Treatment and Multiple Therapeutic Strategies

Chapter 5

Abstract

Use of Neuroprotective agents for

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity especially in young ages, while over 30 years of neuroprotective agents use for TBI management provided neither any recommended agent for favorable outcome nor less adverse effects in TBI management yet. This review got selected keywords' search and ran in known international and local databases, with no limitation up to September 6, 2015. Related to the subject, clinical human studies have been selected for the review. Data from 32 studies were classified into 10 subgroups. About 18 studies with a population of 4637 participants were included in 6 topic reviews and meta-analyses. Oxygen use in acute management of TBI to reduce mortality rates could be recommended. Corticosteroid use in solo acute TBI management is prohibited due to increasing risk of mortalities. However, in dual-diagnosed patients (TBI and spinal cord injury (SCI) together), corticosteroid use should be obtained by a Bracken protocol. The use of citicoline in acute TBI is no more supported. The use of cyclosporine-A for ICP control depends on the resources and physician's decision. Rivastigmine use for chronic neurocognitive conditions of TBI management had some beneficence in severely impaired participants. However, the

Traumatic Brain Injury

Mohammad Meshkini, Ali Meshkini

use of other agents in TBI has no field of support yet.

systematic review, meta-analysis

1.1 Description of the condition

intracranial lesions or death." [6].

1. Introduction

87

Keywords: traumatic brain injury, head injury, neuroprotective agents,

Traumatic brain injury (TBI), which is also known as head injury [1–3], is the leading cause of mortality and morbidity [1, 4–6], especially in young ages [1]; that is defined as "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,

and Homayoun Sadeghi-Bazargani

#### Chapter 5

## Use of Neuroprotective agents for Traumatic Brain Injury

Mohammad Meshkini, Ali Meshkini and Homayoun Sadeghi-Bazargani

#### Abstract

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity especially in young ages, while over 30 years of neuroprotective agents use for TBI management provided neither any recommended agent for favorable outcome nor less adverse effects in TBI management yet. This review got selected keywords' search and ran in known international and local databases, with no limitation up to September 6, 2015. Related to the subject, clinical human studies have been selected for the review. Data from 32 studies were classified into 10 subgroups. About 18 studies with a population of 4637 participants were included in 6 topic reviews and meta-analyses. Oxygen use in acute management of TBI to reduce mortality rates could be recommended. Corticosteroid use in solo acute TBI management is prohibited due to increasing risk of mortalities. However, in dual-diagnosed patients (TBI and spinal cord injury (SCI) together), corticosteroid use should be obtained by a Bracken protocol. The use of citicoline in acute TBI is no more supported. The use of cyclosporine-A for ICP control depends on the resources and physician's decision. Rivastigmine use for chronic neurocognitive conditions of TBI management had some beneficence in severely impaired participants. However, the use of other agents in TBI has no field of support yet.

Keywords: traumatic brain injury, head injury, neuroprotective agents, systematic review, meta-analysis

#### 1. Introduction

#### 1.1 Description of the condition

Traumatic brain injury (TBI), which is also known as head injury [1–3], is the leading cause of mortality and morbidity [1, 4–6], especially in young ages [1]; that is defined as "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." [6].

Epidemiological studies, demonstrate following statements in USA [4];


Free oxygen radicals also accumulate and degrade cell membrane; which all if lead to irreversible changes in neuron cells, it "results in unavoidable cell death." There are also Cochrane reviews for hyperbaric oxygen (HBO2) and hyperventilation

Inflammatory process after TBI, which causes brain edema and intracranial pressure (ICP) rise, performed the hypothesis of using corticosteroids for TBI, the primary researches and studies showed the beneficial effect of this intervention, while CRASH trial in 2005 and an updated Cochrane review after that, challenged the efficacy of corticosteroids use for TBI [4]; further from this study's proposal, steroids using for spinal cord injury (SCI) seems to have beneficial effects; also there is a Cochrane review for its neuroprotection beneficence in SCI assaults [13].

It has a wide variety of neuroprotection mechanisms of action, as an antioxidant agent, by reducing brain edema and inflammatory-related factors, controlling of vasogenic edema through blood brain barrier (BBB) reconstitution and aquaporin-4 water transporter modulation, axonal regenerating stimulant, inhibition of inflammatory cytokines production, synaptogenesis and dendritic arborization, altering glutamate receptor activity to reduce excitotoxicity of injury and also taking all these effects by its receptor's key rolling [14–16]. Also inhibition of ion flux cell pores like L-type calcium channel, potassium, and sodium voltage-gates, as well GABA-A receptors, all result in vasoconstriction and reducing edema that seem likely to dihydropyridine's mechanism of action, without its side effects like dizziness, peripheral edema, hypotension, reflex tachycardia and headaches [17, 18].

Amphetamine and other promotors of neuroaminergic neurotransmission have been suggested to improve the functional recovery of the brain after TBI. There is

A glycoprotein hormone of cytokine type-I super family, that its anti-apoptotic and anti-inflammatory properties, also interaction of EPO with neural voltagegated calcium channels, and EPO with EPO-receptors increasing of local production

Reduction in serum magnesium levels after TBI, and beneficial effects of magnesium therapy in animal models, conceptualized its use for human cases, its failure in recent studies, came to the conclusion of blood brain barrier (BBB) effect on this

"Cerebrolysin is a peptide-preparation, produced by the bio-technologically standardized enzymatic breakdown of purified porcine brain proteins." mechanism

(NBH) use in TBI [1, 2].

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

2.2 Corticosteroids

2.3 Progesterone

2.4 Monoaminergic agents

2.5 Erythropoietin (EPO)

agent's transmission [23].

2.7 Cerebrolysin

89

also a Cochrane review for these agents [19].

after TBI, seems to be EPO's mechanisms of action [20–22].

2.6 Magnesium sulfate and other magnesium salts


#### 1.2 Description of the intervention

According to medical subheadings (MeSH) definition, 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" [8]. As mentioned in the MeSH definition, there are variety of drugs and their action mechanisms to minimize the TBI damage; the breadth list of trials on www.clinicaltrial.gov for "Neuroprotective Agents" and "Traumatic Brain Injury" terms, states this. A recent study of Burns et al. declared 30 years of using Neuroprotective agents on animal models forecasting the same effect on humans failed, and represents to use animal models as new cases for stem cell studies as well, rather than formerly known for using Neuroprotective agents [9], which is confirmed by other studies too [10, 11].

The recent challenging review and meta-analyses study of Leucht et al. about efficacy of commonly used major drugs for medical and psychological conditions, seems to be a practice-challenging article for all physicians over the world [12]; this meta-analyzed article's results on major commonly used drugs showed the small to medium effect of 13 drugs and nearly medium to favorable effect of 3 drugs out of 19 major commonly used drugs for variety of clinical or mental conditions; collecting these information together rings a bell; how to use the most effective interventions for conditions?

#### 2. Literature review

There are wide variety of Neuroprotective agents, and breadth studies on human and animal cases, the following lists the agents which were studied on human clinical trials:

#### 2.1 Oxygen

The vital element of life and viability of neurons. Hypoxia leads to anaerobic metabolism, acidosis, and reduction in cellular metabolism. Neurons messaging conduction ability disturbs due to loss of their ability to maintain ionic homeostasis. Free oxygen radicals also accumulate and degrade cell membrane; which all if lead to irreversible changes in neuron cells, it "results in unavoidable cell death." There are also Cochrane reviews for hyperbaric oxygen (HBO2) and hyperventilation (NBH) use in TBI [1, 2].

#### 2.2 Corticosteroids

Epidemiological studies, demonstrate following statements in USA [4];

• TBI related disability estimated as 33 new cases per 100,000 people in a year,

• Motor vehicle collisions (MVC) is the responsible for 50% of TBI causes, following by falls (38%), and violence (also including attempted suicide) 4%,

• TBI costs more than \$48 billion a year. About 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" [7]. According to the chronology period and the state of the condition, it

According to medical subheadings (MeSH) definition, 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" [8]. As mentioned in the MeSH definition, there are variety of drugs and their action mechanisms to minimize the TBI damage; the breadth list of trials on www.clinicaltrial.gov for "Neuroprotective Agents" and "Traumatic Brain Injury" terms, states this. A recent study of Burns et al. declared 30 years of using Neuroprotective agents on animal models forecasting the same effect on humans failed, and represents to use animal models as new cases for stem cell studies as well, rather than formerly known for using Neuroprotective agents [9],

The recent challenging review and meta-analyses study of Leucht et al. about efficacy of commonly used major drugs for medical and psychological conditions, seems to be a practice-challenging article for all physicians over the world [12]; this meta-analyzed article's results on major commonly used drugs showed the small to medium effect of 13 drugs and nearly medium to favorable effect of 3 drugs out of

There are wide variety of Neuroprotective agents, and breadth studies on human

The vital element of life and viability of neurons. Hypoxia leads to anaerobic metabolism, acidosis, and reduction in cellular metabolism. Neurons messaging conduction ability disturbs due to loss of their ability to maintain ionic homeostasis.

and animal cases, the following lists the agents which were studied on human

19 major commonly used drugs for variety of clinical or mental conditions; collecting these information together rings a bell; how to use the most effective

• The incidence rate of 558 cases per 100,000 person each year,

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

categorizes under "Primary" and "Secondary" injury [1].

• More than 50,000 deaths each year,

1.2 Description of the intervention

which is confirmed by other studies too [10, 11].

interventions for conditions?

2. Literature review

clinical trials:

2.1 Oxygen

88

Inflammatory process after TBI, which causes brain edema and intracranial pressure (ICP) rise, performed the hypothesis of using corticosteroids for TBI, the primary researches and studies showed the beneficial effect of this intervention, while CRASH trial in 2005 and an updated Cochrane review after that, challenged the efficacy of corticosteroids use for TBI [4]; further from this study's proposal, steroids using for spinal cord injury (SCI) seems to have beneficial effects; also there is a Cochrane review for its neuroprotection beneficence in SCI assaults [13].

#### 2.3 Progesterone

It has a wide variety of neuroprotection mechanisms of action, as an antioxidant agent, by reducing brain edema and inflammatory-related factors, controlling of vasogenic edema through blood brain barrier (BBB) reconstitution and aquaporin-4 water transporter modulation, axonal regenerating stimulant, inhibition of inflammatory cytokines production, synaptogenesis and dendritic arborization, altering glutamate receptor activity to reduce excitotoxicity of injury and also taking all these effects by its receptor's key rolling [14–16]. Also inhibition of ion flux cell pores like L-type calcium channel, potassium, and sodium voltage-gates, as well GABA-A receptors, all result in vasoconstriction and reducing edema that seem likely to dihydropyridine's mechanism of action, without its side effects like dizziness, peripheral edema, hypotension, reflex tachycardia and headaches [17, 18].

#### 2.4 Monoaminergic agents

Amphetamine and other promotors of neuroaminergic neurotransmission have been suggested to improve the functional recovery of the brain after TBI. There is also a Cochrane review for these agents [19].

#### 2.5 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 voltagegated calcium channels, and EPO with EPO-receptors increasing of local production after TBI, seems to be EPO's mechanisms of action [20–22].

#### 2.6 Magnesium sulfate and other magnesium salts

Reduction in serum magnesium levels after TBI, and beneficial effects of magnesium therapy in animal models, conceptualized its use for human cases, its failure in recent studies, came to the conclusion of blood brain barrier (BBB) effect on this agent's transmission [23].

#### 2.7 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 and free oxygen radical concentrations [24].

3. Methods

3.1 Types of studies

3.2 Types of participants

trials included in this study.

3.3 Types of interventions

3.4 Types of outcome measures

• Mortality and vegetative state

• Good recovery and mild disability

3.5 Search methods for identification of studies

3.4.1 Primary outcomes

3.4.2 Secondary outcomes

neurocognitive state.

analyses.

91

Criteria for considering studies for this review.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

with any frequency, any chronicity and any mode of use.

The back-bone of present study's meta-analyses made by including RCTs, which their reporting quality, compared to CONsolidated Standards Of Reporting Trials (CONSORT-statement) 2010 (http://www.consort-statement.org/); other related to subject articles, with good and qualitative methods in reporting, included according to the study's statistical consultant's point of view. Guidelines or protocols, letter to editors and systematic reviews are excluded from the data analyses.

Humans of any age, and with any severity (mild, moderate, severe) of focal or diffuse TBI, have been included; neither animal studies nor pre-clinical (in-vivo)

The related studies about the mentioned agents in "Literature Review" section

Outcomes were analyzed in two main groups for acute TBI management:

As measured by Glasgow Outcome Scale (GOS) or Extended Type (GOS-E) after 3–6 months of patient follow-up; severe disabilities weren't included in the

• Any adverse effects or events of interventions during the trial.

search results, also limiting results to human studies where possible.

For chronic TBI management, outcomes were mostly analyzed for

The search strategy was not restricted by language, date, participants race, gender or publication status; but date limitation implemented to the referencing databases (i.e., SCOPUS and Thomson Reuters Web of Science) for after 2000

#### 2.8 Citicoline (CDP-choline) and other cholinergics

Adenosine tri-phosphate (ATP) is responsible for cell membrane sodiumpotassium (Na-K) ATPase pump's function; TBI related cell membrane un-integrity and accumulation of extracellular water, leads to the known brain edema, also formation of lipid peroxidase. Cholinergic agents' effects in cell-oxygenation cycles and formation of ATP indirectly may cause cell wall integrity formation as well as prevent further secondary injuries [25].

#### 2.9 NeuroAid

A Chinese medicine, also known as MCL601 and MCL901 (a.k.a. Simplified to NeuroAid or NeuroAid-II, respectively), which showed Neuroprotective effects in stroke trials [26, 27].

#### 2.10 Cyclosporine A (CsA)

Preservation of mitochondrial function after TBI is the recommended mechanism of action for this agent [28, 29].

#### 2.11 Rivastigmine

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 [30, 31].

#### 2.12 Piracetam

This intervention seems to improve neurocognitive state of patients without any remarkable effects on the mortalities.

#### 2.13 Anti-epileptic drugs

Anti-epileptic drugs may have some Neuroprotective effects as well, but they are not included in this study, however these drugs have their own Cochrane review [3].

#### 2.14 Why it is important to do this review?

The review, been performed on Neuroprotective agents for TBI, fulfill the systematic review & analysis on each one of the mentioned agents in "Literature Review" section of this study; "Drug data is complex and requires thoughtful consideration regarding which medication and therapies are best suited for certain situation and patients." Leucht et al. declared [12]. Burns et al. work didn't clearly demonstrate the use of new stem cell studies on TBI, but it has hopes for SCI [9]. Studies showed people may not feel comfortable with stem cell therapies because of "don't want to get the risk of cancer" or "don't want to have another surgery" who also are about 58–63% of patients [9] that may lead our current hopes to neuroprotective use, despite stem cells.

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

#### 3. Methods

of action is not fully understood, but animal studies, suggest improved neuronal oxygen utilization, reduction of cerebral lactic acid concentration and free oxygen

Adenosine tri-phosphate (ATP) is responsible for cell membrane sodiumpotassium (Na-K) ATPase pump's function; TBI related cell membrane un-integrity and accumulation of extracellular water, leads to the known brain edema, also formation of lipid peroxidase. Cholinergic agents' effects in cell-oxygenation cycles and formation of ATP indirectly may cause cell wall integrity formation as well as

A Chinese medicine, also known as MCL601 and MCL901 (a.k.a. Simplified to NeuroAid or NeuroAid-II, respectively), which showed Neuroprotective effects in

Preservation of mitochondrial function after TBI is the recommended mecha-

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 [30, 31].

This intervention seems to improve neurocognitive state of patients without any

Anti-epileptic drugs may have some Neuroprotective effects as well, but they are not included in this study, however these drugs have their own Cochrane

The review, been performed on Neuroprotective agents for TBI, fulfill the systematic review & analysis on each one of the mentioned agents in "Literature Review" section of this study; "Drug data is complex and requires thoughtful consideration regarding which medication and therapies are best suited for certain situation and patients." Leucht et al. declared [12]. Burns et al. work didn't clearly demonstrate the use of new stem cell studies on TBI, but it has hopes for SCI [9]. Studies showed people may not feel comfortable with stem cell therapies because of "don't want to get the risk of cancer" or "don't want to have another surgery" who also are about 58–63% of patients [9] that may lead our current hopes to neuro-

radical concentrations [24].

2.9 NeuroAid

stroke trials [26, 27].

2.11 Rivastigmine

2.12 Piracetam

review [3].

90

2.10 Cyclosporine A (CsA)

nism of action for this agent [28, 29].

remarkable effects on the mortalities.

2.14 Why it is important to do this review?

protective use, despite stem cells.

2.13 Anti-epileptic drugs

prevent further secondary injuries [25].

2.8 Citicoline (CDP-choline) and other cholinergics

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Criteria for considering studies for this review.

#### 3.1 Types of studies

The back-bone of present study's meta-analyses made by including RCTs, which their reporting quality, compared to CONsolidated Standards Of Reporting Trials (CONSORT-statement) 2010 (http://www.consort-statement.org/); other related to subject articles, with good and qualitative methods in reporting, included according to the study's statistical consultant's point of view. Guidelines or protocols, letter to editors and systematic reviews are excluded from the data analyses.

#### 3.2 Types of participants

Humans of any age, and with any severity (mild, moderate, severe) of focal or diffuse TBI, have been included; neither animal studies nor pre-clinical (in-vivo) trials included in this study.

#### 3.3 Types of interventions

The related studies about the mentioned agents in "Literature Review" section with any frequency, any chronicity and any mode of use.

#### 3.4 Types of outcome measures

Outcomes were analyzed in two main groups for acute TBI management:

#### 3.4.1 Primary outcomes


As measured by Glasgow Outcome Scale (GOS) or Extended Type (GOS-E) after 3–6 months of patient follow-up; severe disabilities weren't included in the analyses.

#### 3.4.2 Secondary outcomes

• Any adverse effects or events of interventions during the trial.

For chronic TBI management, outcomes were mostly analyzed for neurocognitive state.

#### 3.5 Search methods for identification of studies

The search strategy was not restricted by language, date, participants race, gender or publication status; but date limitation implemented to the referencing databases (i.e., SCOPUS and Thomson Reuters Web of Science) for after 2000 search results, also limiting results to human studies where possible.

#### 3.5.1 Electronic searches

The web-based searched data-bases are:


#### 3.5.2 Searching other resources

Other related articles, came out through Internet search for full-text articles, and full-text requests through www.researchgate.net, and skimming in bibliographies of articles. Also contacting with experts to enrich the including data.

#### 3.6 Data collection and analysis

Zotero v.4.0.28 (available from www.zotero.org) was used as Reference Manager of this review, while Cochrane's Review Manager (RevMan v5.3) taken the role of meta-analyses and conducting the whole study as well.

#### 3.7 Selection of studies

Screening of related articles via their titles and abstracts done by two review authors (AM and MM); further assessment of including articles obtained by applying CONSORT-statement 2010 on full-texts of the articles by two review authors (HSB and MM), also disagreements of the screening-phase articles and the decision to include non-RCT studies referred to statistical consultant of study (HSB). The Preferred Reporting Items for Systematic Reviews & Meta-Analyses (PRISMA) statement, lead authors to diagram the process of study-selection (Figure 1).

#### 3.8 Data extraction and management

Two review authors (AM and MM) extracted data from the included studies using CONSORT 2010 characteristics; any disagreements, referred to the third author (HSB).

#### 3.9 Assessment of risk of bias in included studies

Two review authors (HSB and MM) assessed RCTs using the "risk of bias" assessment tool of "Cochrane Handbook for Systematic Reviews of Interventions v. 5.1.0" [32].

Figure 1.

93

PRISMA template (study flowchart).

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

3.5.1 Electronic searches

The web-based searched data-bases are:

• SCOPUS (September 6, 2015)

• SID.ir (September 6, 2015)

3.5.2 Searching other resources

3.6 Data collection and analysis

3.8 Data extraction and management

3.9 Assessment of risk of bias in included studies

3.7 Selection of studies

author (HSB).

5.1.0" [32].

92

MEDEX) (September 6, 2015)

• ClinicalTrials.gov (September 6, 2015).

• Cochrane CENTRAL (September 6, 2015)

• MedLine through PUBMED (September 6, 2015)

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

• Thomson Reuters Web of Science (September 6, 2015)

of articles. Also contacting with experts to enrich the including data.

of meta-analyses and conducting the whole study as well.

• Barekat Knowledge Deployment Foundation (formerly known as IRAN-

Other related articles, came out through Internet search for full-text articles, and full-text requests through www.researchgate.net, and skimming in bibliographies

Zotero v.4.0.28 (available from www.zotero.org) was used as Reference Manager of this review, while Cochrane's Review Manager (RevMan v5.3) taken the role

Screening of related articles via their titles and abstracts done by two review authors (AM and MM); further assessment of including articles obtained by applying CONSORT-statement 2010 on full-texts of the articles by two review authors (HSB and MM), also disagreements of the screening-phase articles and the decision to include non-RCT studies referred to statistical consultant of study (HSB). The Preferred Reporting Items for Systematic Reviews & Meta-Analyses (PRISMA) statement, lead authors to diagram the process of study-selection (Figure 1).

Two review authors (AM and MM) extracted data from the included studies using CONSORT 2010 characteristics; any disagreements, referred to the third

Two review authors (HSB and MM) assessed RCTs using the "risk of bias" assessment tool of "Cochrane Handbook for Systematic Reviews of Interventions v.

#### 3.10 Measures of treatment effect

Glasgow Outcome Scale (GOS) or its Extended type used as the assessment tool for severe TBIs outcome, considered to take place in the analyses; otherwise, patients preference of interventions [i.e., patient reported outcome (PRO)] in studies' results, were taken as outcome measurements of included studies in mild and moderate TBIs. More information of each intervention outcome analysis is represented under "Results" section of the study.

3.16 Sensitivity analysis

4.1 Description of studies

4.2 Results of the search

Neuroprotective Total no.

RCTs

4.2.1 Oxygen

Table 1.

95

Neuroprotective RCTs for TBI at a glance.

4. Results

of results with p < 0.05 and CI = 95%.

