anne Brenner | Dr. Jose Leon-Carion | Dr.
Andrew I.R. Maas | Dr. Olli Tenovuo
Prof. Cordian Beyer | Dr. Burns

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OurPleasureAcknowledgmentsbelongsto:

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DescriptionofCondition • Traumatic Brain Injury (TBI) a.k.a. Head Injury
• Morbidity – Mortality (LEADING CAUSE)
• Young Ages
• “the occurrence of Injury to the head, that is associated with symptoms or
signs attributable to the injury such as decreased level of consciousness,
amnesia, other neurological or neuropsychological abnormalities, skull
fracture, intracranial lesions or death” (Sahuquillo, 2006)

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EpidemiologicalFacts • The incidence rate of 558 cases per 100,000 person each year
• TBI related disability estimated as 33 new cases per 100,000 people in a year
• More than 50,000 Deaths each year
• TBI's costs more than $48 billion a year
• among 2.5 and 6.5 million Americans alive today have had a TBI assault
• "Survivors of TBI are often left with significant cognitive, behavioral, and
communicative disabilities" (NIH-TBI 2002)

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EtiologyAssessment • Motor Vehicle Collisions (MVC) 50%
• Falls 38%
• Violence (incl. attempted suicide) 4%

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DescriptionofIntervention Neuroprotective Agents are “Drugs intended to prevent damage to the brain or
spinal cord from ischemia, stroke, convulsions, or trauma. Some must be
administered before the event, but others may be effective for some time after.
They act by a variety of mechanisms, but often directly or indirectly
minimize the damage produced by endogenous excitatory amino acids”
(MeSH 1995)

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Objectives • Primary Objectives
• What’s NEW???
• Burns 2015 | Leucht 2015

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Methods • Criteria for Considering Studies for this Review
• Types of outcome measures
• Search Methods for Identification of Studies
• Data Collection & Analysis
• Selection of studies
• Data Extraction and Management
• Risk of Bias Assessment
• Measures of Treatment Effect
• Unit of Analysis issues

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CriteriaforConsideringStudies
forthisReview
• Types of Studies
• RCTs→ CONSORT 2010 Checklist
• Other Studies
• Types of Participants
• Types of Interventions

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Typesofoutcomemeasures • Acute TBI
• Primary Outcomes
Mortality & Vegetative-state
Good Recovery & mild Disability
• Secondary Outcomes
Side-Effects
• Chronic TBI
• mostly for Neurocognitive state

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SearchMethodsforIdentificationofStudies
ID Search
#1 traumatic brain injur*:ti,ab,kw (Word variations have been searched)
#2 traumatic head injur*:ti,ab,kw
#3 brain injur*:ti,ab,kw
#4 #1 or #2 or #3
#5 Neuroprotect*:ti,ab,kw
#6 Neuro-protect*:ti,ab,kw
#7 Piracetam:ti,ab,kw
#8 Neuroaid:ti,ab,kw
#9 citicoline:ti,ab,kw
#10 hyperventilation:ti,ab,kw
#11 hyperbaric oxygen:ti,ab,kw
#12 hyperbaric O2:ti,ab,kw
#13 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12
#14 #4 and #13
Supplements1-7

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DataCollection&Analysis
Zotero 4.0.28 (www.zotero.org )
Cochrane Review Manager – RevMan 5.3 (
http://tech.cochrane.org/revman )

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Selectionofstudies
1756 records identified through database search 3 additional records
1291 records after removing duplicates
101 records screened1190 records excluded
93 of full-text articles assessed for eligibility
38 articles included in qualitative review
18 articles included in quantitative analysis
55 full-texts excluded
26 Review-like
29 covered by others

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DataExtractionandManagement
Supplement 8
CONsolidated Standards Of Reporting Trials

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RiskofBiasAssessment:

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RiskofBiasAssessment:

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TheAgents

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Erythropoietin(EPO) A glycoprotein hormone of cytokine type-I super family, that its anti-
apoptotic and anti-inflammatory properties, also interaction of EPO with
neural voltage-gated calcium channels, and EPO with EPO-receptors
increasing of local production after TBI, seems to be EPO's mechanisms of
action.
Agent Tota
l #
RCT
s
This
study's
RCTs
Included
RCTs
# Acute
TBI RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Erythropoietin 4 4 2 2 - 645 1

