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

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)

Meshkini M. 4Our

Ple

asur

e A

ckno

wle

dgm

ents

bel

ongs

to:

Meshkini M. 5

Des

crip

tion

of C

ondi

tion

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)

Meshkini M. 6

Epid

emio

logi

cal F

acts

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)

Meshkini M. 7

Etio

logy

Ass

essm

ent

Motor Vehicle Collisions (MVC) 50%

Falls 38%

Violence (incl. attempted suicide) 4%

Meshkini M. 8

Des

crip

tion

of In

terv

entio

n 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)

Meshkini M. 9

Obj

ectiv

es Primary Objectives

What’s NEW???

Burns 2015 | Leucht 2015

Meshkini M. 10

Met

hods

• 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

Meshkini M. 11Crit

eria

for C

onsi

derin

g St

udie

s fo

r thi

s R

evie

w• Types of Studies

• RCTs→ CONSORT 2010 Checklist

• Other Studies

• Types of Participants

• Types of Interventions

Meshkini M. 12

Type

s of

out

com

e m

easu

res • Acute TBI

• Primary Outcomes

Mortality & Vegetative-state

Good Recovery & mild Disability

• Secondary Outcomes

Side-Effects

• Chronic TBI

• mostly for Neurocognitive state

Meshkini M. 13Sear

ch M

etho

ds fo

r Ide

ntifi

catio

n of

Stu

dies 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

Meshkini M. 14

Dat

a C

olle

ctio

n &

Ana

lysi

s

Zotero 4.0.28 (www.zotero.org )

Cochrane Review Manager – RevMan 5.3 (

http://tech.cochrane.org/revman )

http://www.zotero.org/

http://tech.cochrane.org/revman

Meshkini M. 15

Sele

ctio

n of

stu

dies

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

Meshkini M. 16

Dat

a Ex

trac

tion

and

Man

agem

ent

Supplement 8

CONsolidated Standards Of Reporting Trials

Meshkini M. 17

Ris

k of

Bia

s A

sses

smen

t:

Meshkini M. 18

Ris

k of

Bia

s A

sses

smen

t:

Meshkini M. 19

The

Age

nts

Meshkini M. 20

Eryt

hrop

oiet

in (E

PO)

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 Total #

RCTs

This study's RCTs

Included RCTs

# Acute TBI RCTs

# Chronic TBI RCTs

Studies Population

# Phase-III RCTs

Erythropoietin 4 4 2 2 - 645 1

Meshkini M. 21

Eryt

hrop

oiet

in (E

PO)

Favourable Outcome - Total

Meshkini M. 22

Eryt

hrop

oiet

in (E

PO)

Favourable Outcome

Meshkini M. 23

Eryt

hrop

oiet

in (E

PO)

Mortality

Meshkini M. 24

Eryt

hrop

oiet

in (E

PO)

Vascular Adverse-Effects

Meshkini M. 25

Eryt

hrop

oiet

in (E

PO)

Non-Vascular Adverse-Effects

Meshkini M. 26

Eryt

hrop

oiet

in (E

PO)

• 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

Meshkini M. 27

Citi

colin

eAdenosine 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 .

Meshkini M. 28

Citi

colin

eIncluded Studies:

COBRIT → Zafonte 2012 (Phase-III)

Shokouhi 2014

Leon-Carrion 1999 (Chronic study | 10 patients)

Maldonado 1991

Agent Total #

RCTs

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

Meshkini M. 29

Citi

colin

e

GOS Favourable Outcome

Meshkini M. 30

Citi

colin

e

Favourable Outcome – At all (Neurocognitive)

Meshkini M. 31

Citi

colin

e

Mortality

Meshkini M. 32

Citi

colin

e

Side-effects

Meshkini M. 33

Citi

colin

e• 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

Meshkini M. 34

Prog

este

rone

Meshkini M. 35

Prog

este

rone

• Cochrane Review → Ma 2012• Included Studies:

• SYNAPSE (Skolnick 2014)

• ProTECT (Wright 2014)

• Wright 2007

• Mazzeo 2008

Agent Total #

RCTs

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

Meshkini M. 36

Prog

este

rone

Favourable Outcome

Meshkini M. 37

Prog

este

rone

Mortality

Meshkini M. 38

Prog

este

rone

Side-effects analyzed as the most happened not solely.Xiao 2008 → no adverse effectSYNAPSE → confusion statement