DOI: http://dx.doi.org/10.5772/intechopen.85720

Use of Neuroprotective agents for Traumatic Brain Injury

under each topic of "Results of the search" section.

All of the search studies results reporting, were based on significant meaningful

Qualitative report of study results, was completed with RCTs meta-analyses. Which from 38 RCTs included in this study, 18 RCTs been meta-analyzed. Also previous review papers in this field covered RCTs which are not included in this review again, i.e., 27 of these RCTs were discussed by Alderson et al. Cochrane review of corticosteroids [4]; Monoaminergic agents Cochrane review by Forsyth et al. covered 20 of them [19]. However previously discussed papers in HBO2 and NBH Cochrane reviews, didn't take part in this review again [1, 2], which limited oxygen topic's studies to seven papers and no new articles found for those other two topics; Figure 1 and Table 1 summarize the finding information. The 18 included meta-analyzed studies, have a population of 4637 patients, of which 3650 patients were for four new phase-III RCTs altogether. Furthermore information is available

This intervention is the most eligible one of all other experimental trials of TBI

No. acute TBI RCTs No. chronic TBI RCTs

Studies populations

No. phase-3 RCTs

neuroprotectives. Two Cochrane reviews were conducted under the title

No. RCTs included

Oxygen 24 7 4 1 3 205 0 Corticosteroid 27 All study results from Alderson 2006 Cochrane review [4] Progesterone 7 7 4 4 – 2320 2 Monoaminergics 20 All study results from Forsyth 2011 Cochrane review [19] Erythropoietin 4 4 2 2 – 645 1 Magnesium 4 1 Vink et al. [23] results combined with this pilot study 0 Cerebrolysin 1 1 1 1 – 32 0 Citicoline 4 4 4 3 1 1196 1 NeuroAid 0 0 0 0 0 0 0 Cyclosporine A 5 5 2 2 – 89 0 Rivastigmine 3 3 1 – 1 157 0 Piracetam 3 0 0 unknown unknown unknown unknown Miscellaneous unknown 6 0 – – –– Total 102 38 18 13 5 4637 4

No. RCTs in this study

#### 3.11 Unite of analysis issues

All meta-analyses of fixed effects model for dichotomous quantitative results, done by their risk ratio and confidence interval (CI) = 95%; continuous data results analyzed by their mean difference and CI = 95%; random effects model applied if I <sup>2</sup> > 50% [33].

#### 3.12 Dealing with missing data

According to search strategy, authors have to conclude as possible as the available studies for the review, reduce selection and information biases as well; but some data would never been available even after contacting the original investigators or correspondence authors; the authors strategy for dealing with these kind of missing data was to ignore the missing data and to analyze only the available data, but if it's assumed that the missing data, had a huge effect on the analysis, in the HSB's point of view, using statistical models to allow missing data in analysis, making assumptions about their relationships with the available data were taken, fortunately there was no such conflict during this study's process.

#### 3.13 Assessment of heterogeneity

Any heterogeneity of studies referred to HSB, for statistical consultant's point of view to reassess their use in the study, if they didn't have the availability to take part in study, they had been excluded.

#### 3.14 Assessment of reporting biases

Probable reporting biases of studies, reported by using "Cochrane Handbook for Systematic Reviews of Interventions v. 5.1.0" method [32].

#### 3.15 Subgroup analysis and investigation of heterogeneity

Data analyses based on:


If some interesting results of study(ies) are brought, they'd be analyzed separately.

#### 3.16 Sensitivity analysis

All of the search studies results reporting, were based on significant meaningful of results with p < 0.05 and CI = 95%.

#### 4. Results

3.10 Measures of treatment effect

3.11 Unite of analysis issues

3.12 Dealing with missing data

3.13 Assessment of heterogeneity

part in study, they had been excluded.

3.14 Assessment of reporting biases

Data analyses based on:

separately.

94

• Mortality and vegetative-state analysis

• Probable side-effects of interventions.

I

<sup>2</sup> > 50% [33].

represented under "Results" section of the study.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Glasgow Outcome Scale (GOS) or its Extended type used as the assessment tool

All meta-analyses of fixed effects model for dichotomous quantitative results, done by their risk ratio and confidence interval (CI) = 95%; continuous data results analyzed by their mean difference and CI = 95%; random effects model applied if

According to search strategy, authors have to conclude as possible as the available studies for the review, reduce selection and information biases as well; but some data would never been available even after contacting the original investigators or correspondence authors; the authors strategy for dealing with these kind of missing data was to ignore the missing data and to analyze only the available data, but if it's assumed that the missing data, had a huge effect on the analysis, in the HSB's point of view, using statistical models to allow missing data in analysis, making assumptions about their relationships with the available data were taken,

Any heterogeneity of studies referred to HSB, for statistical consultant's point of view to reassess their use in the study, if they didn't have the availability to take

Probable reporting biases of studies, reported by using "Cochrane Handbook for

• Favorable outcome of intervention (mostly based on GOS or GOS-E);

If some interesting results of study(ies) are brought, they'd be analyzed

fortunately there was no such conflict during this study's process.

Systematic Reviews of Interventions v. 5.1.0" method [32].

3.15 Subgroup analysis and investigation of heterogeneity

for severe TBIs outcome, considered to take place in the analyses; otherwise, patients preference of interventions [i.e., patient reported outcome (PRO)] in studies' results, were taken as outcome measurements of included studies in mild and moderate TBIs. More information of each intervention outcome analysis is

#### 4.1 Description of studies

Qualitative report of study results, was completed with RCTs meta-analyses. Which from 38 RCTs included in this study, 18 RCTs been meta-analyzed. Also previous review papers in this field covered RCTs which are not included in this review again, i.e., 27 of these RCTs were discussed by Alderson et al. Cochrane review of corticosteroids [4]; Monoaminergic agents Cochrane review by Forsyth et al. covered 20 of them [19]. However previously discussed papers in HBO2 and NBH Cochrane reviews, didn't take part in this review again [1, 2], which limited oxygen topic's studies to seven papers and no new articles found for those other two topics; Figure 1 and Table 1 summarize the finding information. The 18 included meta-analyzed studies, have a population of 4637 patients, of which 3650 patients were for four new phase-III RCTs altogether. Furthermore information is available under each topic of "Results of the search" section.

#### 4.2 Results of the search

#### 4.2.1 Oxygen


This intervention is the most eligible one of all other experimental trials of TBI neuroprotectives. Two Cochrane reviews were conducted under the title

#### Table 1.

Neuroprotective RCTs for TBI at a glance.

"Hyperventilation therapy for acute traumatic brain injury (Review)," which established in 1997 and continued till the last updated paper of 2009 [2], and "Hyperbaric Oxygen therapy for the adjunctive treatment of traumatic brain injury (Review)," which started from 2004 and was last revised in 2012 [1]. These reviews demonstrated reduction in mortality rates while using oxygen in TBI, but there was no adequate evidences to support better clinical outcomes. This review's search results got eight more new additional studies. One observational study to investigate guideline adherence about pre-hospital advanced airway attempt for oxygenation in 54 severe TBI patients, that resulted in good adherence of performers to the guidelines [34], which also reported in other studies aimed to assess practitioners' adherence to guidelines, even better if they were supported by strong evidences [35, 36], but not satisfied results which recommended revision for guidelines; and seven clinical trials, mostly case-sham control design method, that five of them were pilot phase-II studies supported by Department of Defense/Veteran Affair (DoD/VA) for a huge phase-III RCT on HBO2 use [37–41], the other two trials were Rockswold et al. and Boussi-Gross et al. for combined HBO2/NBH treatment and HBO2 in a case control and cross-over method trials respectively [42, 43]. Except than Rockswold et al. study on acute TBI patients, other studies' participants were of chronic impaired TBI patients.

update of this review at January 7, 2009, found no novel study to investigate. There

The 2012 Cochrane review of "Progesterone for acute traumatic brain injury (Review)," based on three phase-II trials, declared that it would be updated as two more multi-centric clinical trials' results came out [5]; at the time of current review's searching for Neuroprotective agents, those mentioned trials and one more study been achieved [10, 11, 44]. Authors complete reading each one of the studies by comparing them to CONSORT 2010 checklist, finally included four studies

Included studies consisted of 2320 cases (1192 in progesterone group and 1128

The analyses of favorable intervention outcome and mortality in these studies

Intervention's side-effects also analyzed as the most happened for patients in each group as a whole but not on each of the side-effects solely. Also two studies didn't take part in this analysis. Skolnick et al.'s outcome results for adverse effects were different from case-control group's total number. It seems that five cases from control group have been analyzed in case group. An E-mail has been sent to the corresponding author for this confusing part, but till date, there is no reply [11].

The analyses showed no significant differences between progesterone and placebo groups in favorable treatment [(p = 0.75; RR 1.02, 95% CI 0.88–1.19; participants = 2320; studies = 4; I2 = 53%) Figure 2], neither in mortalities [(p = 0.21; RR 0.77, 95% CI 0.50–1.17; participants = 2320; studies = 4; I2 = 82%) Figure 3], nor in adverse effects analysis [(p = 085; RR 1.03, 95% CI 0.72–1.48;

in placebo-control group); SYNAPSE study and ProTECT-III respectively by Skolnick et al. and Wright et al. (in 2014) are the new phase 3, multi-centric, RCTs with the weight of 93.5% of whole cases [10, 11]. ProTECT-III halted in its secondary interim analysis, but SYNAPSE completed the predicted proposal and

based on GOS report analysis in current method: favorably outcome (good recovery and moderate disability), mortality (vegetative state and death), the severe disability didn't included in the analysis. All of these studies analyzed their outcomes in a 6 month period but Wright et al. (in 2007), had a follow-up of

Xiao et al. reported no adverse effects for the intervention [46].

participants = 982; studies = 2; I2 = 87%) Figure 4].

was no more study in current review's search results too.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

[10, 11, 45, 46] and excluded three of them [44, 47, 48].

4.2.3 Progesterone

consists 51.5% of cases.

30 days [10, 11, 45, 46].

Figure 2.

97

Progesterone favorable outcome.

Overall patients analyses without loss to follow-ups are 205 patients as 48 in Wolf et al., 42 in Rockswald et al., 56 in Boussi-Gross et al. and 59 in Cifu et al.; This review, include all of these trials in narrative review, but because of their heterogeneity in reporting outcomes, no meta-analysis conducted for the results [37, 40, 42, 43].

The only study reported mortality was Rockswold et al. for 16% in HBO2/NBH combined group and 42% in control group, that might be due to its acute phase design for TBI management [43] in comparison to other three trials were about mild chronic TBI management. Boussi-Gross et al. study reports significant improvements in cognitive states (memory, attention, executive function, information processing speed) of patients with mild TBI in chronic phase, while DoD/VA related studies didn't state any significant changes of cognitive functions between HBO2 and sham-control groups according to their Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) and Post-Traumatic Stress Disorder Check List-Military (PCL-M) assessment tools [37, 40, 42]; Rockswald et al. acute phase study's GOS outcome for HBO2/NBH combined group, demonstrated significant improvements (p = 0.024), and better outcomes for cerebral metabolism, partial oxygen pressure in brain and ICP [43].

Also only side-effect report was in Wolf et al. study that ear barotrauma and headache were the most common conditions [41], while Cifu et al. study on eye tracking abnormalities didn't demonstrate any significantly meaningful improvements for HBO2 treatment participants, Wolf et al. results on Snellen chart assessment of visual acuity showed improvements in both HBO2 and Sham-control groups (22 of 47 eyes and 25 of 46 eyes respectively), also reduction of visual acuity was less in the sham-control group (6 of 47 eyes and 3 of 46 eyes) [39, 41].

#### 4.2.2 Corticosteroids

Cochrane updated review for corticosteroids in 2006, recommended no more trials of corticosteroids for TBI according to phase-III CRASH trial's results, another update of this review at January 7, 2009, found no novel study to investigate. There was no more study in current review's search results too.

#### 4.2.3 Progesterone

"Hyperventilation therapy for acute traumatic brain injury (Review)," which established in 1997 and continued till the last updated paper of 2009 [2], and "Hyperbaric Oxygen therapy for the adjunctive treatment of traumatic brain injury (Review)," which started from 2004 and was last revised in 2012 [1]. These reviews demonstrated reduction in mortality rates while using oxygen in TBI, but there was no adequate evidences to support better clinical outcomes. This review's search results got eight more new additional studies. One observational study to investigate guideline adherence about pre-hospital advanced airway attempt for oxygenation in 54 severe TBI patients, that resulted in good adherence of performers to the guidelines [34], which also reported in other studies aimed to assess practitioners' adherence to guidelines, even better if they were supported by strong evidences [35, 36], but not satisfied results which recommended revision for guidelines; and seven clinical trials, mostly case-sham control design method, that five of them were pilot phase-II studies supported by Department of Defense/Veteran Affair (DoD/VA) for a huge phase-III RCT on HBO2 use [37–41], the other two trials were Rockswold et al. and Boussi-Gross et al. for combined HBO2/NBH treatment and HBO2 in a case control and cross-over method trials respectively [42, 43]. Except than Rockswold et al. study on acute TBI patients, other studies' participants were

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Overall patients analyses without loss to follow-ups are 205 patients as 48 in Wolf et al., 42 in Rockswald et al., 56 in Boussi-Gross et al. and 59 in Cifu et al.; This review, include all of these trials in narrative review, but because of their heterogeneity in reporting outcomes, no meta-analysis conducted for the results [37, 40,

The only study reported mortality was Rockswold et al. for 16% in HBO2/NBH combined group and 42% in control group, that might be due to its acute phase design for TBI management [43] in comparison to other three trials were about mild chronic TBI management. Boussi-Gross et al. study reports significant improvements in cognitive states (memory, attention, executive function, information processing speed) of patients with mild TBI in chronic phase, while DoD/VA related studies didn't state any significant changes of cognitive functions between HBO2 and sham-control groups according to their Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) and Post-Traumatic Stress Disorder Check List-Military (PCL-M) assessment tools [37, 40, 42]; Rockswald et al. acute phase study's GOS outcome for HBO2/NBH combined group, demonstrated significant improvements (p = 0.024), and better outcomes for cerebral metabolism, partial oxygen

Also only side-effect report was in Wolf et al. study that ear barotrauma and headache were the most common conditions [41], while Cifu et al. study on eye tracking abnormalities didn't demonstrate any significantly meaningful improvements for HBO2 treatment participants, Wolf et al. results on Snellen chart assessment of visual acuity showed improvements in both HBO2 and Sham-control groups (22 of 47 eyes and 25 of 46 eyes respectively), also reduction of visual acuity was less in the sham-control group (6 of 47 eyes and 3 of 46

Cochrane updated review for corticosteroids in 2006, recommended no more trials of corticosteroids for TBI according to phase-III CRASH trial's results, another

of chronic impaired TBI patients.

pressure in brain and ICP [43].

eyes) [39, 41].

96

4.2.2 Corticosteroids

42, 43].

The 2012 Cochrane review of "Progesterone for acute traumatic brain injury (Review)," based on three phase-II trials, declared that it would be updated as two more multi-centric clinical trials' results came out [5]; at the time of current review's searching for Neuroprotective agents, those mentioned trials and one more study been achieved [10, 11, 44]. Authors complete reading each one of the studies by comparing them to CONSORT 2010 checklist, finally included four studies [10, 11, 45, 46] and excluded three of them [44, 47, 48].

Included studies consisted of 2320 cases (1192 in progesterone group and 1128 in placebo-control group); SYNAPSE study and ProTECT-III respectively by Skolnick et al. and Wright et al. (in 2014) are the new phase 3, multi-centric, RCTs with the weight of 93.5% of whole cases [10, 11]. ProTECT-III halted in its secondary interim analysis, but SYNAPSE completed the predicted proposal and consists 51.5% of cases.

The analyses of favorable intervention outcome and mortality in these studies based on GOS report analysis in current method: favorably outcome (good recovery and moderate disability), mortality (vegetative state and death), the severe disability didn't included in the analysis. All of these studies analyzed their outcomes in a 6 month period but Wright et al. (in 2007), had a follow-up of 30 days [10, 11, 45, 46].

Intervention's side-effects also analyzed as the most happened for patients in each group as a whole but not on each of the side-effects solely. Also two studies didn't take part in this analysis. Skolnick et al.'s outcome results for adverse effects were different from case-control group's total number. It seems that five cases from control group have been analyzed in case group. An E-mail has been sent to the corresponding author for this confusing part, but till date, there is no reply [11]. Xiao et al. reported no adverse effects for the intervention [46].

The analyses showed no significant differences between progesterone and placebo groups in favorable treatment [(p = 0.75; RR 1.02, 95% CI 0.88–1.19; participants = 2320; studies = 4; I2 = 53%) Figure 2], neither in mortalities [(p = 0.21; RR 0.77, 95% CI 0.50–1.17; participants = 2320; studies = 4; I2 = 82%) Figure 3], nor in adverse effects analysis [(p = 085; RR 1.03, 95% CI 0.72–1.48; participants = 982; studies = 2; I2 = 87%) Figure 4].

Figure 2. Progesterone favorable outcome.

Figure 4. Progesterone adverse-effects.

#### 4.2.4 Monoaminergic agents

The Cochrane review of "Monoaminergic agonists for acute traumatic brain injury," first established in 2006, and updated later on, till its last update was in 2011 didn't included any studies [19]. Search results didn't collect any new studies.

#### 4.2.5 Erythropoietin (EPO)

The primary search results for this topic, consists of a review on in-vitro and invivo studies till 2009 [49]. One retrospective case-control study [50] and four prospective RCTs [20, 22, 51, 52]; two of these studies were reports of a same phase-III multi-centric placebo-control trial known as EPO-TBI, and Nichol et al.'s reporting was more complete than the other one, which persuades authors to exclude Presneil et al. from quantitative analysis [21, 22]. Abrishamkar et al.'s paper has been excluded from meta-analysis too, due to its restricted study design on male patients [20].

The whole studies population analysis related to Aloizos et al. and Nichol et al. were 645 patients [21, 51]. Both studies followed patient up to 6 months analyzing total better outcomes of patients showed no significant difference between study groups [(p = 0.30; MD 1.22, 95% CI 1.09–3.53; participants = 638; studies = 2; I <sup>2</sup> = 99%) Figure 5], also EPO-TBI trial's GOS reporting outcome showed no significant difference too [(p = 0.90; RR 1.01, 95% CI 0.87–1.17; participants = 596; studies = 1; I2 = 0%) Figure 6]. Mortality and vegetative-state analysis, was significantly skewed toward intervention group [(p = 0.04; RR 0.65, 95% CI 0.43–0.98; participants = 644; studies = 2; I2 = 0%) Figure 7]; while side-effect analysis showed nearly significant less vascular side effects in intervention group [(p = 0.06; RR 0.86, 95% CI 0.73–1.00; participants = 603; studies = 1; I<sup>2</sup> = 100%) Figure 8] and no significant difference in non-vascular side-effects between two groups of EPO-TBI

trial [(p = 0.73; RR 0.93, 95% CI 0.62–1.39; participants = 603; studies = 1; I2 = 0%)

An updated review on magnesium, published in 2009 [23]; and no new studies been established in current review's search results after that timeline, the only study which was not mentioned in Vink et al. paper, was a pilot study on pediatric population with severe TBI, to maintain magnesium's feasibility and bio-availably for this population [52]. The common result of these studies, could be summarized

Figure 9], there was no side effect report in Aloizos et al. [51].

4.2.6 Magnesium sulfate and other magnesium salts

Figure 5.

Figure 6.

Figure 7.

Figure 8.

99

Erythropoietin mortality.

Erythropoietin vascular side-effects.

Erythropoietin total outcome assessment.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

Erythropoietin favorable outcome.

#### Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

#### Figure 8.

4.2.4 Monoaminergic agents

Progesterone adverse-effects.

Figure 3.

Figure 4.

Progesterone mortality.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

4.2.5 Erythropoietin (EPO)

patients [20].

I

98

The Cochrane review of "Monoaminergic agonists for acute traumatic brain injury," first established in 2006, and updated later on, till its last update was in 2011 didn't included any studies [19]. Search results didn't collect any new studies.

The primary search results for this topic, consists of a review on in-vitro and in-

The whole studies population analysis related to Aloizos et al. and Nichol et al. were 645 patients [21, 51]. Both studies followed patient up to 6 months analyzing total better outcomes of patients showed no significant difference between study groups [(p = 0.30; MD 1.22, 95% CI 1.09–3.53; participants = 638; studies = 2;

<sup>2</sup> = 99%) Figure 5], also EPO-TBI trial's GOS reporting outcome showed no significant difference too [(p = 0.90; RR 1.01, 95% CI 0.87–1.17; participants = 596; studies = 1; I2 = 0%) Figure 6]. Mortality and vegetative-state analysis, was significantly skewed toward intervention group [(p = 0.04; RR 0.65, 95% CI 0.43–0.98; participants = 644; studies = 2; I2 = 0%) Figure 7]; while side-effect analysis showed nearly significant less vascular side effects in intervention group [(p = 0.06; RR 0.86, 95% CI 0.73–1.00; participants = 603; studies = 1; I<sup>2</sup> = 100%) Figure 8] and no significant difference in non-vascular side-effects between two groups of EPO-TBI

vivo studies till 2009 [49]. One retrospective case-control study [50] and four prospective RCTs [20, 22, 51, 52]; two of these studies were reports of a same phase-

III multi-centric placebo-control trial known as EPO-TBI, and Nichol et al.'s reporting was more complete than the other one, which persuades authors to exclude Presneil et al. from quantitative analysis [21, 22]. Abrishamkar et al.'s paper has been excluded from meta-analysis too, due to its restricted study design on male

Erythropoietin vascular side-effects.

trial [(p = 0.73; RR 0.93, 95% CI 0.62–1.39; participants = 603; studies = 1; I2 = 0%) Figure 9], there was no side effect report in Aloizos et al. [51].