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Erythropoietin(EPO)
Favourable Outcome - Total

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Erythropoietin(EPO)
Favourable Outcome

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Erythropoietin(EPO)
Mortality

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Erythropoietin(EPO)
Vascular Adverse-Effects

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Erythropoietin(EPO)
Non-Vascular Adverse-Effects

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Erythropoietin(EPO) • EPO-TBI (Nichol 2015) side-effect → 40000 IU up to 3 doses
• Recommended dose of treatment 1000-30000 (Aloizos 2015)
• Reduction in mortality rates | No significant difference of outcome
• RECOMMEND
• Another phase-III RCT with modified dose

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Citicoline Adenosine Tri-Phosphate(ATP) is responsible for Cell Membrane Sodium-
Potassium(Na-K) ATPase Pump's Function; TBI related cell membrane un-
integrity & accumulation of extracellular water, leads to the known brain
edema, also formation of lipid peroxidase.
Cholinergic agents effects in cell-oxygenation cycles &
formation of ATP, indirectly may cause in cell wall integrity
formation & reduction of further secondary injuries .

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Citicoline Included Studies:
COBRIT → Zafonte 2012 (Phase-III)
Shokouhi 2014
Leon-Carrion 1999 (Chronic study | 10 patients)
Maldonado 1991
Agent Tota
l #
RCT
s
This
study's
RCTs
Included
RCTs
# Acute
TBI RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Citicoline 4 4 4 3 1 1196 1
NO PLACEBO GROUP

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Citicoline
GOS Favourable Outcome

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Citicoline
Favourable Outcome – At all (Neurocognitive)

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Citicoline
Mortality

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Citicoline
Side-effects

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Citicoline • COBRIT (Zafonte 2012)
• Heterogeneity of intervention doses and outcome assessments in included
studies surrounded by Zafonte et al. Study's results
• current use of citicoline for TBI in acute or chronic phase, is no more
recommended
However it may have neurocognitive beneficiaries for mild TBI

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Progesterone

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Progesterone • Cochrane Review → Ma 2012
• Included Studies:
• SYNAPSE (Skolnick 2014)
• ProTECT (Wright 2014)
• Wright 2007
• Mazzeo 2008
Agent Tota
l #
RCT
s
This
study's
RCTs
Included
RCTs
# Acute
TBI RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Progesterone 7 7 4 4 - 2320 2
Phase-III RCTs

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Progesterone
Favourable Outcome

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Progesterone
Mortality

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Progesterone Side-effects analyzed as the most happened not solely.
Xiao 2008 → no adverse effect
SYNAPSE → confusion statement

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Progesterone
Adverse Effects

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Progesterone • “Despite these design strategies and extensive efforts, the trial did not
confirm the efficacy of progesterone in patients with acute TBI. It is
possible that the heterogeneity of the injury, confounding preexisting
conditions, and characteristics of individual patients (e.g., resilience),
which can be well controlled in animal models play too large a role to
overcome in human disease.” (Wright 2014)
• Dr. Beyer’s Recommendation
• Pediatric | Elederly (+ vitD)

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Oxygen The vital element of life & viability of neurons;
Agent Total #
RCTs
This study's
RCTs
Included
RCTs
# Acute TBI
RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Oxygen 24 7 4 1 3 205 0

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Oxygen • 8 more studies (1 Observational , 7 RCTs)
• Observational → investigate guideline adherence about pre-hospital
advanced airway attempt for oxygenation in 54 severe TBI patients, that
resulted in good adherence of performers to guidelines (Rognås 2014),
which also reported in other studies aimed to assess practitioners adherence
to guidelines, as well as their support by strong evidences (Bell 2013;
Huizenga 2002), but not satisfied results which recommended revision
for guidelines.
• The RCTs

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Oxygen • Mortality Report → Rockswold [only acute TBI study]
• 16% Combined vs. 42 % Control
• Significant better outcomes of Combined Group (P=0.024) in Cerebral
Metabolism, Partial oxygen pressure in brain & ICP.
• Neurocognitive changes:
• Boussi-Gross → improvement in (Memory, Attention, Executive function, Information
processing speed)
• DoD/VA → no significant change of cognitive function (ImPACT , PCL-M)