Meshkini M. 39

Prog

este

rone

Adverse Effects

Meshkini M. 40

Prog

este

rone

• “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)

Meshkini M. 41

Oxy

gen

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

42

Oxy

gen

• 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

Meshkini M. 43

Oxy

gen

• 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)

Meshkini M. 44

Oxy

gen

• 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

Meshkini M. 45

Oxy

gen

• 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

Cor

ticos

tero

ids

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 #

RCTsThis

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

Meshkini M. 47

Mon

oam

iner

gic

agen

tsAmphetamine & 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

Meshkini M. 48

Mag

nesi

umReduction 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 #

RCTsThis study's

RCTsIncluded

RCTs# Acute TBI

RCTs# Chronic TBI RCTs

Studies Population

# Phase-III RCTs

Magnesium 4 1Vink 2009's results combined with this pilot study

0

Meshkini M. 49

Neu

roA

idA 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!

Meshkini M. 50

Pira

ceta

m• One of study’s primary objectives.

• Three titles achieved, but no full-texts.

Meshkini M. 51

Cer

ebro

lysi

n"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 #

RCTsThis study's

RCTsIncluded

RCTs# Acute TBI

RCTs# Chronic TBI RCTs

Studies Population

# Phase-III RCTs

Cerebrolysin 1 1 1 1 - 32 0

Meshkini M. 52

Cer

ebro

lysi

n

Cognitive Changes

Meshkini M. 53

Cer

ebro

lysi

n• Limited evidences

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

Meshkini M. 54

Cyc

losp

orin

e A

Preservation of mitochondrial function after TBI is the recommended

mechanism of action for this agent

Agent Total #

RCTs

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

Meshkini M. 55

Cyc

losp

orin

e A

Favourable Outcome

Meshkini M. 56

Cyc

losp

orin

e A

Mortality

Meshkini M. 57

Cyc

losp

orin

e A

Adverse-Efects (ICP rise)

Meshkini M. 58

Riv

astig

min

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

Meshkini M. 59

Riv

astig

min

Favourable Outcome

Meshkini M. 60

Riv

astig

min

Side-Effects

Meshkini M. 61

Riv

astig

min

• 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

Meshkini M.62

Mis

cella

neou

s Fi

ndin

gs• 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 Total #

RCTs

This study's RCTs

Included RCTs

Miscellaneous ? 6 2

Meshkini M. 63

Mis

cella

neou

s Fi

ndin

gs• 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

https://www.coursera.org/course/psychfirstaid

Meshkini M. 64

Phas

e-III

RC

Ts

Favourable Outcome

Meshkini M. 65

Phas

e-III

RC

Ts

Mortality

Meshkini M.66

Impl

icat

ion

for P

ract

ice

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)

Meshkini M. 67

Impl

icat

ion

for R

esea

rch

1Phase-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)

Meshkini M. 68

Impl

icat

ion

for R

esea

rch

2Oxygen

“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 viewMonoaminergicsNeuroAidPiracetam - Cerebrolysine

Magnesium

Other route than IV administrationRivastigmin

Chronic management of severe impaired neurocognitive conditions

Meshkini M. 69

The Evidences for current Review's process, are achievable from:

1. meshkini522.persiangig.com2.

3. 4.

http://meshkini522.persiangig.com/

http://meshkini522.persiangig.com/%D9%85%D9%82%D8%A7%D9%84%D9%87%E2%80%8C%D9%87%D8%A7%DB%8C%20%D8%A7%D9%88%D9%84%20%D8%B4%D8%AE%D8%B5/%D9%BE%D8%B2%D8%B4%DA%A9%E2%80%8C%DB%8C%20%D9%88%20%D8%B3%D9%84%D8%A7%D9%85%D8%AA/%D9%BE%D8%A7%DB%8C%D8%A7%D9%86%E2%80%8C%D9%86%D8%A7%D9%85%D9%87%E2%80%8C%DB%8C%20%D9%BE%D8%B2%D8%B4%DA%A9%E2%80%8C%DB%8C%20%D8%B9%D9%85%D9%88%D9%85%E2%80%8C%DB%8C/

Meshkini M. 70

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