#### 4.2.6 Magnesium sulfate and other magnesium salts

An updated review on magnesium, published in 2009 [23]; and no new studies been established in current review's search results after that timeline, the only study which was not mentioned in Vink et al. paper, was a pilot study on pediatric population with severe TBI, to maintain magnesium's feasibility and bio-availably for this population [52]. The common result of these studies, could be summarized

primary outcome assessment on day 90 of patients, was available for 996 cases,

In total, this meta-analysis included four studies with 1196 patients, which COBRIT study weighs about 75% of the analysis. The starting citicoline dose in studies was 2 g/day in Zafonte et al. and Shokouhi et al.'s trials, 1 g/day in Leon-Carrion et al.'s study, and 4 g/day in Maldonado et al.'s (that reduced to 3 g/day after day 3–4 of intervention and 2 g/day in case phlebitis would recognized). Meta-analysis of outcomes showed no significant change in GOS outcome [(p = 0.76; RR 1.03, 95% CI 0.86–1.24; participants = 1128; studies = 2; I2 = 71%) Figure 11], but significant favorable of neurocognitive changes in placebo-control group despite studies heterogeneity [(p < 0.00001; SMD 1.00, 95% CI 0.75–1.25; participants = 971; studies = 3) Figure 12]. However the comparison of COBRIT study's days-90 and 180 GOS outcomes, demonstrated improvements in day 180 outcomes [58]. Mortality and vegetative-state outcomes were analyzed together in studies, which only two studies (Maldonado et al. and Zafonte et al.) reported these outcomes with no significant difference [(p = 0.96; RR 0.98, 95% CI 0.51–1.86; participants = 1429; studies = 2; I<sup>2</sup> = 67%) Figure 13]. The side-effects of intervention at all has no significant difference between trial groups either [(p = 0.53; RR 1.03, 95% CI 0.94–1.12; participants = 1429; studies = 2; I2 = 57%) Figure 14].

Search strategies results, brought five articles for this topic; and all were prospective clinical trials, Brophy et al., Empey et al., and Mazzeo et al. (in 2008) reported and analyzed Cyclosporine's concentration and safety dose for human use

while 180-day outcome enrolled 902 cases [58].

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

There was no trial for NeuroAid use in TBI.

4.2.9 NeuroAid

Figure 11.

Figure 12.

101

4.2.10 Cyclosporine A (CysA)

Citicoline favorable outcome (GOS results).

Citicoline favorable outcome (at all).

#### Figure 9.

Erythropoietin non-vascular side-effects.

as despite pre-clinical in-vivo studies of magnesium concentration in cerebrospinal fluid (CSF), that decline after acute TBI, and magnesium administration enhances its disposition in this field; no BBB feasibility seen in human studies for magnesium, and predicted mechanisms of actions for this intervention on human-beings are out of clinical evidence support [23, 52].

#### 4.2.7 Cerebrolysin

There was a cohort-study by Wong et al. and a phase-II RCT by Chen et al. for cerebrolysin use in the search results [24, 53], also an ongoing huge multi-centric study held from third quarter of 2015 as well [54]. Cohort study, followed 42 patients with moderate to severe TBI, in 1:1 ratio, and report the outcomes in GOS scale after 6 months, which resulted in 67% good outcomes with cerebrolysin: placebo ratio of 19:14 in both study groups. The RCT reported cognitive outcomes with Mini-Mental Status Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI) scales for mild TBI patients after 3 months that showed significant favorable outcome in intervention group [(p = 0.02; MD 13.40, 95% CI 24.87 to 1.93; participants = 32; studies = 1; I<sup>2</sup> = 0%) Figure 10].

#### 4.2.8 Citicoline (CDP-choline) and other cholinergics

Articles related to citicoline intervention published from 1991–2014 [55–58]. Zafonte et al.'s study was a huge multicentric study a.k.a. COBRIT (citicoline brain injury treatment) and halted in its forth interim analysis due to non-significant outcome differences between placebo and intervention groups, but patients followed up to 180 days after injury, that 180 day's results are included in this review's analysis. Maldonado et al. and Shokouhi et al. studies didn't have placebo group, they were case-control studies, both included patients with severe or moderate acute TBI (216 and 58 patients respectively) [56, 57]. Leon-Carrion et al. study was a limited RCT of 10 patients for assessing neurocognitive effects of citicoline [55]. COBRIT planned to enroll 1292 patients, which halted in its forth interim analysis with 1213 patients randomized in two placebo and citicoline groups, the

Figure 10. Cognitive changes for cerebrolysin.

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

primary outcome assessment on day 90 of patients, was available for 996 cases, while 180-day outcome enrolled 902 cases [58].

In total, this meta-analysis included four studies with 1196 patients, which COBRIT study weighs about 75% of the analysis. The starting citicoline dose in studies was 2 g/day in Zafonte et al. and Shokouhi et al.'s trials, 1 g/day in Leon-Carrion et al.'s study, and 4 g/day in Maldonado et al.'s (that reduced to 3 g/day after day 3–4 of intervention and 2 g/day in case phlebitis would recognized).

Meta-analysis of outcomes showed no significant change in GOS outcome [(p = 0.76; RR 1.03, 95% CI 0.86–1.24; participants = 1128; studies = 2; I2 = 71%) Figure 11], but significant favorable of neurocognitive changes in placebo-control group despite studies heterogeneity [(p < 0.00001; SMD 1.00, 95% CI 0.75–1.25; participants = 971; studies = 3) Figure 12]. However the comparison of COBRIT study's days-90 and 180 GOS outcomes, demonstrated improvements in day 180 outcomes [58]. Mortality and vegetative-state outcomes were analyzed together in studies, which only two studies (Maldonado et al. and Zafonte et al.) reported these outcomes with no significant difference [(p = 0.96; RR 0.98, 95% CI 0.51–1.86; participants = 1429; studies = 2; I<sup>2</sup> = 67%) Figure 13]. The side-effects of intervention at all has no significant difference between trial groups either [(p = 0.53; RR 1.03, 95% CI 0.94–1.12; participants = 1429; studies = 2; I2 = 57%) Figure 14].

#### 4.2.9 NeuroAid

as despite pre-clinical in-vivo studies of magnesium concentration in cerebrospinal fluid (CSF), that decline after acute TBI, and magnesium administration enhances its disposition in this field; no BBB feasibility seen in human studies for magnesium, and predicted mechanisms of actions for this intervention on human-beings are out

There was a cohort-study by Wong et al. and a phase-II RCT by Chen et al. for cerebrolysin use in the search results [24, 53], also an ongoing huge multi-centric study held from third quarter of 2015 as well [54]. Cohort study, followed 42 patients with moderate to severe TBI, in 1:1 ratio, and report the outcomes in GOS scale after 6 months, which resulted in 67% good outcomes with cerebrolysin: placebo ratio of 19:14 in both study groups. The RCT reported cognitive outcomes with Mini-Mental Status Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI) scales for mild TBI patients after 3 months that showed significant favorable outcome in intervention group [(p = 0.02; MD 13.40, 95% CI

Articles related to citicoline intervention published from 1991–2014 [55–58]. Zafonte et al.'s study was a huge multicentric study a.k.a. COBRIT (citicoline brain injury treatment) and halted in its forth interim analysis due to non-significant outcome differences between placebo and intervention groups, but patients followed up to 180 days after injury, that 180 day's results are included in this review's analysis. Maldonado et al. and Shokouhi et al. studies didn't have placebo group, they were case-control studies, both included patients with severe or moderate acute TBI (216 and 58 patients respectively) [56, 57]. Leon-Carrion et al. study was a limited RCT of 10 patients for assessing neurocognitive effects of citicoline [55]. COBRIT planned to enroll 1292 patients, which halted in its forth interim analysis with 1213 patients randomized in two placebo and citicoline groups, the

24.87 to 1.93; participants = 32; studies = 1; I<sup>2</sup> = 0%) Figure 10].

4.2.8 Citicoline (CDP-choline) and other cholinergics

of clinical evidence support [23, 52].

Erythropoietin non-vascular side-effects.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

4.2.7 Cerebrolysin

Figure 10.

100

Cognitive changes for cerebrolysin.

Figure 9.

There was no trial for NeuroAid use in TBI.

#### 4.2.10 Cyclosporine A (CysA)

Search strategies results, brought five articles for this topic; and all were prospective clinical trials, Brophy et al., Empey et al., and Mazzeo et al. (in 2008) reported and analyzed Cyclosporine's concentration and safety dose for human use

#### Figure 12.

Citicoline favorable outcome (at all).

Citicoline side-effects.

were [28, 59, 60]. The other two papers' population been analyzed at all were 89 patients [29, 61]. Cyclosporine's favorable GOS outcome analysis showed no significant difference between two interventional and placebo groups [(p = 0.83; RR 1.28, 95% CI 0.14–11.86; participants = 75; studies = 2; I2 = 65%) Figure 15]; either there was no significant difference in mortalities [(p = 0.76; RR 1.17, 95% CI 0.443.12; participants = 89; studies = 2; I2 = 0%) Figure 16] but CysA had significant effect on ICP control, and less ICP rise in comparison to placebo [(p = 0.01; RR 0.70, 95% CI 0.53–0.92; participants = 89; studies = 2; I2 = 39%) Figure 17].

#### 4.2.11 Rivastigmine

Three articles were related to this intervention in search results [30, 31, 62]. Silver et al. [31] was the continuation follow-up of Silver et al. [30] trial, which all placebo and rivastigmine group of 2006 study, got through rivastigmine intervention for 26 extra weeks, the results of this article, didn't differ significantly from the last report, so the 2009 study was excluded from the analysis; Tenovuo's study was

an out-patient clinic practice on 111 patients with three ChE-inh (Rivastigmine, Galantamine, and Donepezil), randomly assigned to patients by author, was excluded because of no placebo group, no blinding allocation statement and no obvious concealment reporting. Which all of these three articles lead results reporting to Silver et al. [30] trial, with 157 randomized patients in 77 placebo and

Silver et al. [30] study, has no mortality report in cases, but patients whom completed 12 weeks of trial time-line, were 70 in rivastigmine and 64 in placebo groups, also three patients in total lost to follow up (one in rivastigmine and two in placebo group); There was no significant difference for favorable outcome results of this intervention in comparison to placebo [(p = 0.80; RR 0.96, 95% CI 0.69–1.33;

rivastigmine was efficient for more severe impaired patients in both 2006 and 2009 reports [30, 31]; it was analyzed as a sub-group analysis of 25% of patients and its raw results were not declared in the studies. Side-effect analysis show no meaningful difference too [(p = 0.74; RR 1.04, 95% CI 0.84–1.27; participants = 157; stud-

participants = 143; studies = 1; I<sup>2</sup> = 0%) Figure 18]. But authors stated that

80 rivastigmine groups.

Rivastigmine favorable outcome.

Figure 16.

Figure 17.

Figure 18.

Cyclosporine side effects (ICP rise).

Cyclosporine mortality.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

ies = 1; I<sup>2</sup> = 0%) Figure 19].

103

#### Figure 15.

Cyclosporine favorable outcome.

#### Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

#### Figure 18.

were [28, 59, 60]. The other two papers' population been analyzed at all were 89 patients [29, 61]. Cyclosporine's favorable GOS outcome analysis showed no significant difference between two interventional and placebo groups [(p = 0.83; RR 1.28, 95% CI 0.14–11.86; participants = 75; studies = 2; I2 = 65%) Figure 15]; either there was no significant difference in mortalities [(p = 0.76; RR 1.17, 95% CI 0.443.12; participants = 89; studies = 2; I2 = 0%) Figure 16] but CysA had significant effect on ICP control, and less ICP rise in comparison to placebo [(p = 0.01; RR 0.70, 95% CI

Three articles were related to this intervention in search results [30, 31, 62]. Silver et al. [31] was the continuation follow-up of Silver et al. [30] trial, which all placebo and rivastigmine group of 2006 study, got through rivastigmine intervention for 26 extra weeks, the results of this article, didn't differ significantly from the last report, so the 2009 study was excluded from the analysis; Tenovuo's study was

0.53–0.92; participants = 89; studies = 2; I2 = 39%) Figure 17].

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

4.2.11 Rivastigmine

Figure 15.

102

Cyclosporine favorable outcome.

Figure 13. Citicoline mortality.

Figure 14. Citicoline side-effects.

an out-patient clinic practice on 111 patients with three ChE-inh (Rivastigmine, Galantamine, and Donepezil), randomly assigned to patients by author, was excluded because of no placebo group, no blinding allocation statement and no obvious concealment reporting. Which all of these three articles lead results reporting to Silver et al. [30] trial, with 157 randomized patients in 77 placebo and 80 rivastigmine groups.

Silver et al. [30] study, has no mortality report in cases, but patients whom completed 12 weeks of trial time-line, were 70 in rivastigmine and 64 in placebo groups, also three patients in total lost to follow up (one in rivastigmine and two in placebo group); There was no significant difference for favorable outcome results of this intervention in comparison to placebo [(p = 0.80; RR 0.96, 95% CI 0.69–1.33; participants = 143; studies = 1; I<sup>2</sup> = 0%) Figure 18]. But authors stated that rivastigmine was efficient for more severe impaired patients in both 2006 and 2009 reports [30, 31]; it was analyzed as a sub-group analysis of 25% of patients and its raw results were not declared in the studies. Side-effect analysis show no meaningful difference too [(p = 0.74; RR 1.04, 95% CI 0.84–1.27; participants = 157; studies = 1; I<sup>2</sup> = 0%) Figure 19].

Rivastigmine favorable outcome.

scenarios, showed significant improvements. Patients responses to these emotional recognitions, was not favorable, as authors recommend further

studies to instruct participants on how to response too [66].

might be due to different purposes of studies.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

significant [69].

4.2.14 Risk of bias in included studies

bias in included studies.

4.2.15 Effects of interventions

studies = 4; I<sup>2</sup> = 52%) Figure 23].

Figure 20.

105

included studies.

• Hyperthermia after acute TBI, significantly results in unfavorable outcomes and mortality rates of especially severe head injured patients [67]; a Cochrane review of "Cooling for cerebral protection during brain surgery" didn't show significant result for this intervention [68], which

• And Finally a before-after clinical trial of 35 patients for "Effect of light music on physiological parameters of patients with traumatic brain injuries at intensive care units" using Dr. ArndStein's 70–80 metronome rhythmic melody, showed better significant physiologic outcomes in decreasing systolic and diastolic blood pressure, pulse rate, respiratory rate, arterial blood pressure and body temperature and increasing arterial oxygen saturation (<0.001); however pulse pressure decreasing was not

As a whole, "randomization part" of studies has a good assessment overall; however "allocation concealment" or "how blinding participants or personnel take place" didn't seem to be well reported. Finally RCTs reporting didn't accommodate well enough to CONSORT statement (i.e., this review study's tool for analyzing study reports). Figures 20 and 21 are at a glance quick look assessment of risk of

Overall, by the analysis of only phase-III studies results, no significant difference

Risk of biases graph: review author's judgments about each risk of bias item presented as percentages across all

seen between neuroprotectives and placebo groups in favorable outcomes [(p = 0.30; RR 0.97, 95% CI 0.90–1.03; participants = 3560; studies = 4; I2 = 0%) Figure 22]; or mortalities [(p = 0.51; RR 0.92, 95% CI 0.73–1.17; participants = 3876;

#### 4.2.12 Piracetam

Search results brought following three titles for this intervention "Clinical Evaluation of Nootropil (Piracetam) in Severe Craniocerebral Injuries," "Clinical trial of piracetam in disorders of consciousness due to head injury," and "A controlled clinical study piracetam V. Placebo in disorders of consciousness due to head injuries" but there was no achievement to their full-texts. However attempts to contact authors had no success too.

#### 4.2.13 Miscellaneous findings

There were review-like studies and RCTs, further than these 12 categorized neuroprotectives, for TBI management, that a quick review of them proceeds in the following paragraphs

	- Better significant emotion recognition training outcome by the mean of 11 years after TBI in facial affect recognition better than participants of stories group in comparison to control group, showed impaired cognitive abilities improvement in moderate to severe TBI patients in "A randomized controlled trial of emotion recognition training after traumatic brain injury" [66]; however hypothetical testing of stories group to assess their ability to infer and label their feelings in given

scenarios, showed significant improvements. Patients responses to these emotional recognitions, was not favorable, as authors recommend further studies to instruct participants on how to response too [66].


#### 4.2.14 Risk of bias in included studies

4.2.12 Piracetam

Rivastigmine side effects.

Figure 19.

authors had no success too.

4.2.13 Miscellaneous findings

following paragraphs

104

Search results brought following three titles for this intervention "Clinical Evaluation of Nootropil (Piracetam) in Severe Craniocerebral Injuries," "Clinical trial of piracetam in disorders of consciousness due to head injury," and "A controlled clinical study piracetam V. Placebo in disorders of consciousness due to head injuries" but there was no achievement to their full-texts. However attempts to contact

There were review-like studies and RCTs, further than these 12 categorized neuroprotectives, for TBI management, that a quick review of them proceeds in the

a. A 2013 "meta-analysis of treating acute traumatic brain injury with calcium channel blockers," of nine RCTs, showed slightly better outcome of placebo group, but it was not statistically significant (p = 0.52; RR 1.18, 95% CI 0.72– 1.95; participants = 171; studies = 2; I2 = 52%), however there was no significant difference between intervention and placebo groups in mortalities (p = 0.44; RR 0.93, 95% CI 0.77–1.12; participants = 1337; studies = 5; I2 = 0%), nor adverse effects (p = 0.33; RR 1.11, 95% CI 0.90–1.37; participants = 1358; studies = 4; I2 = 0%) [63]. The former hypothesis of "The role of mitochondrial calcium uni-porter in neuroprotection in traumatic brain injury" may be

b.A parallel study to COBRIT "Early trajectory of Psychiatric Symptoms after Traumatic Brain Injury: Relationship to patient and Injury Characteristic," show overall an improvement process of psychiatric characteristic of TBI patient over 180 days assessment, with better outcomes on days 30–90; better

outcomes of female participants in comparison to males; not statistical significant but Hispanic's most and African-American's least improvement process in comparison to whites as the ethnic/race analysis' reference group [65].

abilities improvement in moderate to severe TBI patients in "A randomized controlled trial of emotion recognition training after traumatic brain injury" [66]; however hypothetical testing of stories group to assess their ability to infer and label their feelings in given

• Better significant emotion recognition training outcome by the mean of 11 years after TBI in facial affect recognition better than participants of stories group in comparison to control group, showed impaired cognitive

disclaimed as a result of this meta-analysis [64].

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

As a whole, "randomization part" of studies has a good assessment overall; however "allocation concealment" or "how blinding participants or personnel take place" didn't seem to be well reported. Finally RCTs reporting didn't accommodate well enough to CONSORT statement (i.e., this review study's tool for analyzing study reports). Figures 20 and 21 are at a glance quick look assessment of risk of bias in included studies.

#### 4.2.15 Effects of interventions

Overall, by the analysis of only phase-III studies results, no significant difference seen between neuroprotectives and placebo groups in favorable outcomes [(p = 0.30; RR 0.97, 95% CI 0.90–1.03; participants = 3560; studies = 4; I2 = 0%) Figure 22]; or mortalities [(p = 0.51; RR 0.92, 95% CI 0.73–1.17; participants = 3876; studies = 4; I<sup>2</sup> = 52%) Figure 23].

#### Figure 20.

Risk of biases graph: review author's judgments about each risk of bias item presented as percentages across all included studies.

5. Discussion

Figure 23.

Figure 22.

5.1.1 Oxygen

5.1 Summary of main results

Phase-III neuroprotectives favorable outcome.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

has no enough evidences yet.

107

Despite other trials of oxygen intervention in acute phase TBI, Rockswald et al. study's new design in combination of HBO2/NBH, rather than solely attempt of each one results in better and significant outcomes [43]; it could be a new recommendation for future trials of acute phase TBI management, as its mortality report was the

Boussi-Gross et al. study's improvement results in cognitive function of mild chronic TBI patients despite other DoD-/VA-related studies' results may be due to differences in civilian and service member populations of each study design, probable posttraumatic syndrome disorder (PTSD) symptoms of DoD/VA members, and different assessment tools; also, controversies of eye problem conditioning between Cifu et al. and Wolf et al. may resolve in a large group study with a common manifest of study objectives and participant evaluation [37, 38, 40–42]. In conclusion, there were lots of controversies between oxygen phase-II trials till now, but no multi-centric phase-III trial been conducted for this intervention, the one is strongly recommended also in a normal population and not just for DoD/VAs

[41]. A Trial of HBO2/NBH—(sham) control design may have most cost-

beneficence than other kinds of solo intervention trials especially in acute phase TBI management [43]. Using oxygen (especially HBO2) in chronic management of TBI

same as past trials, but with better GOS outcome [1, 43].

Phase-III neuroprotectives mortality (CRASH 2005 not included).

Figure 21.

Risk of biases summary: review author's judgments about each risk of bias item for each included study.

#### Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

#### Figure 22.

Phase-III neuroprotectives favorable outcome.

Figure 23. Phase-III neuroprotectives mortality (CRASH 2005 not included).

#### 5. Discussion

#### 5.1 Summary of main results

#### 5.1.1 Oxygen

Despite other trials of oxygen intervention in acute phase TBI, Rockswald et al. study's new design in combination of HBO2/NBH, rather than solely attempt of each one results in better and significant outcomes [43]; it could be a new recommendation for future trials of acute phase TBI management, as its mortality report was the same as past trials, but with better GOS outcome [1, 43].

Boussi-Gross et al. study's improvement results in cognitive function of mild chronic TBI patients despite other DoD-/VA-related studies' results may be due to differences in civilian and service member populations of each study design, probable posttraumatic syndrome disorder (PTSD) symptoms of DoD/VA members, and different assessment tools; also, controversies of eye problem conditioning between Cifu et al. and Wolf et al. may resolve in a large group study with a common manifest of study objectives and participant evaluation [37, 38, 40–42].

In conclusion, there were lots of controversies between oxygen phase-II trials till now, but no multi-centric phase-III trial been conducted for this intervention, the one is strongly recommended also in a normal population and not just for DoD/VAs [41]. A Trial of HBO2/NBH—(sham) control design may have most costbeneficence than other kinds of solo intervention trials especially in acute phase TBI management [43]. Using oxygen (especially HBO2) in chronic management of TBI has no enough evidences yet.

Figure 21.