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Oxygen • Wolf 2012b [only side-effect reported study] → Ear barotrauma | Headache
• No Improvement in eye-tracking abnormalities of Cifu 2014c
• Wolf 2012b results on visual acuity:
• 22/47 eyes in HBO2
| 25/46 eyes in Sham-Control → improvement in Snellen chart
• 6/47 eyes in HBO2
| 3/46 eyes in Sham-Control → reduction in Snellen chart

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Oxygen • Rockswold new combined treatment strategy
• Difference of Civilians & PTSD related neurocognitive of VA (Boussi-Gross
2013 & DoD/VA studies)
• RECOMMENDATION
• A new multi-centric phase-III
• HBO2
/NBH combined vs. Sham-Control
• No enough evidence for Chronic TBI management

46. Corticosteroids Inflammatory process after TBI, which causes brain edema & Intra Cranial
Pressure (ICP) rise, perform the hypothesis of using Corticosteroids for
TBI, the primary researches & studies show the beneficial effect of this
intervention, while CRASH work in 2005 and an updated Cochrane Review
after that, challenged the efficacy of Corticosteroids use for TBI.
NO NEW STUDY FOUND FOR THIS TOPIC
Agent Total
#
RCTs
This
study's
RCTs
Included
RCTs
# Acute TBI
RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Corticosteroids 27 all study results from Alderson 2006 Cochrane Review

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Monoaminergicagents Amphetamine & other promotors of Neuroaminergic neurotransmission,
have been suggested to improve the functional recovery of the brain after
TBI.
NO NEW STUDIES AFTER COCHRANE 2011 REVISED REVIEW
Agent Total #
RCTs
This
study
's
RCTs
Included
RCTs
# Acute TBI
RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Monoaminergics 20 all study results from Forysth 2011 Cochrane Review

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Magnesium Reduction in serum magnesium after TBI, and beneficial effects of
magnesium therapy for animal models, conceptualized its use in human
cases, its failure in recent studies, came to the conclusion of Blood Brain
Barrier (BBB) effect on this agent's transmission.
RECOMMEND
New Trial via Other route of administration rather than I.V. route
Agent Total
#
RCTs
This study's
RCTs
Included
RCTs
# Acute TBI
RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Magnesium 4 1
Vink 2009's results combined with this pilot study
0

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NeuroAid A Chinese medicine, also known as MCL601 and MCL901(a.k.a. Simplified
to NeuroAid or NeuroAid-II, respectively), which showed Neuroprotctive
effects in stroke trials.
BUT NO TRIAL FOR TBI yet!

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Piracetam • One of study’s primary objectives.
• Three titles achieved, but no full-texts.

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Cerebrolysin "Cerebrolysin is a peptide-preparation, produced by the bio-
technologically standardized enzymatic breakdown of purified porcine
brain proteins." mechanism of action is not fully understood, but animal
studies, suggest improved neuronal oxygen utilization, reduction of
cerebral lactic acid concentration & free oxygen radical concentrations
decrease (Wong 2005).
Agent Total
#
RCTs
This study's
RCTs
Included
RCTs
# Acute TBI
RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Cerebrolysin 1 1 1 1 - 32 0

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Cerebrolysin
Cognitive Changes

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Cerebrolysin • Limited evidences
• CAPTAIN (Poon 2015) → Ongoing phase-III RCT

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CyclosporineA Preservation of mitochondrial function after TBI is the recommended
mechanism of action for this agent
Agent Tota
l #
RCT
s
This
study's
RCTs
Included
RCTs
# Acute
TBI RCTs
# Chronic
TBI RCTs
Studies
Population
# Phase-III
RCTs
Cyclosporine A
5 5 2 2 - 89 0

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CyclosporineA
Favourable Outcome

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CyclosporineA
Mortality

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CyclosporineA
Adverse-Efects (ICP rise)

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Rivastigmin Mostly known for its cholinesterase inhibitory (ChE-inh) effects, that
improves cholinergic function of brain in Alzheimer Disease(AD) trials;
there are also TBI trials based on hypothesis of Post-Traumatic
Cholinergic Deficiencies.
Agent Total
#
RCTs
This study's
RCTs
Included RCTs # Acute TBI
RCTs
# Chronic TBI
RCTs
Studies
Population
# Phase-III
RCTs
Rivastigmin 3 3 1 - 1 157 0