106

Risk of biases summary: review author's judgments about each risk of bias item for each included study.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

#### 5.1.2 Corticosteroids

CRASH study's results that weigh about 95% of the Alderson's Cochrane review in "Corticosteroids for acute traumatic brain injury—last revised 2009," made the fact of increasing mortalities in TBI, by using corticosteroids [4]; no new trials found on steroids effect for TBI after these papers.

paradigms, including innovative clinical-trial methods (e.g., adaptive designs and profiling of patients who have a response) in early-phase clinical trials to identify effective drug doses and timing (e.g., pre-hospital administration), the use of targeted outcomes based on the mechanism of injury, and rigorous preclinical multicentric trials in animals that better simulate subsequent human trials and make more accurate predictions regarding results." [10] "From Bench to Bed," "From Mice to Mind"; these statements declare incompatibility of basic studies with clinical trials; the basic science consortium approach, is one of good options for pharmaceutical intervention selection on human beings trials, it's on the way, as part of Combat Casualty Care Research Program-Operational Brain Trauma Ther-

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

Concluding all these results together, may associate the future attempts on medicine to cellular-molecular field of bio-medicine in all of its era, as well as trauma management [9]. Review results should declare that using progesterone in the recommended I.V. doses has no significant beneficial effects than placebo; recommendation of using progesterone for pediatric patients in TBI insults [16], has no proof, as there is no structured RCT for that, and this age group's recovery of TBI effects, may naturally take place with controlling the damage by current guidelines. "Combination therapy of 17-Beta-E2 and Progesterone while applying a basis of Emulsion I.V. together with Omega-3 fatty acids, using high short-term dosages of treatments rather than normal long-term treatments" mentioned by Beyer as request of expertise-comment for his interests and experience since 1988 on Gonadal Steroids use for CNS problems [15] may present the clue for further researches in this field. Combination therapy of progesterone and vitamin D, especially in aged TBI patients [10, 14] is not proved in human cases, and beneficence of this combination recommended therapy, might be questioned for not significant efficacy of progesterone use in lately human phase-III RCTs; however another RCTs

should hold for vitamin D use for TBI patients to verify this statement.

Cochrane review for this topic didn't include any articles, also there was no new studies in this review's search results too, and as they recommended in their article "in the absence of clear evidence of benefit from Neuroprotective drug use, there is an urgent need to explore other potential modulators of late outcome from TBI. The reported results of these studies require replication in larger studies, extended to other groups including more severely injured patients, and children" would be the

The total analysis and results of this topic demonstrate that, it reduces mortality rates but no significant efficacy of EPO rather than placebo or control groups is noted; also EPO-TBI resulted in side-effects, which didn't report in other two trials [20, 21, 51], that might be due to EPO-TBI's higher EPO dose use (40,000 IU up to 3 doses) in comparison to 10,000 IU for 7 days of Aloizos et al. and 1000 IU in 6 doses during 2 weeks of Abrishamkar et al. There were side effects in placebo group of EPO-TBI trial too; that challenges this statement. Nearly significant better outcome of side-effects for EPO group in Nichol et al. EPO-TBI trial is far away from last expectations of EPO trials [21, 49] that confirms Leucht et al. statement on drugs complexity effect [12]. All three trials administered the intervention through subcutaneous (S.C.) route, as Abrishamkar et al. declared, despite LAB trials, it's

apy Consortium [11].

5.1.4 Monoaminergic agents

5.1.5 Erythropoietin (EPO)

109

clue of further researches and trials.

Current review's applicability on using corticosteroids for CNS acute traumas, leads to another Cochrane review of "Steroids for acute spinal cord injury—last revised 2012" [13]; however these conditions (TBI and SCI) may coincide (dualdiagnoses). So what are the practical recommendations for these situations?

According to Bracken's review "Methylprednisolone sodium succinate must be started within 8 hours of injury, using an initial bolus of 30 mg/kg by IV for 15 minutes followed 45 minutes later by a continuous infusion of 5.4 mg/kg/hour for 24 hours. Further improvement in motor function recovery has been shown to occur when the maintenance therapy is extended for 48 hours. This is particularly evident when the initial bolus dose could only be administered 3–8 hours after injury"; dosage and limited time of intervention for SCI patients, mentioned in the review by contemplate of situations with cohesion of TBI and SCI literally 16–59% [70], therefore challenging decision making on using corticosteroids (especially Methylprednisolone, as recommended in the review) on these conditions needs awareness of reviews results combination. It's suggested to use the recommended methylprednisolone protocol for dual-diagnose patients only in the initial bolus dose timing of 3–8 hours after acute injury, following therapy for only 48 hours; neither other corticosteroids nor extensive use of this protocol, are not suggested or acceptable for dual-diagnose patients management, also Nott et al. study brings hopes in cognitive behavior of dual-diagnosed ones [70], that discussed by social effects of condition in the study, this may persuade health-care practitioner and cost-benefit analyst about using this intervention for dual-diagnoses.

#### 5.1.3 Progesterone

SYNAPSE and ProTECT-III trials results for progesterone, changed the former vision of this intervention's effect on TBI management, as CRASH trial did for corticosteroid in 2005.

Progesterones are gonadal steroids, and assume to have been more favorable in neurodegenerative disorders like multiple sclerosis (MS), Alzheimer disease (AD), and maybe TBI, i.e., neurodegenerative effects of microglia after injury and induced inflammatory response in whole body [14, 16, 71], as mentioned by Beyer [15].

Leucht et al. and Burns et al. studies results are good challenging statements for current visions of pharmaceutical interventions for major chronic disorders and central nervous system (CNS) injuries respectively [9, 12]. The pharmaceutical interventions failure in huge phase-III trials for TBI in the last decade (i.e., from CRASH 2005 to EPO-TBI 2015), even as smoothly penetration of progesterone through BBB to take its promising effects in pre-clinical studies [10, 11, 14, 15, 17, 18], made this statement from Wright et al. who designed and proceed three trials of progesterone use in TBI [10, 45, 47] "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. Approaches are needed to reduce heterogeneity, but they come at the cost of more homogeneous pathological findings and decreased generalization of the results. Success at translating from bench to bedside may require new

#### Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

5.1.2 Corticosteroids

5.1.3 Progesterone

108

corticosteroid in 2005.

found on steroids effect for TBI after these papers.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

CRASH study's results that weigh about 95% of the Alderson's Cochrane review in "Corticosteroids for acute traumatic brain injury—last revised 2009," made the fact of increasing mortalities in TBI, by using corticosteroids [4]; no new trials

Current review's applicability on using corticosteroids for CNS acute traumas, leads to another Cochrane review of "Steroids for acute spinal cord injury—last revised 2012" [13]; however these conditions (TBI and SCI) may coincide (dualdiagnoses). So what are the practical recommendations for these situations?

According to Bracken's review "Methylprednisolone sodium succinate must be

started within 8 hours of injury, using an initial bolus of 30 mg/kg by IV for 15 minutes followed 45 minutes later by a continuous infusion of 5.4 mg/kg/hour for 24 hours. Further improvement in motor function recovery has been shown to occur when the maintenance therapy is extended for 48 hours. This is particularly evident when the initial bolus dose could only be administered 3–8 hours after injury"; dosage and limited time of intervention for SCI patients, mentioned in the review by contemplate of situations with cohesion of TBI and SCI literally 16–59% [70], therefore challenging decision making on using corticosteroids (especially Methylprednisolone, as recommended in the review) on these conditions needs awareness of reviews results combination. It's suggested to use the recommended methylprednisolone protocol for dual-diagnose patients only in the initial bolus dose timing of 3–8 hours after acute injury, following therapy for only 48 hours; neither other corticosteroids nor extensive use of this protocol, are not suggested or acceptable for dual-diagnose patients management, also Nott et al. study brings hopes in cognitive behavior of dual-diagnosed ones [70], that discussed by social effects of condition in the study, this may persuade health-care practitioner and

cost-benefit analyst about using this intervention for dual-diagnoses.

SYNAPSE and ProTECT-III trials results for progesterone, changed the former vision of this intervention's effect on TBI management, as CRASH trial did for

Progesterones are gonadal steroids, and assume to have been more favorable in neurodegenerative disorders like multiple sclerosis (MS), Alzheimer disease (AD), and maybe TBI, i.e., neurodegenerative effects of microglia after injury and induced inflammatory response in whole body [14, 16, 71], as mentioned by Beyer [15]. Leucht et al. and Burns et al. studies results are good challenging statements for current visions of pharmaceutical interventions for major chronic disorders and central nervous system (CNS) injuries respectively [9, 12]. The pharmaceutical interventions failure in huge phase-III trials for TBI in the last decade (i.e., from CRASH 2005 to EPO-TBI 2015), even as smoothly penetration of progesterone through BBB to take its promising effects in pre-clinical studies [10, 11, 14, 15, 17, 18], made this statement from Wright et al. who designed and proceed three trials of progesterone use in TBI [10, 45, 47] "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. Approaches are needed to reduce heterogeneity, but they come at the cost of more homogeneous pathological findings and decreased generalization of the results. Success at translating from bench to bedside may require new

paradigms, including innovative clinical-trial methods (e.g., adaptive designs and profiling of patients who have a response) in early-phase clinical trials to identify effective drug doses and timing (e.g., pre-hospital administration), the use of targeted outcomes based on the mechanism of injury, and rigorous preclinical multicentric trials in animals that better simulate subsequent human trials and make more accurate predictions regarding results." [10] "From Bench to Bed," "From Mice to Mind"; these statements declare incompatibility of basic studies with clinical trials; the basic science consortium approach, is one of good options for pharmaceutical intervention selection on human beings trials, it's on the way, as part of Combat Casualty Care Research Program-Operational Brain Trauma Therapy Consortium [11].

Concluding all these results together, may associate the future attempts on medicine to cellular-molecular field of bio-medicine in all of its era, as well as trauma management [9]. Review results should declare that using progesterone in the recommended I.V. doses has no significant beneficial effects than placebo; recommendation of using progesterone for pediatric patients in TBI insults [16], has no proof, as there is no structured RCT for that, and this age group's recovery of TBI effects, may naturally take place with controlling the damage by current guidelines. "Combination therapy of 17-Beta-E2 and Progesterone while applying a basis of Emulsion I.V. together with Omega-3 fatty acids, using high short-term dosages of treatments rather than normal long-term treatments" mentioned by Beyer as request of expertise-comment for his interests and experience since 1988 on Gonadal Steroids use for CNS problems [15] may present the clue for further researches in this field. Combination therapy of progesterone and vitamin D, especially in aged TBI patients [10, 14] is not proved in human cases, and beneficence of this combination recommended therapy, might be questioned for not significant efficacy of progesterone use in lately human phase-III RCTs; however another RCTs should hold for vitamin D use for TBI patients to verify this statement.

#### 5.1.4 Monoaminergic agents

Cochrane review for this topic didn't include any articles, also there was no new studies in this review's search results too, and as they recommended in their article "in the absence of clear evidence of benefit from Neuroprotective drug use, there is an urgent need to explore other potential modulators of late outcome from TBI. The reported results of these studies require replication in larger studies, extended to other groups including more severely injured patients, and children" would be the clue of further researches and trials.

#### 5.1.5 Erythropoietin (EPO)

The total analysis and results of this topic demonstrate that, it reduces mortality rates but no significant efficacy of EPO rather than placebo or control groups is noted; also EPO-TBI resulted in side-effects, which didn't report in other two trials [20, 21, 51], that might be due to EPO-TBI's higher EPO dose use (40,000 IU up to 3 doses) in comparison to 10,000 IU for 7 days of Aloizos et al. and 1000 IU in 6 doses during 2 weeks of Abrishamkar et al. There were side effects in placebo group of EPO-TBI trial too; that challenges this statement. Nearly significant better outcome of side-effects for EPO group in Nichol et al. EPO-TBI trial is far away from last expectations of EPO trials [21, 49] that confirms Leucht et al. statement on drugs complexity effect [12]. All three trials administered the intervention through subcutaneous (S.C.) route, as Abrishamkar et al. declared, despite LAB trials, it's

nearly impossible to gather Intra-Ventricular route for agent administration in edematous TBI brain [20].

5.1.9 NeuroAid

5.1.11 Rivastigmine

5.1.12 Piracetam

111

5.1.10 Cyclosporine A (CysA)

Trials on Neuroaid for brain injury conditions mostly studied its effects on stroke brain injuries; none of current study's search results, related to Neuroaid use

Cyclosporine A's use may prevent ICP rise or reduce it, in comparison to placebo as this analysis showed. However there is no significant effect of its use in 6-month favorable outcomes or mortality rates. Also cohort study groups of Hatton et al. and other drug concentration studies confirm that best blood and cerebrospinal fluid (CSF) CysA depositions resulted from its high doses and fortunately the wide therapeutic window [28, 59–61]. Both of the included studies have a 5 mg/kg intervention on their design protocols, also Hatton et al. recommended a 2.5 mg/kg bolus dose in 2 hours of TBI insult following by 5 mg/kg/day for 72 hours, as optimal dosing strategy for further clinical trials study design. As there would be a huge multi-centric, prospective, phase-III RCT for CysA after National Institute of Health (NIH) proves its proposal [29]; that might bring future evidences on using

Rivastigmine and other ChE-inh use for TBI, mostly known for their cognitive behavioral effects, and their trials take part in chronic TBI managements, Tenovuo's

There were studies for this intervention but no achievement to their full-texts, it

Following statements are recommendations for "Miscellaneous Findings" sec-

• Improvement in psychiatric assessments of TBI patient, after assault differ between individuals, there should be supportive psychological first aid (PFA) tools for primary survivors of the assault; a Johns Hopkins University's course of PFA-RAPID which stands for Rapport and Reflective Listening, Assessment

may be one of this review's reporting biases, which no clinical judgment may

study didn't show a significant difference between three drugs that patients assigned to use, but mostly preferred Galantamine for its fewer side effects [62]. Silver et al. (both 2006 and 2009 studies) with 157 patients and better study design in comparison to Tenovuo's, didn't show significant difference of rivastigmine and placebo groups at all, but in severe impaired patients. These results support the need of more RCTs especially multi-centric phase-III RCTs of rivastigmine and other ChE-inh for chronic TBI management in severe impaired patients, the recommended protocol as Silver et al. Stated, is to start with 3 mg of rivastigmine/ day and slowly increase to maximum dose of 12 mg/day if the previous dose was well tolerated for at least 4 weeks. Routine use of rivastigmine for chronic TBI management is not recommended, as it has no significant effect for patients rather

in TBI; that may suggest the clue for future trials.

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

this intervention for TBI (especially acute) management.

than placebo, as current evidences declared.

presented for this intervention.

tion of "Results" section of the study:

5.1.13 Miscellaneous findings

Final conclusion on this topic, otherwise its prospective phase-III multi-centric placebo-controlled RCT, cannot obviously be presented, due to different dose of interventions between studies (i.e., more than recommended does 1000–30,000 IU in EPO-TBI trial [21, 51]; better outcomes in mortality-rate and side-effects reduction for intervention group; But overall, it showed better outcome in placebo group, which makes the clinical decision-making a challenge on using EPO for acute TBI. It should be recommended to conduct another prospective phase-III multi-centric placebo-controlled RCT with intervention dose of no more than 30,000 IU during EPO-administration to conduct better decision about choosing this intervention wisely for acute TBI assaults.

#### 5.1.6 Magnesium sulfate and other magnesium salts

Magnesium beneficence for human beings through its CSF concentration didn't proved with the former trials, and Vink et al. reported the fact in 2009 [23]. Further trials on magnesium concentration in CSF may conducted via its administration through Intra Ventricular route, to find out its probable Neuroprotective effect, however it seems not to be successful [20].

#### 5.1.7 Cerebrolysin

Limited evidences for this intervention's effect on TBI patients, also in different severities of TBI, mild TBI in RCT study and moderate to severe TBI in cohort study [24, 55], couldn't investigate its reliability for generalized use recommendation in TBIs; Cerebrolysin Asian Pacific Trial in Acute Brain Injury and Neurorecovery (CAPTAIN) results [54] is going to lead the future responsibilities and decisions to use this intervention in TBI situations.

#### 5.1.8 Citicoline (CDP-choline) and other cholinergics

COBRIT study for citicoline seems to be like CRASH, SYNAPSE and ProTECT-III or EPO-TBI, as it was a huge multicentric placebo-control RCT of citicoline, its halt in forth interim analysis, may resulted to less participant of patients in followup process, but it was none of significantly difference between groups' analysis, overall assessment of outcomes didn't demonstrate any significant effect of citicoline favorable especially in GOS, yet in COBRIT study's assessment of GOS for day-90 and 180, improvements are slightly better but not significant at all (from p = 0.97 to p = 0.43), there is significant improvement of placebo-control group patients in neurocognitive state rather than intervention group. Yet neither mortality nor side-effects of intervention versus control groups were significant.

Maldonado et al. study was the more notable one after Zafonte et al. COBRIT in these search results; this study, Leon-Carrion et al. and Shokouhi et al. studies' beneficence in citicoline use for severe and moderate TBIs, questioned by COBRIT overall outcomes both in day-90 and 180 outcomes [55–58]. Also a significant better outcome change was obvious in mildly complicated cases on day-180 outcome in COBRIT study [58]. Heterogeneity of intervention doses and outcome assessments in included studies surrounded by Zafonte et al. Study's results; though current use of citicoline for TBI in acute or chronic phase, is no more recommended by the results of this review, however it may have neurocognitive beneficiaries for mild TBI, that decision of using this experiment on these conditions, belongs to attending physician's opinion and other assessments.

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

#### 5.1.9 NeuroAid

nearly impossible to gather Intra-Ventricular route for agent administration in

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Final conclusion on this topic, otherwise its prospective phase-III multi-centric placebo-controlled RCT, cannot obviously be presented, due to different dose of interventions between studies (i.e., more than recommended does 1000–30,000 IU in EPO-TBI trial [21, 51]; better outcomes in mortality-rate and side-effects reduction for intervention group; But overall, it showed better outcome in placebo group, which makes the clinical decision-making a challenge on using EPO for acute TBI. It should be recommended to conduct another prospective phase-III multi-centric placebo-controlled RCT with intervention dose of no more than 30,000 IU during EPO-administration to conduct better decision about choosing this intervention

Magnesium beneficence for human beings through its CSF concentration didn't proved with the former trials, and Vink et al. reported the fact in 2009 [23]. Further trials on magnesium concentration in CSF may conducted via its administration through Intra Ventricular route, to find out its probable Neuroprotective effect,

Limited evidences for this intervention's effect on TBI patients, also in different severities of TBI, mild TBI in RCT study and moderate to severe TBI in cohort study [24, 55], couldn't investigate its reliability for generalized use recommendation in TBIs; Cerebrolysin Asian Pacific Trial in Acute Brain Injury and Neurorecovery (CAPTAIN) results [54] is going to lead the future responsibilities and decisions to

COBRIT study for citicoline seems to be like CRASH, SYNAPSE and ProTECT-III or EPO-TBI, as it was a huge multicentric placebo-control RCT of citicoline, its halt in forth interim analysis, may resulted to less participant of patients in followup process, but it was none of significantly difference between groups' analysis, overall assessment of outcomes didn't demonstrate any significant effect of

citicoline favorable especially in GOS, yet in COBRIT study's assessment of GOS for day-90 and 180, improvements are slightly better but not significant at all (from p = 0.97 to p = 0.43), there is significant improvement of placebo-control group patients in neurocognitive state rather than intervention group. Yet neither mortal-

Maldonado et al. study was the more notable one after Zafonte et al. COBRIT in

ity nor side-effects of intervention versus control groups were significant.

these search results; this study, Leon-Carrion et al. and Shokouhi et al. studies' beneficence in citicoline use for severe and moderate TBIs, questioned by COBRIT overall outcomes both in day-90 and 180 outcomes [55–58]. Also a significant better outcome change was obvious in mildly complicated cases on day-180 outcome in COBRIT study [58]. Heterogeneity of intervention doses and outcome assessments in included studies surrounded by Zafonte et al. Study's results; though current use of citicoline for TBI in acute or chronic phase, is no more recommended by the results of this review, however it may have neurocognitive beneficiaries for mild TBI, that decision of using this experiment on these conditions, belongs to attending

edematous TBI brain [20].

wisely for acute TBI assaults.

5.1.7 Cerebrolysin

5.1.6 Magnesium sulfate and other magnesium salts

however it seems not to be successful [20].

use this intervention in TBI situations.

physician's opinion and other assessments.

110

5.1.8 Citicoline (CDP-choline) and other cholinergics

Trials on Neuroaid for brain injury conditions mostly studied its effects on stroke brain injuries; none of current study's search results, related to Neuroaid use in TBI; that may suggest the clue for future trials.

#### 5.1.10 Cyclosporine A (CysA)

Cyclosporine A's use may prevent ICP rise or reduce it, in comparison to placebo as this analysis showed. However there is no significant effect of its use in 6-month favorable outcomes or mortality rates. Also cohort study groups of Hatton et al. and other drug concentration studies confirm that best blood and cerebrospinal fluid (CSF) CysA depositions resulted from its high doses and fortunately the wide therapeutic window [28, 59–61]. Both of the included studies have a 5 mg/kg intervention on their design protocols, also Hatton et al. recommended a 2.5 mg/kg bolus dose in 2 hours of TBI insult following by 5 mg/kg/day for 72 hours, as optimal dosing strategy for further clinical trials study design. As there would be a huge multi-centric, prospective, phase-III RCT for CysA after National Institute of Health (NIH) proves its proposal [29]; that might bring future evidences on using this intervention for TBI (especially acute) management.

#### 5.1.11 Rivastigmine

Rivastigmine and other ChE-inh use for TBI, mostly known for their cognitive behavioral effects, and their trials take part in chronic TBI managements, Tenovuo's study didn't show a significant difference between three drugs that patients assigned to use, but mostly preferred Galantamine for its fewer side effects [62]. Silver et al. (both 2006 and 2009 studies) with 157 patients and better study design in comparison to Tenovuo's, didn't show significant difference of rivastigmine and placebo groups at all, but in severe impaired patients. These results support the need of more RCTs especially multi-centric phase-III RCTs of rivastigmine and other ChE-inh for chronic TBI management in severe impaired patients, the recommended protocol as Silver et al. Stated, is to start with 3 mg of rivastigmine/ day and slowly increase to maximum dose of 12 mg/day if the previous dose was well tolerated for at least 4 weeks. Routine use of rivastigmine for chronic TBI management is not recommended, as it has no significant effect for patients rather than placebo, as current evidences declared.

#### 5.1.12 Piracetam

There were studies for this intervention but no achievement to their full-texts, it may be one of this review's reporting biases, which no clinical judgment may presented for this intervention.

#### 5.1.13 Miscellaneous findings

Following statements are recommendations for "Miscellaneous Findings" section of "Results" section of the study:

• Improvement in psychiatric assessments of TBI patient, after assault differ between individuals, there should be supportive psychological first aid (PFA) tools for primary survivors of the assault; a Johns Hopkins University's course of PFA-RAPID which stands for Rapport and Reflective Listening, Assessment of Needs, Prioritization, Intervention, Disposition; is available at https://www. coursera.org/course/psychfirstaid to triage and primary effective intervene of health-care providers for trauma assaults survivors, as further than the insult, sub-acute complications during recovery of patients, especially in two-third of severe impaired TBI patients [72], may have affects on their family's life too.

5.5 Final pluralization

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

obtained)

through IV route:

improvements seen in placebo group.

i. Bolus dose: 2.5 mg/kg in 2 hours,

dose if tolerated for 4 weeks of last dose [30].

management [61]:

no field of support yet.

113

Overall conclusion of these results and outcome findings of neuroprotective agents for traumatic brain injury management could be summarized as follows:

obvious, however no significant change seen in favorable outcomes, if a setting has HBO2 resource available, combined use of HBO2/NBH, may have better patient outcomes than using HBO2 or NBH solely; recommended approach for this facility is "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" [43]; also there is no significant evidence for using HBO2 in chronic TBI management.

b.Corticosteroid use in solo acute TBI management is prohibited, as its increased risk of mortalities; in dual-diagnosed patients (TBI and SCI together),

i. patient came through 2–3 hours after assault (if longer, should not be

ii. only methylprednisolone (other corticosteroids, has no beneficent effect in SCI management) with following protocol should be administered

• Following drip of: 5.4 mg/kg/day for the next 24–48 hours.

c. Current routine use of citicoline in acute TBI is no more supported, while no significant difference in comparison to placebo been reported. Citicoline use for managing neurocognitive conditions of chronic TBI, depends on attended physician's evaluation of patient's condition and local setting's evidence based medicine (EBM) community's decision. Rather its probable benefice in mild TBI patients, it's not recommended for all severity of TBI, while significant

d.Using of Cyclosporine A for ICP control, depends on the setting's available resources, and attending physician's point of view, there is no other significant difference for its favorable outcome in comparison to placebo. it should be recommend to administer through IV route by following protocol in acute TBI

e. Rivastigmine use for chronic TBI management of neurocognitive conditions, had some beneficence in severe impaired participants through phase-II trials of 3 mg/day and slowly increasing to 12 mg/day by adding 1.5 mg/day to previous

f. Other neuroprotective agents use for acute or chronic management of TBI, has

ii. Following drip of: 5 mg/kg/day for the next 72 hours.

corticosteroid use, should be obtained by this protocol [13]:

• Bolus dose: 30 mg/kg in 15 minutes,

a. Oxygen using for acute management of TBI to reduce mortality rates is


#### 5.2 Overall completeness and applicability of evidence

All of RCTs checked with CONSORT 2010 checklist; the applicability of this tool for further analysis of probable biases from participant randomization to outcome report used on each of the included studies as well.

#### 5.3 Potential biases in the review process

Primary database search strategy, didn't consist interventions as search keywords separately, the consultation with a medical librarian, persuade authors to revise the strategy with search of Piracetam, NeuroAid and Citicoline (as commonly used Neuroprotectives in their tertiary center, and for meta-analysis purpose of these interventions), the re-run search strategy added few (about 7–10) records in each database search, that skim review on their title and abstracts (duplicated records, assessed with Zotero reference manager software for exclusion), didn't show significant change of eligible studies, and further search on all interventions as solo keywords, didn't take place. Current meta-analyses based on second search strategy results. This may be a selection bias of this study and future reviews should be aware of this bias; another probable bias in this review was in reporting outcomes and mortalities analyses; Authors decide to report GOS or GOS-E outcomes analyses in two groups: (1) favorable outcome, which consists of good outcome and mild disability (GOS 4,5 and GOS-E 5-8) outcome; and (2) mortalities, that reported vegetative state and mortalities analysis (GOS 1,2 and GOS-E 1,2). Some of the articles, reported severe disability, vegetative-state and mortality outcomes together; if it was possible to get special reports on outcomes, analyses get through them, but if not, they'd been analyzed as the original article's authors decision.

#### 5.4 Agreements and disagreements with other studies or reviews

This review was a brand-new in interventions analyses for TBI (mostly acute) management; other previous reviews based on significant intervention's effect analysis; some parts of this review used the former reviews or meta-analyses results conducting new one, are referred through the text.

### 5.5 Final pluralization

of Needs, Prioritization, Intervention, Disposition; is available at https://www. coursera.org/course/psychfirstaid to triage and primary effective intervene of health-care providers for trauma assaults survivors, as further than the insult, sub-acute complications during recovery of patients, especially in two-third of severe impaired TBI patients [72], may have affects on their family's life too.

• Cerebral and body cooling for acute TBI impaired patients, may have better outcomes in patients survival and reducing mortality rates, due to significant unfavorable outcomes and mortality rates of high fevered patients after acute TBI in Li et al. study; a strong evidence of phase-III multi-centric international

• Music-therapy use for TBI patient, seem to have better outcomes in physiologic parameters, however other double-blinded RCTs need to prove this statement. However Maleki et al. study's aim was not to assess participants outcomes; as well actual efficacy of this intervention on patients outcomes, might took

All of RCTs checked with CONSORT 2010 checklist; the applicability of this tool for further analysis of probable biases from participant randomization to outcome

Primary database search strategy, didn't consist interventions as search keywords separately, the consultation with a medical librarian, persuade authors to revise the strategy with search of Piracetam, NeuroAid and Citicoline (as commonly used Neuroprotectives in their tertiary center, and for meta-analysis purpose of these interventions), the re-run search strategy added few (about 7–10) records in each database search, that skim review on their title and abstracts (duplicated records, assessed with Zotero reference manager software for exclusion), didn't show significant change of eligible studies, and further search on all interventions as solo keywords, didn't take place. Current meta-analyses based on second search strategy results. This may be a selection bias of this study and future reviews should be aware of this bias; another probable bias in this review was in reporting outcomes and mortalities analyses; Authors decide to report GOS or GOS-E outcomes analyses in two groups: (1) favorable outcome, which consists of good outcome and

mild disability (GOS 4,5 and GOS-E 5-8) outcome; and (2) mortalities, that

5.4 Agreements and disagreements with other studies or reviews

conducting new one, are referred through the text.

112

reported vegetative state and mortalities analysis (GOS 1,2 and GOS-E 1,2). Some of the articles, reported severe disability, vegetative-state and mortality outcomes together; if it was possible to get special reports on outcomes, analyses get through them, but if not, they'd been analyzed as the original article's authors decision.

This review was a brand-new in interventions analyses for TBI (mostly acute) management; other previous reviews based on significant intervention's effect analysis; some parts of this review used the former reviews or meta-analyses results

RCT, needed to prove this statement.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

5.2 Overall completeness and applicability of evidence

report used on each of the included studies as well.

5.3 Potential biases in the review process

under survey too [9, 73, 74].

Overall conclusion of these results and outcome findings of neuroprotective agents for traumatic brain injury management could be summarized as follows:

	- i. patient came through 2–3 hours after assault (if longer, should not be obtained)
	- ii. only methylprednisolone (other corticosteroids, has no beneficent effect in SCI management) with following protocol should be administered through IV route:
		- Bolus dose: 30 mg/kg in 15 minutes,
		- Following drip of: 5.4 mg/kg/day for the next 24–48 hours.
	- i. Bolus dose: 2.5 mg/kg in 2 hours,
	- ii. Following drip of: 5 mg/kg/day for the next 72 hours.

### 6. Conclusions

#### 6.1 Recommendations for practice

To use oxygen in acute management of TBI in order to reduce mortality rates seems to be obvious, however no significant change seen in favorable outcomes; corticosteroid use in solo acute TBI management is prohibited, as it increases risk of mortalities, however in dual-diagnosed patients (TBI & SCI together), corticosteroid use, should be obtained by a protocol introduced by Bracken et al. Current routine use of citicoline in acute TBI is no more supported, while no significant difference in comparison to placebo been reported. Cyclosporine A usage for ICP control, depends on the available resources, and attending physician's point of view; Rivastigmine use for chronic TBI management of neurocognitive conditions, had some beneficence in severe impaired participants. However other Neuroprotective agents use for acute or chronic management of TBI, has no field of support yet and they needed more researches and trials.

Cellular-molecular experiences in CNS conditions, has not been provided acceptable outcomes for TBI to date, but as a recommendation of an expert "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

Use of Neuroprotective agents for Traumatic Brain Injury

DOI: http://dx.doi.org/10.5772/intechopen.85720

It's also recommended for RCT authors to use CONSORT-assessment guidelines

Our kind regards and appreciations belong to Mrs. Fathifar and Mr. Saeidi, the librarians of Tabriz Nutritional Sciences Faculty and Tabriz University of Medical Sciences Central Library, who also commented to our primary search strategy to revise it into better applicability and help us come through the full-texts of related articles; also Mr. Ahadi, MA in English literature and language, who reviewed our primary draft and his precious recommendations made better outfit of this manuscript. The following authors, make the meaningfulness of "Standing on the shoul-

ders of Giants" & "Open Accessed World Wide Web (WWW)" for us; by providing their own papers' full-texts for our study, despite the limitations of known routes in WWW, via www.researchgate.net; our appreciations belongs to them and to whom else endeavors on making these Ottos possible: Dr. David B. Arciniegas, Dr. Lisa Anne Brenner, Dr. Jose Leon-Carion, Dr. Andrew I.R. Maas & Dr. Olli Tenovuo. Prof. Cordian Beyer's Comments on "Gonadal Esteroids and Progesterone" as his most experience on the topic since 1988, may bring new hopes in this era; Dr. Burns' comments on probable effectiveness of Cellular Medicine for TBI management, should be valuable route of future studies & researches. And We used bunch of Libre/Open Source Software to surf the web, collect information, analyze data & publish the paper; our kind pleasures belongs to alumni of "Mozilla FireFox," "LibreOffice," "Zotero," "uGet" & "Cochrane RevMan" (hope the last one some day would be published under software freedoms Two and Three too); and "Richard Stallman" founder of "Free Software Foundation (www.fsf.org)," for bringing these useful elaborate software and the philosophy of software freedom for human beings. Also Our Kind regards and appreciations belong to Ms. Rozmari Marijan for her really kind and supportive help, feed-backs and follow-ups for performing this manuscript of Intech-Open format, and made the meaningfulness

This chapter is the reporting result of a GP graduation thesis from Tabriz University of Medical Sciences, which was defended on June 2016 under thesis

in their study designs and paper reports; and report clinical outcomes of mild, moderate and severe suffered acute TBI patients in separate subgroup analyses, which an eight-pointed GOS-E reporting scale is preferred to five-pointed GOS one [75]; till better outcome assessment tool been developed; however studies on hypotheses of drugs concentration in serum, or assessing physiological parameters of patients; resulted in no more significant outcome of TBI patients in large phase-

plasticity" [9].

III studies.

Acknowledgements

of "Publishing Science in Peace."

Conflict of interest

number 92/1-1/6.

115

#### 6.2 Recommendations for research

Lastly phase-III RCTs for TBI management, change the former evidences of Neuroprotective agents use (i.e., CRASH 2005 for corticosteroid [4], COBRIT 2012 for citicoline [58]. SYNAPSE 2014 [11] and ProTECT 2014 [10] for Progesterone and EPO-TBI 2015 for erythropoietin [21]; despite current process of phase-I to phase-III (IV) new drug evaluation to use in human-beings, it should be recommended to skip phase-II trials for TBI related studies; heterogeneity of the condition, make its accurate interpretation so difficult in restricted single-centered phase-II trials. Scheduling large double (or more)-blinded huge multi-centric international phase-III RCTs, including low-income countries too as recommended by Menon in "Unique challenges in clinical trials in traumatic brain injury" [75], with acceptable design of interim analyses for number needed to harm (NNH) and number needed to treat (NNT) at regular checkpoints, seem to have more accuracy and cost-beneficent effects than current known processes. There was no strongevidenced well-designed trials for these interventions:


Also a Cerebrolysin phase-III trial is in the ongoing-list of current study [54]. And despite NeuroAid's trials for stroke injured brain, there was no trial (even phase-II) of this intervention for TBI.

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

Cellular-molecular experiences in CNS conditions, has not been provided acceptable outcomes for TBI to date, but as a recommendation of an expert "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" [9].

It's also recommended for RCT authors to use CONSORT-assessment guidelines in their study designs and paper reports; and report clinical outcomes of mild, moderate and severe suffered acute TBI patients in separate subgroup analyses, which an eight-pointed GOS-E reporting scale is preferred to five-pointed GOS one [75]; till better outcome assessment tool been developed; however studies on hypotheses of drugs concentration in serum, or assessing physiological parameters of patients; resulted in no more significant outcome of TBI patients in large phase-III studies.

#### Acknowledgements

6. Conclusions

6.1 Recommendations for practice

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

they needed more researches and trials.

evidenced well-designed trials for these interventions:

• Combined therapy of HBO2/NBH

SYNAPSE and ProTECT results;

phase-II) of this intervention for TBI.

• Monoaminergics;

conditions;

assault.

114

6.2 Recommendations for research

To use oxygen in acute management of TBI in order to reduce mortality rates seems to be obvious, however no significant change seen in favorable outcomes; corticosteroid use in solo acute TBI management is prohibited, as it increases risk of mortalities, however in dual-diagnosed patients (TBI & SCI together), corticosteroid use, should be obtained by a protocol introduced by Bracken et al. Current routine use of citicoline in acute TBI is no more supported, while no significant difference in comparison to placebo been reported. Cyclosporine A usage for ICP control, depends on the available resources, and attending physician's point of view; Rivastigmine use for chronic TBI management of neurocognitive conditions, had some beneficence in severe impaired participants. However other Neuroprotective agents use for acute or chronic management of TBI, has no field of support yet and

Lastly phase-III RCTs for TBI management, change the former evidences of Neuroprotective agents use (i.e., CRASH 2005 for corticosteroid [4], COBRIT 2012 for citicoline [58]. SYNAPSE 2014 [11] and ProTECT 2014 [10] for Progesterone and EPO-TBI 2015 for erythropoietin [21]; despite current process of phase-I to phase-III (IV) new drug evaluation to use in human-beings, it should be

recommended to skip phase-II trials for TBI related studies; heterogeneity of the condition, make its accurate interpretation so difficult in restricted single-centered phase-II trials. Scheduling large double (or more)-blinded huge multi-centric international phase-III RCTs, including low-income countries too as recommended by Menon in "Unique challenges in clinical trials in traumatic brain injury" [75], with acceptable design of interim analyses for number needed to harm (NNH) and number needed to treat (NNT) at regular checkpoints, seem to have more accuracy and cost-beneficent effects than current known processes. There was no strong-

• "High-dose, short-time administration of progesterone with 17-Beta-E2 in emulsion of Omega-3," as an expert advice for future studies [15] rather than

• Administering magnesium solutions via Intra-Ventricular or other achievable routes in TBI patients for rising its concentration in TBI patient's CSF;

• Rivastigmine use for chronic management of severe impaired neurocognitive

• Cerebral or body cooling, especially in severely impaired patients of acute TBI

Also a Cerebrolysin phase-III trial is in the ongoing-list of current study [54]. And despite NeuroAid's trials for stroke injured brain, there was no trial (even

Our kind regards and appreciations belong to Mrs. Fathifar and Mr. Saeidi, the librarians of Tabriz Nutritional Sciences Faculty and Tabriz University of Medical Sciences Central Library, who also commented to our primary search strategy to revise it into better applicability and help us come through the full-texts of related articles; also Mr. Ahadi, MA in English literature and language, who reviewed our primary draft and his precious recommendations made better outfit of this manuscript. The following authors, make the meaningfulness of "Standing on the shoulders of Giants" & "Open Accessed World Wide Web (WWW)" for us; by providing their own papers' full-texts for our study, despite the limitations of known routes in WWW, via www.researchgate.net; our appreciations belongs to them and to whom else endeavors on making these Ottos possible: Dr. David B. Arciniegas, Dr. Lisa Anne Brenner, Dr. Jose Leon-Carion, Dr. Andrew I.R. Maas & Dr. Olli Tenovuo. Prof. Cordian Beyer's Comments on "Gonadal Esteroids and Progesterone" as his most experience on the topic since 1988, may bring new hopes in this era; Dr. Burns' comments on probable effectiveness of Cellular Medicine for TBI management, should be valuable route of future studies & researches. And We used bunch of Libre/Open Source Software to surf the web, collect information, analyze data & publish the paper; our kind pleasures belongs to alumni of "Mozilla FireFox," "LibreOffice," "Zotero," "uGet" & "Cochrane RevMan" (hope the last one some day would be published under software freedoms Two and Three too); and "Richard Stallman" founder of "Free Software Foundation (www.fsf.org)," for bringing these useful elaborate software and the philosophy of software freedom for human beings. Also Our Kind regards and appreciations belong to Ms. Rozmari Marijan for her really kind and supportive help, feed-backs and follow-ups for performing this manuscript of Intech-Open format, and made the meaningfulness of "Publishing Science in Peace."

#### Conflict of interest

This chapter is the reporting result of a GP graduation thesis from Tabriz University of Medical Sciences, which was defended on June 2016 under thesis number 92/1-1/6.

References

[1] Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. Cochrane Database of Systematic Reviews. 2012. [Internet]. [cited 2015 Dec 27];12. Available from: http://dev. biologists.org/content/3/4/326.short

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Use of Neuroprotective agents for Traumatic Brain Injury

refractory high intracranial pressure in traumatic brain injury. In: The Cochrane

[7] National Institute of Neurological Disorders and Stroke. National Institute of Health - Traumatic Brain Injury. Traumatic Brain Injury; 2012

[8] MeSH. Neuroprotective Agents. Internet Based Definitions: NCBI. 1995. Available from: http://www.ncbi.nlm.

[9] Burns TC, Verfaillie CM. From mice to mind: Strategies and progress in translating neuroregeneration. European Journal of Pharmacology.

[10] Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. The New England Journal of Medicine. 2014;371(26):2457-2466

[11] Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, et al. A clinical trial of progesterone for severe traumatic brain injury. The New England Journal of Medicine. 2014;

[12] Leucht S, Helfer B, Gartlehner G, Davis JM. How effective are common medications—A perspective based on meta-analyses of major drugs. BioMed Centeral Ltd—BMC Medicine. 2015;

[13] Bracken MB. Steroids for acute spinal cord injury. Cochrane Database of Systematic Reviews. 2002. [Internet]. [cited 2015 Dec 26];3(3). Available

nih.gov/mesh/68018696

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371(26):2467-2476

13(1):253

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[2] Roberts I, Schierhout G.

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[3] Thompson K, Pohlmann-Eden B,

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life\_in\_sepsis\_.6.aspx

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[5] Ma J, Huang S, Qin S, You C. Progesterone for acute traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2012. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD008409.pub3

[6] Sahuquillo J. Decompressive craniectomy for the treatment of

117

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Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 1997. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD000566

#### Author details

Mohammad Meshkini1,2\*, Ali Meshkini1,3 and Homayoun Sadeghi-Bazargani1,4

1 Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Emergency Medicine Resident, Emergency Medicine Department, Iran University of Medical Sciences, Tehran, Iran

3 Department of Neurological-Surgery, Faculty of Medicine, Imam-Reza Hospital, Tabriz University of Medical Sciences, Tabriz, Iran

4 Department of Bio-statistics and Epidemiology, Faculty of Health and Nutrition Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

\*Address all correspondence to: meshkini522@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

#### References

[1] Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. Cochrane Database of Systematic Reviews. 2012. [Internet]. [cited 2015 Dec 27];12. Available from: http://dev. biologists.org/content/3/4/326.short

[2] Roberts I, Schierhout G. Hyperventilation therapy for acute traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 1997. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD000566

[3] Thompson K, Pohlmann-Eden B, Campbell Leslie A, Abel H. Pharmacological treatments for preventing epilepsy following traumatic head injury (Review). Cochrane Database of Systematic Reviews. 2015. [Internet]. [cited 2015 Dec 26];8. Available from: http://journals.lww. com/ccmjournal/Abstract/2010/05000/ Long\_term\_mortality\_and\_quality\_of\_ life\_in\_sepsis\_.6.aspx

[4] Alderson P, Roberts I. Corticosteroids for acute traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2005. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD000196.pub2

[5] Ma J, Huang S, Qin S, You C. Progesterone for acute traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2012. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD008409.pub3

[6] Sahuquillo J. Decompressive craniectomy for the treatment of refractory high intracranial pressure in traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2006. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD003983.pub2

[7] National Institute of Neurological Disorders and Stroke. National Institute of Health - Traumatic Brain Injury. Traumatic Brain Injury; 2012

[8] MeSH. Neuroprotective Agents. Internet Based Definitions: NCBI. 1995. Available from: http://www.ncbi.nlm. nih.gov/mesh/68018696

[9] Burns TC, Verfaillie CM. From mice to mind: Strategies and progress in translating neuroregeneration. European Journal of Pharmacology. 2015;759:90-100

[10] Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. The New England Journal of Medicine. 2014;371(26):2457-2466

[11] Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, et al. A clinical trial of progesterone for severe traumatic brain injury. The New England Journal of Medicine. 2014; 371(26):2467-2476

[12] Leucht S, Helfer B, Gartlehner G, Davis JM. How effective are common medications—A perspective based on meta-analyses of major drugs. BioMed Centeral Ltd—BMC Medicine. 2015; 13(1):253

[13] Bracken MB. Steroids for acute spinal cord injury. Cochrane Database of Systematic Reviews. 2002. [Internet]. [cited 2015 Dec 26];3(3). Available

Author details

Tabriz, Iran

116

of Medical Sciences, Tehran, Iran

Tabriz University of Medical Sciences, Tabriz, Iran

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

provided the original work is properly cited.

Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

\*Address all correspondence to: meshkini522@gmail.com

Mohammad Meshkini1,2\*, Ali Meshkini1,3 and Homayoun Sadeghi-Bazargani1,4

1 Road Traffic Injury Research Center, Tabriz University of Medical Sciences,

2 Emergency Medicine Resident, Emergency Medicine Department, Iran University

3 Department of Neurological-Surgery, Faculty of Medicine, Imam-Reza Hospital,

4 Department of Bio-statistics and Epidemiology, Faculty of Health and Nutrition

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

from: http://info.onlinelibrary.wiley. com/userfiles/ccoch/file/CD001046.pdf

[14] Atif F, Sayeed I, Ishrat T, Stein DG. Progesterone with vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Molecular Medicine. 2009;15(9–10):328

[15] Hoffmann S, Beyer C. Gonadal steroid hormones as therapeutic tools for brain trauma: The time is ripe for more courageous clinical trials to get into emergency medicine. The Journal of Steroid Biochemistry and Molecular Biology. 2015;146:1-2

[16] Robertson CL, Fidan E, Stanley RM, Noje C, Bayir H. Progesterone for neuroprotection in pediatric traumatic brain injury. Pediatric Critical Care Medicine. 2015;16(3):236-244

[17] Kelley BG, Mermelstein PG. Progesterone blocks multiple routes of ion flux. Molecular and Cellular Neurosciences. 2011;48(2):137-141

[18] Luoma JI, Kelley BG, Mermelstein PG. Progesterone inhibition of voltagegated calcium channels is a potential neuroprotective mechanism against excitotoxicity. Steroids. 2011. [Internet]. [cited 2015 Dec 26]; Available from: http://linkinghub.elsevier.com/retrieve/ pii/S0039128X11000535

[19] Forsyth RJ, Jayamoni B, Paine TC, Mascarenhas S. Monoaminergic agonists for acute traumatic brain injury. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2006. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD003984.pub2

[20] Abrishamkar S, Safavi M, Honarmand A. Effect of erythropoietin on Glasgow coma scale and Glasgow outcome Sale in patient with diffuse axonal injury. Journal of Research in Medical Sciences. 2012;17(1):51

[21] Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, et al. Erythropoietin in traumatic brain injury (EPO-TBI): A double-blind randomised controlled trial. The Lancet. 2015; 386(10012):2499-2506

MLC901), a Chinese medicine, in vitro and in vivo. Neuropharmacology. 2010;

DOI: http://dx.doi.org/10.5772/intechopen.85720

Use of Neuroprotective agents for Traumatic Brain Injury

[35] Bell MJ, Adelson PD, Hutchison JS, Kochanek PM, Tasker RC, Vavilala MS, et al. Differences in medical therapy goals for children with severe traumatic brain injury—An international study. Pediatric Critical Care Medicine. 2013;

[36] Huizenga JE, Zink BJ, Maio RF, Hill EM. Guidelines for the management of severe head injury: Are emergency physicians following them? Academic Emergency Medicine. 2002;9(8):

[37] Cifu DX, Hart BB, West SL, Walker W, Carne W. The effect of hyperbaric oxygen on persistent postconcussion symptoms. The Journal of Head Trauma

Rehabilitation. 2014;29(1):11-20

[38] Cifu DX, Walker WC, West SL, Hart BB, Franke LM, Sima A, et al. Hyperbaric oxygen for blast-related postconcussion syndrome: Three-month outcomes: HBO2 RCT for PCS outcomes. Annals of Neurology. 2014;75(2):

[39] Cifu DX, Hoke KW, Wetzel PA, Wares JR, Gitchel G, Carne W. Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild traumatic brain injury. Journal of Rehabilitation Research and

Development. 2014;(7):51, 1047-1056

[41] Wolf EG, Prye J, Michaelson R, Brower G, Profenna L, Boneta O. Hyperbaric side effects in a traumatic brain injury randomized clinical trial. [Internet]. DTIC Document; 2012 [cited 2015 Dec 26]. Available from: http://oai.dtic.mil/

oai/oai?verb=getRecord&

ADA611409

metadataPrefix=html&identifier=

[40] Wolf G, Cifu D, Baugh L, Carne W, Profenna L. The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. Journal of Neurotrauma. 2012;29(17):2606-2612

14(8):811-818

806-812

277-286

[28] Mazzeo AT, Alves ÓL, Gilman CB, Hayes RL, Tolias C, Niki Kunene K, et al. Brain metabolic and hemodynamic effects of cyclosporin a after human severe traumatic brain injury: A microdialysis study. Acta Neurochirurgica. 2008;150(10):

[29] Mazzeo AT, Brophy GM, Gilman CB, Alves ÓL, Robles JR, Hayes RL, et al. Safety and tolerability of

cyclosporin a in severe traumatic brain

prospective randomized trial. Journal of Neurotrauma. 2009;26(12):2195-2206

[30] Silver JM, Koumaras B, Chen M, Mirski D, Potkin SG, Reyes P, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology. 2006;67(5):

[31] Silver JM, Koumaras B, Meng X, Potkin SG, Reyes PF, Harvey PD, et al. Long-term effects of rivastigmine capsules in patients with traumatic brain injury. Brain Injury. 2009;23(2):

[32] Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 2011. Available from: http://handbook.cochra

[33] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal.

[34] Rognås L, Hansen TM, Kirkegaard H, Tønnesen E. Anaesthesiologistprovided prehospital airway

management in patients with traumatic brain injury: An observational study. European Journal of Emergency Medicine. 2014;21(6):418-423

injury patients: Results from a

58(7):987-1001

1019-1031

748-755

123-132

ne.org

119

2003;327(7414):557

[22] Presneill J, Little L, Nichol A, French C, Cooper D, Haddad S, et al. Statistical analysis plan for the erythropoietin in traumatic brain injury trial: A randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury. Trials. 2014;15(1):501

[23] Vink R, Cook NL, van den Heuvel C. Magnesium in acute and chronic brain injury: An update. Magnesium Research. 2009;22(3):158-162

[24] Wong GKC, Zhu XL, Poon WS. Beneficial effect of cerebrolysin on moderate and severe head injury patients: Result of a cohort study. In: Intracranial Pressure and Brain Monitoring XII. Springer; 2005. [Internet]. [cited 2015 Dec 26]. p. 59–60. Available from: http://link. springer.com/chapter/10.1007/3-211- 32318-X\_13

[25] Tan HB, Wasiak J, Rosenfeld JV, O'Donohoe TJ, Gruen RL. Citicoline (CDP-choline) for traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2014. [Internet]. [cited 2015 Dec 26]. Available from: http://doi. wiley.com/10.1002/14651858.CD011217

[26] Chen C, Venketasubramanian N, Gan RN, Lambert C, Picard D, Chan BP, et al. Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke recovery. Stroke. 2009; 40(3):859-863

[27] Heurteaux C, Gandin C, Borsotto M, Widmann C, Brau F, Lhuillier M, et al. Neuroprotective and neuroproliferative activities of NeuroAid (MLC601,

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

MLC901), a Chinese medicine, in vitro and in vivo. Neuropharmacology. 2010; 58(7):987-1001

from: http://info.onlinelibrary.wiley. com/userfiles/ccoch/file/CD001046.pdf

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

[21] Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, et al. Erythropoietin in traumatic brain injury (EPO-TBI): A double-blind randomised controlled trial. The Lancet. 2015;

[22] Presneill J, Little L, Nichol A, French C, Cooper D, Haddad S, et al. Statistical analysis plan for the erythropoietin in

386(10012):2499-2506

traumatic brain injury trial: A randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain

injury. Trials. 2014;15(1):501

[23] Vink R, Cook NL, van den Heuvel C. Magnesium in acute and chronic brain injury: An update. Magnesium Research. 2009;22(3):158-162

[24] Wong GKC, Zhu XL, Poon WS. Beneficial effect of cerebrolysin on moderate and severe head injury patients: Result of a cohort study. In: Intracranial Pressure and Brain Monitoring XII. Springer; 2005. [Internet]. [cited 2015 Dec 26]. p. 59–60. Available from: http://link. springer.com/chapter/10.1007/3-211-

[25] Tan HB, Wasiak J, Rosenfeld JV, O'Donohoe TJ, Gruen RL. Citicoline (CDP-choline) for traumatic brain injury. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2014. [Internet]. [cited 2015 Dec 26]. Available from: http://doi. wiley.com/10.1002/14651858.CD011217

[26] Chen C, Venketasubramanian N, Gan RN, Lambert C, Picard D, Chan BP, et al. Danqi Piantang Jiaonang (DJ), a traditional Chinese medicine, in poststroke recovery. Stroke. 2009;

[27] Heurteaux C, Gandin C, Borsotto M, Widmann C, Brau F, Lhuillier M, et al. Neuroprotective and neuroproliferative activities of NeuroAid (MLC601,

32318-X\_13

40(3):859-863

[14] Atif F, Sayeed I, Ishrat T, Stein DG. Progesterone with vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Molecular Medicine. 2009;15(9–10):328

[15] Hoffmann S, Beyer C. Gonadal steroid hormones as therapeutic tools for brain trauma: The time is ripe for more courageous clinical trials to get into emergency medicine. The Journal of Steroid Biochemistry and Molecular

[16] Robertson CL, Fidan E, Stanley RM, Noje C, Bayir H. Progesterone for neuroprotection in pediatric traumatic brain injury. Pediatric Critical Care Medicine. 2015;16(3):236-244

[17] Kelley BG, Mermelstein PG. Progesterone blocks multiple routes of ion flux. Molecular and Cellular Neurosciences. 2011;48(2):137-141

pii/S0039128X11000535

[18] Luoma JI, Kelley BG, Mermelstein PG. Progesterone inhibition of voltagegated calcium channels is a potential neuroprotective mechanism against excitotoxicity. Steroids. 2011. [Internet]. [cited 2015 Dec 26]; Available from: http://linkinghub.elsevier.com/retrieve/

[19] Forsyth RJ, Jayamoni B, Paine TC, Mascarenhas S. Monoaminergic agonists

for acute traumatic brain injury. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2006. [Internet]. [cited 2015 Dec 26]. Available from: http://doi.wiley. com/10.1002/14651858.CD003984.pub2

[20] Abrishamkar S, Safavi M,

118

Honarmand A. Effect of erythropoietin on Glasgow coma scale and Glasgow outcome Sale in patient with diffuse axonal injury. Journal of Research in Medical Sciences. 2012;17(1):51

Biology. 2015;146:1-2

[28] Mazzeo AT, Alves ÓL, Gilman CB, Hayes RL, Tolias C, Niki Kunene K, et al. Brain metabolic and hemodynamic effects of cyclosporin a after human severe traumatic brain injury: A microdialysis study. Acta Neurochirurgica. 2008;150(10): 1019-1031

[29] Mazzeo AT, Brophy GM, Gilman CB, Alves ÓL, Robles JR, Hayes RL, et al. Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: Results from a prospective randomized trial. Journal of Neurotrauma. 2009;26(12):2195-2206

[30] Silver JM, Koumaras B, Chen M, Mirski D, Potkin SG, Reyes P, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology. 2006;67(5): 748-755

[31] Silver JM, Koumaras B, Meng X, Potkin SG, Reyes PF, Harvey PD, et al. Long-term effects of rivastigmine capsules in patients with traumatic brain injury. Brain Injury. 2009;23(2): 123-132

[32] Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. 2011. Available from: http://handbook.cochra ne.org

[33] Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal. 2003;327(7414):557

[34] Rognås L, Hansen TM, Kirkegaard H, Tønnesen E. Anaesthesiologistprovided prehospital airway management in patients with traumatic brain injury: An observational study. European Journal of Emergency Medicine. 2014;21(6):418-423

[35] Bell MJ, Adelson PD, Hutchison JS, Kochanek PM, Tasker RC, Vavilala MS, et al. Differences in medical therapy goals for children with severe traumatic brain injury—An international study. Pediatric Critical Care Medicine. 2013; 14(8):811-818

[36] Huizenga JE, Zink BJ, Maio RF, Hill EM. Guidelines for the management of severe head injury: Are emergency physicians following them? Academic Emergency Medicine. 2002;9(8): 806-812

[37] Cifu DX, Hart BB, West SL, Walker W, Carne W. The effect of hyperbaric oxygen on persistent postconcussion symptoms. The Journal of Head Trauma Rehabilitation. 2014;29(1):11-20

[38] Cifu DX, Walker WC, West SL, Hart BB, Franke LM, Sima A, et al. Hyperbaric oxygen for blast-related postconcussion syndrome: Three-month outcomes: HBO2 RCT for PCS outcomes. Annals of Neurology. 2014;75(2): 277-286

[39] Cifu DX, Hoke KW, Wetzel PA, Wares JR, Gitchel G, Carne W. Effects of hyperbaric oxygen on eye tracking abnormalities in males after mild traumatic brain injury. Journal of Rehabilitation Research and Development. 2014;(7):51, 1047-1056

[40] Wolf G, Cifu D, Baugh L, Carne W, Profenna L. The effect of hyperbaric oxygen on symptoms after mild traumatic brain injury. Journal of Neurotrauma. 2012;29(17):2606-2612

[41] Wolf EG, Prye J, Michaelson R, Brower G, Profenna L, Boneta O. Hyperbaric side effects in a traumatic brain injury randomized clinical trial. [Internet]. DTIC Document; 2012 [cited 2015 Dec 26]. Available from: http://oai.dtic.mil/ oai/oai?verb=getRecord& metadataPrefix=html&identifier= ADA611409

[42] Boussi-Gross R, Golan H, Fishlev G, Bechor Y, Volkov O, Bergan J, et al. Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury-randomized prospective trial. Ai J, editor. PLoS One. 2013;8(11):e79995

[43] Rockswold SB, Gaylan L, Rockswold DA, Jiannong L. A prospective, randomized phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. Journal of Neurosurgery. 2013; 118(6):1317-1328

[44] Shakeri M, Boustani MR, Pak N, Panahi F, Salehpour F, Lotfinia I, et al. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma. Clinical Neurology and Neurosurgery. 2013;115(10):2019-2022

[45] Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Annals of Emergency Medicine. 2007;49(4): 391-402.e2

[46] Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Critical Care. 2008;12(2):R61

[47] Wright DW, Ritchie JC, Mullins RE, Kellermann AL, Denson DD. Steadystate serum concentrations of progesterone following continuous intravenous infusion in patients with acute moderate to severe traumatic brain injury. Journal of Clinical Pharmacology. 2005;45(6):640-648

[48] Xiao G, Wei J, Wu Z, Wang W, Jiang Q, Cheng J, et al. Clinical study on the therapeutic effects and mechanism of progesterone in the treatment for acute severe head injury. Zhonghua Wai Ke Za Zhi. 2007;45(2):106-108

[55] Leon-Carrion J, Dominguez-Roldan J, Murillo-Cabezas F, del Rosario D, Munoz-Sanchez M. The role of citicholine in neuropsychological training after traumatic brain injury. Neuropsychological Rehabilitation.

DOI: http://dx.doi.org/10.5772/intechopen.85720

Use of Neuroprotective agents for Traumatic Brain Injury

[62] Tenovuo O. Central

acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury—Clinical experience in 111 patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;29(1):61-67

[63] Xu G-Z, Wang M-D, Liu K-G, Bai Y-A, Wu W, Li W. A meta-analysis of

blockers. Brain Research Bulletin. 2013;

[64] Cheng G, Fu L, Zhang H, Wang Y,

treating acute traumatic brain injury with calcium channel

Zhang L, Zhang J. The role of mitochondrial calcium uniporter in neuroprotection in traumatic brain injury. Medical Hypotheses. 2013;80(2):

[65] Hart T, Benn EKT, Bagiella E, Arenth P, Dikmen S, Hesdorffer DC, et al. Early trajectory of psychiatric symptoms after traumatic brain injury: Relationship to patient and injury characteristics. Journal of Neurotrauma.

[66] Neumann D, Babbage DR, Zupan B, Willer B. A randomized controlled trial of emotion recognition training after traumatic brain injury. The Journal of Head Trauma Rehabilitation. 2015;

[67] Li J, Jiang J. Chinese head trauma data bank: Effect of hyperthermia on the outcome of acute head trauma patients. Journal of Neurotrauma. 2012;29(1):

[68] Galvin IM, Levy R, Boyd JG, Day AG, Wallace MC. Cooling for cerebral protection during brain surgery. In: The

Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2015. [cited 2015 Dec 26]. Available from: http://doi.

wiley.com/10.1002/14651858.

CD006638.pub3

99:41-47

115-117

2014;31(7):610-617

30(3):E12-E23

96-100

[56] Maldonado V, Perez J, Escario J. Effects of CDP-choline on the recovery of patients with head injury. Journal of the Neurological Sciences. 1991;103:

[57] Shokouhi G, Ghorbani Haghjoo A,

Sattarnezhad A, Asghari A, et al. Effects of citicoline on level of consciousness, serum level of fetuin-A and matrix Glaprotein (MGP) in trauma patients with diffuse axonal injury (DAI) and GCS ≤ 8. Turkish Journal of Trauma and Emergency. 2014;20(6):410-416

[58] Zafonte RD, Bagiella E, Ansel B, Novack TA, Friedewald WT, Hesdorffer

[59] Brophy GM, Mazzeo AT, Brar S, Alves OL, Bunnell K, Gilman C, et al. Exposure of Cyclosporin A in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury. Journal of Neurotrauma. 2013;30(17):1484-1489

[60] Empey PE, McNamara PJ, Young B, Rosbolt MB, Hatton J. Cyclosporin A disposition following acute traumatic brain injury. Journal of Neurotrauma.

[61] Hatton J, Rosbolt B, Empey P, Kryscio R, Young B. Dosing and safety of cyclosporine in patients with severe brain injury: Clinical article. Journal of Neurosurgery. 2008;109(4):699-707

DC, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline brain injury treatment trial (COBRIT). Journal of the American Medical Association. 2012;308(19):

1993-2000

2006;23(1):109-116

121

Sattarnezhad N, Asghari M,

1999;14(1):33-40

15-18

[49] Mammis A, McIntosh TK, Maniker AH. Erythropoietin as a neuroprotective agent in traumatic brain injury. Surgical Neurology. 2009;71(5):527-531

[50] Talving P, Lustenberger T, Kobayashi L, Inaba K, Barmparas G, Schnüriger B, et al. Erythropoiesis stimulating agent administration improves survival after severe traumatic brain injury: A matched case control study. Annals of Surgery. 2010;251(1): 1-4

[51] Aloizos S, Evodia E, Gourgiotis S, Isaia E, Seretis C, Baltopoulos G. Neuroprotective effects of erythropoietin in patients with severe closed brain injury. Turkish Neurosurgery. 2015. [Internet]. [cited 2015 Dec 26]; Available from: http:// www.turkishneurosurgery.org.tr/ summary\_en\_doi.php3?doi=10.5137/ 1019-5149.JTN.9685-14.4

[52] Natale JE, Guerguerian A-M, Joseph JG, McCarter R, Shao C, Slomine B, et al. Pilot study to determine the hemodynamic safety and feasibility of magnesium sulfate infusion in children with severe traumatic brain injury. Pediatric Critical Care Medicine. 2007; 8(1):1-9

[53] Chen C-C, Wei S-T, Tsaia S-C, Chen X-X, Cho D-Y. Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: Double-blind, placebo-controlled, randomized study. British Journal of Neurosurgery. 2013; 27(6):803-807

[54] Poon W, Vos P, Muresanu D, Vester J, von Wild K, Hömberg V, et al. Cerebrolysin Asian Pacific trial in acute brain injury and neurorecovery: Design and methods. Journal of Neurotrauma. 2015;32(8):571-580

Use of Neuroprotective agents for Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.85720

[55] Leon-Carrion J, Dominguez-Roldan J, Murillo-Cabezas F, del Rosario D, Munoz-Sanchez M. The role of citicholine in neuropsychological training after traumatic brain injury. Neuropsychological Rehabilitation. 1999;14(1):33-40

[42] Boussi-Gross R, Golan H, Fishlev G, Bechor Y, Volkov O, Bergan J, et al. Hyperbaric oxygen therapy can improve post concussion syndrome years after mild traumatic brain injury-randomized prospective trial. Ai J, editor. PLoS One.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

the therapeutic effects and mechanism of progesterone in the treatment for acute severe head injury. Zhonghua Wai

[49] Mammis A, McIntosh TK, Maniker AH. Erythropoietin as a neuroprotective agent in traumatic brain injury. Surgical

improves survival after severe traumatic brain injury: A matched case control study. Annals of Surgery. 2010;251(1):

[51] Aloizos S, Evodia E, Gourgiotis S, Isaia E, Seretis C, Baltopoulos G. Neuroprotective effects of

erythropoietin in patients with severe

Neurosurgery. 2015. [Internet]. [cited 2015 Dec 26]; Available from: http:// www.turkishneurosurgery.org.tr/ summary\_en\_doi.php3?doi=10.5137/

[52] Natale JE, Guerguerian A-M, Joseph JG, McCarter R, Shao C, Slomine B, et al. Pilot study to determine the hemodynamic safety and feasibility of magnesium sulfate infusion in children with severe traumatic brain injury. Pediatric Critical Care Medicine. 2007;

[53] Chen C-C, Wei S-T, Tsaia S-C, Chen X-X, Cho D-Y. Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: Double-blind, placebo-controlled, randomized study. British Journal of Neurosurgery. 2013;

[54] Poon W, Vos P, Muresanu D, Vester

J, von Wild K, Hömberg V, et al. Cerebrolysin Asian Pacific trial in acute brain injury and neurorecovery: Design and methods. Journal of Neurotrauma.

closed brain injury. Turkish

1019-5149.JTN.9685-14.4

Ke Za Zhi. 2007;45(2):106-108

Neurology. 2009;71(5):527-531

[50] Talving P, Lustenberger T, Kobayashi L, Inaba K, Barmparas G, Schnüriger B, et al. Erythropoiesis stimulating agent administration

1-4

8(1):1-9

27(6):803-807

2015;32(8):571-580

[43] Rockswold SB, Gaylan L, Rockswold

[44] Shakeri M, Boustani MR, Pak N, Panahi F, Salehpour F, Lotfinia I, et al. Effect of progesterone administration on prognosis of patients with diffuse axonal injury due to severe head trauma. Clinical Neurology and Neurosurgery.