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Rivastigmin
Favourable Outcome

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Rivastigmin
Side-Effects

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Rivastigmin • No outcome differences between ChE-inh (Rivastigmin, Galantamin, Donezapil) |
Galantamin preferred in less side-effects | Tenovou 2005.
• Silver 2006, 2009:
• BETTER OUTCOMES IN SEVERE IMPIRED PATIENTS
• but no raw data

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MiscellaneousFindings • A Meta-Analysis of CCBs for TBI → Xu 2013
• 9 RCTs | not significant, slightly better outcomes of placebo group (p=0.52) | no difference of
mortalities (p=0.44) nor adverse effects (p=0.33) → ≠ Cheng 2013 "The role of mitochondrial
calcium uni-porter in neuroprotection in traumatic brain injury"
• Emotional Recognition assessment → Hart 2014
• Neumann 2015
• Hypothermia
• Reporting of hyperthermia effect (Li 2012)
• Cochrane Review of Cerebral cooling during Brain Surgery (Galvin 2015)
• Music-therapy → Maleki 2011
• Better significant physiologic outcomes of decreasing systolic and diastolic blood pressure,
pulse rate, respiratory rate, arterial blood pressure and body temperature and Increaseing
arterial oxygen saturation (<0.001); however pulse pressure decreasing was not significant
Agent Tota
l #
RCT
s
This
study's
RCTs
Included
RCTs
Miscellaneous ? 6 2

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MiscellaneousFindings • PFA – RAPID
• Reflective listening
• Assessment of Needs
• Prioritization
• Intervention
• Disposition
• Sub-acute complications of 2/3 of severe impaired TBI patients
during recovery → their families lives (Godbolt 2015)
• Cooling (Fevered patients outcomes)
• Music-therapy
https://www.coursera.org/course/psychfirstaid

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Phase-IIIRCTs
Favourable Outcome

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Phase-IIIRCTs
Mortality

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ImplicationforPractice Oxygen
HBO2
/NBH (Rockswold 2013)
Cortcosteroids
Dual-Diagnose (TBI SCI)
2-3 hours of accident – Methylprednisolone (Bracken 2002) IV route
Bolus → 30mg/kg in 15min
Continuous → 5.4mg/kg/Day for at least 24-48hrs
Citicoline
Neurocognitive of Chronic TBI management – mild impaired | EBM-support needed
Cyclosporine A
ICP Control | EBM-support needed (Hatton 2008) IV route
Bolus → 2.5mg/kg in 2hrs
Continuous → 5mg/kg/Day for at least 72hrs
Rivastigmin (Silver 2006) PO route | EBM-support needed
Neurocognitive of Chronic TBI management – severe impaired | 3-12mg/Day (+1.5mg/4week)

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ImplicationforResearch1 Phase-III RCTs
Double (or more)-blinded | Huge multi-centric international | phase-III RCTs | Regular
interim checkpoint assessments
CONSORT-statement
Reporting outcomes (GOS-E)
Sub-grouping (severity)
“From mice to mind”
"there is potential for TBI" as "mirror pathophysiology of some of the other conditions",
despite "the lack of sensitive outcome measures" there is hope to "promote at least
some improvement in recovery of function via immunomodulation and promoting
plasticity" (Dr. Burns' expert view)

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ImplicationforResearch2 Oxygen
“combined HBO2/NBH treatment, which consisted of 100% FiO2 delivered for 60
minutes at 1.5 ATA followed by 3 hours at 1.0 ATA” → acute TBI
Gonadal Esteroids
“High-dose, short-time administration of progesterone with 17-Beta-E2 in
emulsion of Omega-3” → Prof. Beyer's expert view
Monoaminergics
NeuroAid
Piracetam - Cerebrolysine
Magnesium
Other route than IV administration
Rivastigmin
Chronic management of severe impaired neurocognitive conditions

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The Evidences for current Review's process, are achievable from:
1. meshkini522.persiangig.com
2.
3. 4.

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