DA, Jiannong L. A prospective, randomized phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. Journal of Neurosurgery. 2013;

2013;8(11):e79995

118(6):1317-1328

2013;115(10):2019-2022

391-402.e2

120

[45] Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: A

randomized clinical trial of progesterone for acute traumatic brain injury. Annals of Emergency Medicine. 2007;49(4):

[46] Xiao G, Wei J, Yan W, Wang W, Lu Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: A randomized controlled trial. Critical Care. 2008;12(2):R61

[47] Wright DW, Ritchie JC, Mullins RE, Kellermann AL, Denson DD. Steadystate serum concentrations of progesterone following continuous intravenous infusion in patients with acute moderate to severe traumatic brain injury. Journal of Clinical Pharmacology. 2005;45(6):640-648

[48] Xiao G, Wei J, Wu Z, Wang W, Jiang Q, Cheng J, et al. Clinical study on [56] Maldonado V, Perez J, Escario J. Effects of CDP-choline on the recovery of patients with head injury. Journal of the Neurological Sciences. 1991;103: 15-18

[57] Shokouhi G, Ghorbani Haghjoo A, Sattarnezhad N, Asghari M, Sattarnezhad A, Asghari A, et al. Effects of citicoline on level of consciousness, serum level of fetuin-A and matrix Glaprotein (MGP) in trauma patients with diffuse axonal injury (DAI) and GCS ≤ 8. Turkish Journal of Trauma and Emergency. 2014;20(6):410-416

[58] Zafonte RD, Bagiella E, Ansel B, Novack TA, Friedewald WT, Hesdorffer DC, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline brain injury treatment trial (COBRIT). Journal of the American Medical Association. 2012;308(19): 1993-2000

[59] Brophy GM, Mazzeo AT, Brar S, Alves OL, Bunnell K, Gilman C, et al. Exposure of Cyclosporin A in whole blood, cerebral spinal fluid, and brain extracellular fluid dialysate in adults with traumatic brain injury. Journal of Neurotrauma. 2013;30(17):1484-1489

[60] Empey PE, McNamara PJ, Young B, Rosbolt MB, Hatton J. Cyclosporin A disposition following acute traumatic brain injury. Journal of Neurotrauma. 2006;23(1):109-116

[61] Hatton J, Rosbolt B, Empey P, Kryscio R, Young B. Dosing and safety of cyclosporine in patients with severe brain injury: Clinical article. Journal of Neurosurgery. 2008;109(4):699-707

[62] Tenovuo O. Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury—Clinical experience in 111 patients. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2005;29(1):61-67

[63] Xu G-Z, Wang M-D, Liu K-G, Bai Y-A, Wu W, Li W. A meta-analysis of treating acute traumatic brain injury with calcium channel blockers. Brain Research Bulletin. 2013; 99:41-47

[64] Cheng G, Fu L, Zhang H, Wang Y, Zhang L, Zhang J. The role of mitochondrial calcium uniporter in neuroprotection in traumatic brain injury. Medical Hypotheses. 2013;80(2): 115-117

[65] Hart T, Benn EKT, Bagiella E, Arenth P, Dikmen S, Hesdorffer DC, et al. Early trajectory of psychiatric symptoms after traumatic brain injury: Relationship to patient and injury characteristics. Journal of Neurotrauma. 2014;31(7):610-617

[66] Neumann D, Babbage DR, Zupan B, Willer B. A randomized controlled trial of emotion recognition training after traumatic brain injury. The Journal of Head Trauma Rehabilitation. 2015; 30(3):E12-E23

[67] Li J, Jiang J. Chinese head trauma data bank: Effect of hyperthermia on the outcome of acute head trauma patients. Journal of Neurotrauma. 2012;29(1): 96-100

[68] Galvin IM, Levy R, Boyd JG, Day AG, Wallace MC. Cooling for cerebral protection during brain surgery. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2015. [cited 2015 Dec 26]. Available from: http://doi. wiley.com/10.1002/14651858. CD006638.pub3

[69] Maleki M, Ghaderi M, Ashktorab T, Jabbari-Noghabi H, Zadehmohammadi A. Effect of light music on physiological parameters of patients with traumatic brain injuries at intensive care unit. Ofogh-E-Danesh. 2011;18(1):66-75

[70] Nott M, Baguley I, Heriseanu R, Weber G, Middleton J, Meares S, et al. Effects of concomitant spinal cord injury and brain injury on medical and functional outcomes and community participation. Topics in Spinal Cord Injury Rehabilitation. 2014;20(3): 225-235

[71] Stein DG, Cekic MM. Progesterone and vitamin D hormone as a biologic treatment of traumatic brain injury in the aged. PM & R Journal. 2011;3(6): S100-S110

[72] Godbolt AK, Stenberg M, Jakobsson J, Sorjonen K, Krakau K, Stålnacke B-M, et al. Subacute complications during recovery from severe traumatic brain injury: Frequency and associations with outcome. BMJ Open. 2015;5(4):e007208

[73] Cinotti R, Ichai C, Orban J, Kalfon P, Feuillet F, Roquilly A, et al. Effects of tight computerized glucose control on neurological outcome in severely brain injured patients a multicenter sub-group analysis of the randomized-controlled open-label CGAO-REA study. Critical Care (London, England). 2014;18(5): 498

[74] Rhind SG, Crnko NT, Baker AJ, Morrison LJ, Shek PN, Scarpelini S, et al. Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and endothelial activation marker profiles in severe traumatic brain injured patients. Journal of Neuroinflammation. 2010; 7(5):1-17

[75] Menon DK. Unique challenges in clinical trials in traumatic brain injury. Critical Care Medicine. 2009;37 (Supplement):S129-S135

**123**

**Chapter 6**

**Abstract**

of this cooling machine.

**1. Introduction**

updated from time to time [1, 2].

Direct Brain Cooling in Treating

Severe Traumatic Head Injury

*Zamzuri Idris, Ang Song Yee, Regunath Kandasamy,* 

*Asrulnizam Abd Manaf, Mohd Hasyizan Bin Hassan* 

**Keywords:** hypothermia, trauma, brain oxygenation, brain temperature,

intracranial pressure, severe head injury, focal brain cooling

There are scientific evidences that hypothermia provides a strong neuroprotective effect on the brain following traumatic insults. In this chapter, we describe the pathophysiology of severe head injury with emphasis on benefits of hypothermia. To support these hypothetical or theoretical benefits, we describe our previous study with very encouraging findings done on severe head injuries, treated with direct focal brain cooling, and monitored with intracranial pressure, cerebral perfusion pressure, brain oxygenation, and brain temperature. This chapter ends with our current and still ongoing study in which one of its main objectives is to innovate a direct focal brain cooling machine. This chapter briefly explains the technical part

Severe traumatic brain injury (TBI) is one of the causes contributed to the major source of death and severe disability worldwide. In some countries, the increasing number of severe traumatic brain injury is alarming, bringing negative impact not just toward the individual itself, but also the society. Patients suffering from severe traumatic brain injury usually will end up with disability, as they most often are associated with extensive irreversible damages to the brain. This makes the management of severe TBI to be challenging and very often associate with disappointing outcomes. Thus, severe TBI has become a common issue or interest that requires appropriate attention from various levels in order to reduce the damage impacts often associated with it. Many clinical trials and researches were conducted to improve our understanding and knowledge, with various treatment protocols being

During the trauma impact itself, there will be energy transfer to the brain tissue causing direct neuronal damages, causing irreversible damages to the neuronal structures, and affecting the neurophysiological function of the central nervous system. From the initial impact, primary injuries occur due to the direct impact and the damage that are usually irreversible. Secondary injuries will be subsequently triggered by hypoxic-ischemic event, inflammatory cytokines, and free radicals,

*and Wan Nazaruddin Wan Hassan*

#### **Chapter 6**

[69] Maleki M, Ghaderi M, Ashktorab T, Jabbari-Noghabi H, Zadehmohammadi A. Effect of light music on physiological parameters of patients with traumatic brain injuries at intensive care unit. Ofogh-E-Danesh. 2011;18(1):66-75

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

[70] Nott M, Baguley I, Heriseanu R, Weber G, Middleton J, Meares S, et al. Effects of concomitant spinal cord injury and brain injury on medical and functional outcomes and community participation. Topics in Spinal Cord Injury Rehabilitation. 2014;20(3):

[71] Stein DG, Cekic MM. Progesterone and vitamin D hormone as a biologic treatment of traumatic brain injury in the aged. PM & R Journal. 2011;3(6):

[72] Godbolt AK, Stenberg M, Jakobsson J, Sorjonen K, Krakau K, Stålnacke B-M, et al. Subacute complications during recovery from severe traumatic brain injury: Frequency and associations with outcome. BMJ Open. 2015;5(4):e007208

[73] Cinotti R, Ichai C, Orban J, Kalfon P, Feuillet F, Roquilly A, et al. Effects of tight computerized glucose control on neurological outcome in severely brain injured patients a multicenter sub-group analysis of the randomized-controlled open-label CGAO-REA study. Critical Care (London, England). 2014;18(5):

[74] Rhind SG, Crnko NT, Baker AJ, Morrison LJ, Shek PN, Scarpelini S, et al.

endothelial activation marker profiles in severe traumatic brain injured patients. Journal of Neuroinflammation. 2010;

[75] Menon DK. Unique challenges in clinical trials in traumatic brain injury. Critical Care Medicine. 2009;37 (Supplement):S129-S135

Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and

225-235

S100-S110

498

7(5):1-17

122

## Direct Brain Cooling in Treating Severe Traumatic Head Injury

*Zamzuri Idris, Ang Song Yee, Regunath Kandasamy, Asrulnizam Abd Manaf, Mohd Hasyizan Bin Hassan and Wan Nazaruddin Wan Hassan*

#### **Abstract**

There are scientific evidences that hypothermia provides a strong neuroprotective effect on the brain following traumatic insults. In this chapter, we describe the pathophysiology of severe head injury with emphasis on benefits of hypothermia. To support these hypothetical or theoretical benefits, we describe our previous study with very encouraging findings done on severe head injuries, treated with direct focal brain cooling, and monitored with intracranial pressure, cerebral perfusion pressure, brain oxygenation, and brain temperature. This chapter ends with our current and still ongoing study in which one of its main objectives is to innovate a direct focal brain cooling machine. This chapter briefly explains the technical part of this cooling machine.

**Keywords:** hypothermia, trauma, brain oxygenation, brain temperature, intracranial pressure, severe head injury, focal brain cooling

#### **1. Introduction**

Severe traumatic brain injury (TBI) is one of the causes contributed to the major source of death and severe disability worldwide. In some countries, the increasing number of severe traumatic brain injury is alarming, bringing negative impact not just toward the individual itself, but also the society. Patients suffering from severe traumatic brain injury usually will end up with disability, as they most often are associated with extensive irreversible damages to the brain. This makes the management of severe TBI to be challenging and very often associate with disappointing outcomes. Thus, severe TBI has become a common issue or interest that requires appropriate attention from various levels in order to reduce the damage impacts often associated with it. Many clinical trials and researches were conducted to improve our understanding and knowledge, with various treatment protocols being updated from time to time [1, 2].

During the trauma impact itself, there will be energy transfer to the brain tissue causing direct neuronal damages, causing irreversible damages to the neuronal structures, and affecting the neurophysiological function of the central nervous system. From the initial impact, primary injuries occur due to the direct impact and the damage that are usually irreversible. Secondary injuries will be subsequently triggered by hypoxic-ischemic event, inflammatory cytokines, and free radicals,

which are released by the injured neuronal cells. Secondary injuries play an important role in determining posttraumatic recovery [3–5]. Secondary injuries will lead to breakdown of the cerebral blood brain barrier, leading to worsening cerebral edema and thus forming a vicious cycle toward further neuronal damages.

The management of severe TBI is aiming for restoration and maintenance of adequate brain perfusion to prevent hypoxia, surgical intervention for significant size of hematoma or edema, and prevention or prompt treatment of cerebral edema and raised intracranial pressure (ICP). However, clinical studies and analysis had proven that ICP and cerebral perfusion pressure (CPP) guided treatment alone, does not necessarily prevent hypoxic-ischemic damage to the brain [6]. Despite knowing that ICP remains the most important determinant factors of mortality outcome in severe head injury patients, brain hypoxia (defined as PbtiO2 < 10 mmHg and for more than 15 minutes) is actually more important in determining the morbidity and patient functional outcome [7].

Many new strategies and alternative protocols are introduced to improve the management and outcome of severe TBI patients. Throughout the years, the definition of adequate cerebral resuscitation including the targeted ICP and CPP values are often debatable. Other treatment strategy such as PbtiO2, plus ICP and CPP guided therapy showed promising result, with reduced hypoxic-ischemic damages to the brain and better patient functional outcome recovery.

Controlled systemic hypothermia treatment in managing severe head injury patient, is associated with neuroprotective effect to the injured brain tissue. Hypothermia significantly reduce metabolic rate and energy expenditure, attenuate excitatory amino acids and the synthesis of free radicals, suppresses excessive ischemia-induced and posttraumatic inflammatory reactions, and prevent bloodbrain barrier disruption and brain edema. Furthermore, hyperthermia in head injury increases postischemic injury and is a significant predictor of poor outcome. Induced and controlled systemic hypothermia is used in patient with stroke, perinatal asphyxia, hypoxic encephalopathy following cardiovascular arrest with improved recovery, and functional outcome documented [8–11]. However, the pitfall of the treatment is that it is associated with alteration of the body core temperature and hence induced alteration in the systemic function and affecting the whole body hemostasis. Few possible adverse systemic complications that are associated with induced systemic hypothermia treatment include increase risk of infection and sepsis, pneumonia, poor wound healing and breakdown, cardiac arrhythmias, coagulopathy and electrolytes imbalances such as hypoglycemia and hypokalemia [12–18]. These systemic complications may outweigh the beneficial effect of the hypothermia treatment. Thus, treatment with induced and controlled systemic cooling therapy in head injury patient has become an interesting but controversial subject. Given so much controversy in inducing hypothermia for the injured brain, we sought to design a prospective, randomized pilot study to assess efficacy of new method in brain cooling called "direct regional or focal brain hypothermia." In this chapter, we present our experience with direct focal or regional brain cooling, obtained via direct irrigation of cold fluid onto the surface of severely injured brain of trauma patients who required decompressive craniectomy with Glasgow Coma Score (GCS) of 6–7, and the chapter ends with our current and still ongoing study in which, one of its main objectives is to innovate a direct focal brain cooling machine.

#### **2. Role of hypothermia in head injury patient**

There have been multiple mechanisms suggesting benefit of hypothermia in head injury patient. However, there is likely that no single factor can be used to explain

**125**

**Figure 1.**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

the neuroprotective effect of hypothermia. Understanding the combination of the factors may help us understand better the effect of hypothermia [3]. The proposed mechanisms are summarized below [12, 19, 20] and depicted as in **Figure 1**.

c.It decreases the metabolism as well as decreases the overload of excitatory neu-

e.It suppresses the inflammatory and immunological responses and epileptic

f.It reduces the disruption in blood brain barrier (BBB), vascular permeability,

g.It improves the microcirculatory circuits and intra- and extracellular acidosis.

i.It enhances expression of immediate early genes and cold shock proteins.

*Effect of hypothermia on pathophysiology of brain injury. Therapeutic hypothermia works by reducing the* 

*detrimental consequence of secondary brain injury (black stars).*

j.Hypothermia may also influence neurogenesis, gliogenesis, and angiogenesis.

h.It corrects the hyperthermia after brain injury and influences the local secretion

a.Hypothermia can inhibit the activation of caspase enzymes.

rotransmitters such as glutamate and free oxygen radicals.

d.It modifies the cellular disorders of intracellular ion concentrations.

of various vasoactive mediators secreted by the endothelium.

b.It prevents or mitigates mitochondrial dysfunction.

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

activity.

and edema.

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

morbidity and patient functional outcome [7].

to the brain and better patient functional outcome recovery.

**2. Role of hypothermia in head injury patient**

There have been multiple mechanisms suggesting benefit of hypothermia in head injury patient. However, there is likely that no single factor can be used to explain

which are released by the injured neuronal cells. Secondary injuries play an important role in determining posttraumatic recovery [3–5]. Secondary injuries will lead to breakdown of the cerebral blood brain barrier, leading to worsening cerebral edema and thus forming a vicious cycle toward further neuronal damages.

The management of severe TBI is aiming for restoration and maintenance of adequate brain perfusion to prevent hypoxia, surgical intervention for significant size of hematoma or edema, and prevention or prompt treatment of cerebral edema and raised intracranial pressure (ICP). However, clinical studies and analysis had proven that ICP and cerebral perfusion pressure (CPP) guided treatment alone, does not necessarily prevent hypoxic-ischemic damage to the brain [6]. Despite knowing that ICP remains the most important determinant factors of mortality outcome in severe head injury patients, brain hypoxia (defined as PbtiO2 < 10 mmHg and for more than 15 minutes) is actually more important in determining the

Many new strategies and alternative protocols are introduced to improve the management and outcome of severe TBI patients. Throughout the years, the definition of adequate cerebral resuscitation including the targeted ICP and CPP values are often debatable. Other treatment strategy such as PbtiO2, plus ICP and CPP guided therapy showed promising result, with reduced hypoxic-ischemic damages

Controlled systemic hypothermia treatment in managing severe head injury patient, is associated with neuroprotective effect to the injured brain tissue. Hypothermia significantly reduce metabolic rate and energy expenditure, attenuate excitatory amino acids and the synthesis of free radicals, suppresses excessive ischemia-induced and posttraumatic inflammatory reactions, and prevent bloodbrain barrier disruption and brain edema. Furthermore, hyperthermia in head injury increases postischemic injury and is a significant predictor of poor outcome. Induced and controlled systemic hypothermia is used in patient with stroke, perinatal asphyxia, hypoxic encephalopathy following cardiovascular arrest with improved recovery, and functional outcome documented [8–11]. However, the pitfall of the treatment is that it is associated with alteration of the body core temperature and hence induced alteration in the systemic function and affecting the whole body hemostasis. Few possible adverse systemic complications that are associated with induced systemic hypothermia treatment include increase risk of infection and sepsis, pneumonia, poor wound healing and breakdown, cardiac arrhythmias, coagulopathy and electrolytes imbalances such as hypoglycemia and hypokalemia [12–18]. These systemic complications may outweigh the beneficial effect of the hypothermia treatment. Thus, treatment with induced and controlled systemic cooling therapy in head injury patient has become an interesting but controversial subject. Given so much controversy in inducing hypothermia for the injured brain, we sought to design a prospective, randomized pilot study to assess efficacy of new method in brain cooling called "direct regional or focal brain hypothermia." In this chapter, we present our experience with direct focal or regional brain cooling, obtained via direct irrigation of cold fluid onto the surface of severely injured brain of trauma patients who required decompressive craniectomy with Glasgow Coma Score (GCS) of 6–7, and the chapter ends with our current and still ongoing study in which, one of its main objectives is to innovate a direct focal brain cooling machine.

**124**

the neuroprotective effect of hypothermia. Understanding the combination of the factors may help us understand better the effect of hypothermia [3]. The proposed mechanisms are summarized below [12, 19, 20] and depicted as in **Figure 1**.


#### **Figure 1.**

*Effect of hypothermia on pathophysiology of brain injury. Therapeutic hypothermia works by reducing the detrimental consequence of secondary brain injury (black stars).*

#### **3. Current evidences on the usage of direct brain cooling in treating severe head injury: animal studies**

There are previously multiple papers that suggested targeted brain cooling as a reasonable treatment option to patient with severe traumatic brain injury [21–33]. Targeted brain cooling is a good alternative to systemic hypothermia, as systemic hypothermia has serious side effects such as circulatory constrain, increased risk of infection, electrolyte imbalance, and coagulopathy [15–18].

Jacek et al. [33] suggested in their animal study that selective brain hypothermia, which is applied via a cranial window after decompressive craniectomy seems to be reducing posttraumatic structural and functional damage. However, the study is actually limited by small rodent model and also short observational period. It is suggested that thermodynamic of brain of human rodent may differ as the size is significantly different. It may affect the penetration of the cooling effect in human brain, hence limiting the cooling effect to the superficial areas only.

#### **4. Current evidences on the usage of direct brain cooling in treating severe head injury: our clinical study**

Here, we describe our pilot study on direct focal hypothermia therapy in treating severe head injury with positive and very encouraging results that enable us to proceed with another innovative study to create a direct hypothermia machine, which will be used in our ongoing study.

#### **4.1 Methodology**

This is a randomized controlled trial study, which is designed to answer the research questions regarding the effect of direct focal brain cooling treatment in severe head injury patients. The study has been approved by the research and ethics committee and is sponsored by the Research University Grant. Patients were randomized into two treatment groups of A and B. Group B is the control group.

Group A (treatment group) consists of patients, who have therapy with direct focal brain cooling. All patients have intracranial pressure monitoring, Licox (focal brain oxygenation and temperature) probes inserted, and blood for immunological parameters. The immunological blood parameters are however taken only prior and after local cooling therapy to the brain. The overall monitoring and therapy period was for 48 hours.

The neurosurgical operations are standard operations, decompressive craniectomy covering frontal, parietal and temporal lobes; intracranial pressure probe insertion into the ventricle or parenchyma of the brain, and Licox probe into abnormal brain areas. The monitorings and therapies given after the surgery are the standard therapy for severe head injury patient (**Figure 2**). They include sedation with or without muscle paralysis agents, ventilator support, hypertonic saline or mannitol, draining of cerebrospinal fluid (CSF) for the persistent raise in intracranial pressure (ICP) of more than 20 mmHg and thiopentone coma therapy as a final step to treat persistently raised ICP.

Direct focal brain cooling method done through persistently irrigating the brain with cold Hartmann's solution in which the temperature of the infused fluid is divided into two subgroups as follow:

**127**

**Table 1.**

Gender (number):

Patients with disseminated intravascular coagulopathy (DIVC)

*Basic parameters comparison among three studied groups.*

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

The Hartmann's solution was infused via Neurojaf external ventricular drainage (EVD) catheter, which was inserted superior to the dura flap and at the inner surface of the dura, acting like rains flushing through the surface of the swollen brain (multiple extra holes are made). The catheter is in contact with the surface of the brain. The infusion rate is 70 mls/hr. Due to the position of the head, the second draining tube will be inserted at the lower part of the craniectomy flap outside the dura (which is closed loosely) to drain the excess fluid with low suction pressure. The temperature of the infused Hartmann's solution is checked via the three-way connector draining the fluid out to the collection port for temperature assessment. If temperature reading is under or above the intended value, new solution with

*Direct brain cooling monitoring and therapy. (A) intraoperative bifrontal decompressive craniectomy with insertion of Licox and ICP probes; (B) inset image: Post-op CT scan; (C) neurointensive care management and monitorings with Licox, cardiac parameters, ICP, bispectral index (BIS) and electroencephalography (EEG).*

All patients will have CT scan done if the ICP shows persistently raised values despite of standard therapies given. This is important to exclude any new surgical lesion and to exclude the retention of infused solution as a cause of raised ICP. If

Total patients 13 10 9 32

2. Female 3 2 0 0.40 GCS (median) 6 7 7 0.38

Marshall Score (median) 4 4 3 0.33

Variables No cooling Mild cooling Deep

1. Male 10 8 9

**No cooling Mild** 

**cooling**

[17.3–40.5]

[18.5–29.5]

3 2 4 0.44

**Deep cooling**

cooling

26.7 [11.9–41.4]

28.7 [21.3–36.0] **Total**

P value

0.02

0.56

correct intended temperature will replace the previous one.

Age (mean in years) [95% CI] 45.5 [35.0–56.1] 28.9

Injury Severity Score (mean) [95% CI] 27.8 [21.2–34.5] 24.0

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

**Figure 2.**


#### **Figure 2.**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

infection, electrolyte imbalance, and coagulopathy [15–18].

brain, hence limiting the cooling effect to the superficial areas only.

**4. Current evidences on the usage of direct brain cooling in treating** 

Here, we describe our pilot study on direct focal hypothermia therapy in treating severe head injury with positive and very encouraging results that enable us to proceed with another innovative study to create a direct hypothermia machine,

This is a randomized controlled trial study, which is designed to answer the research questions regarding the effect of direct focal brain cooling treatment in severe head injury patients. The study has been approved by the research and ethics committee and is sponsored by the Research University Grant. Patients were randomized into two treatment groups of A and B. Group B is the control group. Group A (treatment group) consists of patients, who have therapy with direct focal brain cooling. All patients have intracranial pressure monitoring, Licox (focal brain oxygenation and temperature) probes inserted, and blood for immunological parameters. The immunological blood parameters are however taken only prior and after local cooling therapy to the brain. The overall monitoring and therapy period was for 48 hours. The neurosurgical operations are standard operations, decompressive craniectomy covering frontal, parietal and temporal lobes; intracranial pressure probe insertion into the ventricle or parenchyma of the brain, and Licox probe into abnormal brain areas. The monitorings and therapies given after the surgery are the standard therapy for severe head injury patient (**Figure 2**). They include sedation with or without muscle paralysis agents, ventilator support, hypertonic saline or mannitol, draining of cerebrospinal fluid (CSF) for the persistent raise in intracranial pressure (ICP) of more than 20 mmHg and thiopentone coma therapy as a final

Direct focal brain cooling method done through persistently irrigating the brain

with cold Hartmann's solution in which the temperature of the infused fluid is

**severe head injury: animal studies**

**severe head injury: our clinical study**

which will be used in our ongoing study.

step to treat persistently raised ICP.

divided into two subgroups as follow:

1.Deep cooling: temperature of 20–29°C.

2.Mild cooling: temperature of 30–36°C.

**4.1 Methodology**

**3. Current evidences on the usage of direct brain cooling in treating** 

There are previously multiple papers that suggested targeted brain cooling as a reasonable treatment option to patient with severe traumatic brain injury [21–33]. Targeted brain cooling is a good alternative to systemic hypothermia, as systemic hypothermia has serious side effects such as circulatory constrain, increased risk of

Jacek et al. [33] suggested in their animal study that selective brain hypothermia, which is applied via a cranial window after decompressive craniectomy seems to be reducing posttraumatic structural and functional damage. However, the study is actually limited by small rodent model and also short observational period. It is suggested that thermodynamic of brain of human rodent may differ as the size is significantly different. It may affect the penetration of the cooling effect in human

**126**

*Direct brain cooling monitoring and therapy. (A) intraoperative bifrontal decompressive craniectomy with insertion of Licox and ICP probes; (B) inset image: Post-op CT scan; (C) neurointensive care management and monitorings with Licox, cardiac parameters, ICP, bispectral index (BIS) and electroencephalography (EEG).*

The Hartmann's solution was infused via Neurojaf external ventricular drainage (EVD) catheter, which was inserted superior to the dura flap and at the inner surface of the dura, acting like rains flushing through the surface of the swollen brain (multiple extra holes are made). The catheter is in contact with the surface of the brain. The infusion rate is 70 mls/hr. Due to the position of the head, the second draining tube will be inserted at the lower part of the craniectomy flap outside the dura (which is closed loosely) to drain the excess fluid with low suction pressure. The temperature of the infused Hartmann's solution is checked via the three-way connector draining the fluid out to the collection port for temperature assessment. If temperature reading is under or above the intended value, new solution with correct intended temperature will replace the previous one.

All patients will have CT scan done if the ICP shows persistently raised values despite of standard therapies given. This is important to exclude any new surgical lesion and to exclude the retention of infused solution as a cause of raised ICP. If


#### **Table 1.**

*Basic parameters comparison among three studied groups.*

the ICPs show normal values, the CT scan of the brain is done after 48 hours of therapy prior to removal of the EVD tube to document the location of the EVD tip. The measured outcomes are: (a) trend and values for monitored parameters (ICPs, CPPs, brain temperature and focal brain oxygenation), (b) Glasgow Outcome Score (GOS – good and poor GOS), and (c) immunological parameters.

#### **4.2 Results**

#### *4.2.1 Social demographic data of patients included in the study*

There were 32 patients recruited in this study with 27 male patients and 5 female patients. The median age of patients recruited were 45.5 in no cooling group, whereas 28.9 and 26.7, respectively, for mild cooling and deep cooling groups. Median GCS for the patients recruited were 6–7. The highest injury severity score recruited was 36, whereas the lowest was 18.5. The median Marshall score for patient recruited were 3–4. Patients with disseminated intravascular coagulopathy for no cooling, mild cooling, and deep cooling were 3, 2, and 4 patients, respectively. The demographic data is shown in **Table 1**.

#### *4.2.2 Effects of direct focal brain cooling on median ICP, CPP, brain oxygenation, and temperature*

The trend of the ICPs, CPPs, brain temperature, and focal brain oxygenation for all studied groups are shown in **Figure 3A–D**. During 48 hours of observation and monitoring, there is no significant statistical difference in overall 4 hourly mean ICPs, CPPs, and brain temperature amongst the no cooling, mild cooling, and deep cooling groups; but there is significant statistical difference in overall 4 hourly mean focal brain oxygenation according to repeated measure ANOVA (between groups analysis based on time) (depicted in **Tables 2** and **3**).

#### **Figure 3.**

*(A) Trend of ICPs in the first 48 hours after the treatment. (B) Trend of brain temperature observation for the first 48 hours after treatment. (C) Trend of CPPs in the first 48 hours after the treatment. (D) Trend of brain oxygen observation for the first 48 hours after treatment.*

**129**

**Table 2.**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

**Table 2** shows day 1 of monitoring and treatment, mean brain oxygenation of mild cooling group has mostly fallen outside the 95% CI (confidence interval) of deep cooling group. Therefore, there is significant difference in mean brain oxygen between mild cooling and deep cooling; with mild cooling having significantly higher mean brain oxygen values. On day 2 of monitoring and treatment, mean brain oxygenation of no cooling group has mostly also fallen outside the 95% CI of mild cooling group. Therefore, there is significant difference in mean brain oxygen between no cooling and mild cooling. Likewise to day one findings, there is also a significant difference on day 2 in mean brain oxygen between mild cooling and deep cooling. Interestingly, in all group comparisons, mild brain cooling group has significantly higher mean brain oxygenation values as compared to either deep or

*4.2.3 Effect of regional brain cooling on GOS at discharge and at 6 months*

There is no significant difference in GOS at time of discharge for both studied groups (no cooling vs. cooling groups). However, there is significant difference on good GOS in cooling group compared to no cooling group at 6 months follow-up (as shown in **Table 4** with p < 0.007). On stratifying the cooling group further into deep and mild cooling, it shows that there is significant difference in term of GOS score at 6 months with significant better outcomes noted in mild cooling as compared to no cooling group with p < 0.013. The deep cooling group at 6 months outcome, failed to have significant difference value when compared with either no or mild cooling groups. For this reason, direct and mild brain hypothermia

**Time (Day 1) Treatment group Mean brain oxygen 95% confidence interval (CI)**

Mild cooling 28.27 15.54–41.01 Deep cooling 13.82 1.91–25.73

**Mild cooling** 31.17 *20.35–41.99* Deep cooling 14.43 4.31–24.55

**Mild cooling** 31.39 *20.45–42.32* Deep cooling 15.33 5.10–25.56

**Mild cooling** 31.14 *21.64–40.65* Deep cooling 16.89 8.00–25.78

**Mild cooling** 36.93 *25.38–48.47* Deep cooling 20.36 9.56–31.16

**Mild cooling** 39.11 *26.67–51.56* Deep cooling 22.51 10.86–34.15

0 hour No cooling 18.94 8.29–29.60

4 hour No cooling 20.78 11.72–29.83

8 hour No cooling 21.55 12.40–30.70

12 hour No cooling 23.27 15.31–31.22

16 hours No cooling 25.96 16.30–35.62

20 hours No cooling 26.64 16.22–37.05

*Comparison of mean brain oxygen between three treatment groups based on 4 hourly observations (day 1).*

*Statistical analysis: Repeated Measure ANOVA (between groups analysis based on time).*

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

no cooling group (depicted in **Table 3**).

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

**4.2 Results**

the ICPs show normal values, the CT scan of the brain is done after 48 hours of therapy prior to removal of the EVD tube to document the location of the EVD tip. The measured outcomes are: (a) trend and values for monitored parameters (ICPs, CPPs, brain temperature and focal brain oxygenation), (b) Glasgow Outcome Score

There were 32 patients recruited in this study with 27 male patients and 5 female

patients. The median age of patients recruited were 45.5 in no cooling group, whereas 28.9 and 26.7, respectively, for mild cooling and deep cooling groups. Median GCS for the patients recruited were 6–7. The highest injury severity score recruited was 36, whereas the lowest was 18.5. The median Marshall score for patient recruited were 3–4. Patients with disseminated intravascular coagulopathy for no cooling, mild cooling, and deep cooling were 3, 2, and 4 patients, respec-

*4.2.2 Effects of direct focal brain cooling on median ICP, CPP, brain oxygenation,* 

The trend of the ICPs, CPPs, brain temperature, and focal brain oxygenation for all studied groups are shown in **Figure 3A–D**. During 48 hours of observation and monitoring, there is no significant statistical difference in overall 4 hourly mean ICPs, CPPs, and brain temperature amongst the no cooling, mild cooling, and deep cooling groups; but there is significant statistical difference in overall 4 hourly mean focal brain oxygenation according to repeated measure ANOVA (between

*(A) Trend of ICPs in the first 48 hours after the treatment. (B) Trend of brain temperature observation for the first 48 hours after treatment. (C) Trend of CPPs in the first 48 hours after the treatment. (D) Trend of brain* 

(GOS – good and poor GOS), and (c) immunological parameters.

*4.2.1 Social demographic data of patients included in the study*

groups analysis based on time) (depicted in **Tables 2** and **3**).

tively. The demographic data is shown in **Table 1**.

*and temperature*

**128**

**Figure 3.**

*oxygen observation for the first 48 hours after treatment.*

**Table 2** shows day 1 of monitoring and treatment, mean brain oxygenation of mild cooling group has mostly fallen outside the 95% CI (confidence interval) of deep cooling group. Therefore, there is significant difference in mean brain oxygen between mild cooling and deep cooling; with mild cooling having significantly higher mean brain oxygen values. On day 2 of monitoring and treatment, mean brain oxygenation of no cooling group has mostly also fallen outside the 95% CI of mild cooling group. Therefore, there is significant difference in mean brain oxygen between no cooling and mild cooling. Likewise to day one findings, there is also a significant difference on day 2 in mean brain oxygen between mild cooling and deep cooling. Interestingly, in all group comparisons, mild brain cooling group has significantly higher mean brain oxygenation values as compared to either deep or no cooling group (depicted in **Table 3**).

#### *4.2.3 Effect of regional brain cooling on GOS at discharge and at 6 months*

There is no significant difference in GOS at time of discharge for both studied groups (no cooling vs. cooling groups). However, there is significant difference on good GOS in cooling group compared to no cooling group at 6 months follow-up (as shown in **Table 4** with p < 0.007). On stratifying the cooling group further into deep and mild cooling, it shows that there is significant difference in term of GOS score at 6 months with significant better outcomes noted in mild cooling as compared to no cooling group with p < 0.013. The deep cooling group at 6 months outcome, failed to have significant difference value when compared with either no or mild cooling groups. For this reason, direct and mild brain hypothermia


#### **Table 2.**

*Comparison of mean brain oxygen between three treatment groups based on 4 hourly observations (day 1).*


*Statistical analysis: Repeated Measure ANOVA (between groups analysis based on time).*

#### **Table 3.**

*Comparison of brain oxygen between three treatment groups based on 4 hourly observations (day 2).*

with coolant temperature of 30–36°C might truly be beneficial to the severely head injured patients. Having said that, obviously future studies are still needed to ascertain this finding with higher number of more homogenous recruited patients.

#### *4.2.4 Effects of regional brain cooling on immunological parameters*

There is no significant difference on immunological parameters upon comparing prior and after cooling therapy. Nonetheless, the postcooling immunological parameters seem to have lower values than the precooling ones (depicted in **Table 5**).

#### **4.3 Discussion**

This was a randomized controlled pilot study involving 32 patients, who were admitted to our hospital with severe head injury with GCS of 6 or 7. The aim was to study the effect of direct focal brain cooling therapy in severe head injury patients.

#### *4.3.1 Effect of direct focal brain cooling on brain oxygen level*

All the treatment groups were able to reach the desired mean brain oxygen level within the treatment period. Notwithstanding, the mean brain oxygen of mild cooling group was significantly higher as compared to the no- and deep cooling groups. It remained significantly higher throughout the treatment periods (24–48 hours) with the level of >50 mmHg. The mean brain oxygen of deep cooling group was the

**131**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

**[13 patients]**

b. Good GOS 1 (7.7%) 4 (21.1%)

b. Good GOS 2 (15.4%) 12 (63.2%)

*Comparing 3 groups No cooling [n (%)] Mild cooling* 

b. Good GOS 2 (15.4%) 7 (70%)

*\*Statistically significant. Statistical analysis: Pearson Chi-squared test.*

a. Poor GOS 12 (92.3%) 15 (78.9%) 0.307

a. Poor GOS 11 (84.6%) 7 (36.8%) **0.007\***

a. Poor GOS 11(84.6%) 3 (30%) 4 (44.4%) 0.023\*

a. Poor GOS 11 (84.6%) 3 (30%) 0.013\*

a. Poor GOS 11 (84.6%) 4 (44.4%) 0.074

a. Poor GOS 3 (30%) 4 (44.4%) 0.650

b. Good GOS 2 (15.4%) 7 (70%) 5 (55.6%)

b. Good GOS 2 (15.4%) 5 (55.6%)

b. Good GOS 7 (70%) 5 (55.6%)

*GOS only at 6 months, after stratifying the cooling group further into mild and deep cooling.*

*[n (%)]*

**Cooling group [19 patients] p** 

*Deep cooling [n (%)]*

**value**

lowest but still did not reach the critical ischemic state (10–15 mmHg). Despite of having the lowest brain oxygen level on day 1, the improvement in brain oxygen level in deep cooling group was accelerated and reached the desirable range after

*Effect of regional brain cooling on GOS at discharge and at 6 months; and effect of regional brain cooling on* 

Patients with severe head injury were at higher risk of developing cerebral ischemia particularly in the first 48 hours. Cerebral ischemia was defined by brain oxygen of <10 mmHg for more than 2 hours [34]. Low mean brain oxygen pressure often associated with poorer clinical outcome, while patients with good GOS often had good or normalized reading within 2 hours after the injury. Brain oxygen level is a good indicator of functional outcome in addition to ICP and CPP. Targeted therapy of ICP < 15 mmHg, CPP > 75 mmHg, and brain oxygen >25 mmHg often associated with good clinical outcomes. The clinical trials comparing the ICP-CPP guided therapy to ICP-CPP-brain oxygen guided therapy showed significant better functional outcome at 6 months and lower mortality rate in the latter group [34, 35]. This showed that ICP-CPP-brain oxygen guided therapy is beneficial in treating

16 hours of treatment (with mean brain oxygen of >20 mmHg).

severe head injury patients as it can improve the patient outcomes.

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

**Outcomes (GOS) No cooling** 

Poor GOS (GOS 1–3) Good GOS (GOS 4–5) Comparing 2 groups GOS at discharge:

GOS at 6 months:

*GOS at 6 months:*

GOS at 6 months:

GOS at 6 months:

GOS at 6 months:

**Table 4.**



#### **Table 4.**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

**Time (Day 2) Treatment group Mean brain oxygen 95% confidence interval (CI)**

Mild cooling 48.73 31.89–65.58 Deep cooling 28.91 14.32–43.49

**Mild cooling** 50.17 *31.50–68.84* Deep cooling 28.13 11.96–44.30

**Mild cooling** 52.27 *34.87–69.66* Deep cooling 34.39 19.33–49.46

**Mild cooling** 52.00 *38.51–65.49* Deep cooling 33.69 22.01–45.38

**Mild cooling** 51.60 *37.41–65.79* Deep cooling 35.17 22.88–47.45

**Mild cooling** 50.57 *35.24–65.90* Deep cooling 36.12 22.84–49.39

0 hour No cooling 28.00 16.98–39.03

4 hours No cooling 29.20 16.98–41.43

8 hours No cooling 28.96 17.57–40.35

12 hours No cooling 27.46 18.63–36.30

16 hours No cooling 30.63 21.34–39.92

20 hours No cooling 30.05 20.01–40.08

with coolant temperature of 30–36°C might truly be beneficial to the severely head injured patients. Having said that, obviously future studies are still needed to ascertain this finding with higher number of more homogenous recruited patients.

*Comparison of brain oxygen between three treatment groups based on 4 hourly observations (day 2).*

There is no significant difference on immunological parameters upon comparing prior and after cooling therapy. Nonetheless, the postcooling immunological parameters seem to have lower values than the precooling ones (depicted in **Table 5**).

This was a randomized controlled pilot study involving 32 patients, who were admitted to our hospital with severe head injury with GCS of 6 or 7. The aim was to study the effect of direct focal brain cooling therapy in severe head injury patients.

All the treatment groups were able to reach the desired mean brain oxygen level within the treatment period. Notwithstanding, the mean brain oxygen of mild cooling group was significantly higher as compared to the no- and deep cooling groups. It remained significantly higher throughout the treatment periods (24–48 hours) with the level of >50 mmHg. The mean brain oxygen of deep cooling group was the

*4.2.4 Effects of regional brain cooling on immunological parameters*

*Statistical analysis: Repeated Measure ANOVA (between groups analysis based on time).*

*4.3.1 Effect of direct focal brain cooling on brain oxygen level*

**130**

**4.3 Discussion**

**Table 3.**

*Effect of regional brain cooling on GOS at discharge and at 6 months; and effect of regional brain cooling on GOS only at 6 months, after stratifying the cooling group further into mild and deep cooling.*

lowest but still did not reach the critical ischemic state (10–15 mmHg). Despite of having the lowest brain oxygen level on day 1, the improvement in brain oxygen level in deep cooling group was accelerated and reached the desirable range after 16 hours of treatment (with mean brain oxygen of >20 mmHg).

Patients with severe head injury were at higher risk of developing cerebral ischemia particularly in the first 48 hours. Cerebral ischemia was defined by brain oxygen of <10 mmHg for more than 2 hours [34]. Low mean brain oxygen pressure often associated with poorer clinical outcome, while patients with good GOS often had good or normalized reading within 2 hours after the injury. Brain oxygen level is a good indicator of functional outcome in addition to ICP and CPP. Targeted therapy of ICP < 15 mmHg, CPP > 75 mmHg, and brain oxygen >25 mmHg often associated with good clinical outcomes. The clinical trials comparing the ICP-CPP guided therapy to ICP-CPP-brain oxygen guided therapy showed significant better functional outcome at 6 months and lower mortality rate in the latter group [34, 35]. This showed that ICP-CPP-brain oxygen guided therapy is beneficial in treating severe head injury patients as it can improve the patient outcomes.


**Table 5.**

*Effect of regional brain cooling (both mild and deep cooling groups combined together) on immunological parameters.*

#### *4.3.2 Effect of direct focal brain cooling on ICP and CPP*

The mean ICP did not show any significant difference amongst the studied groups as shown in the results above. There was also no evidence of refractory intracranial hypertension throughout the treatment period in all three groups, indicating that the focal cooling therapy used in this study was safe and not associated with risk of intracranial hypertension. The results seemed to contradict the effect of hypothermia, which supposed to have better control on ICPs, and hence, leading to better CPPs and mean brain oxygenation. Previous clinical study on the effect of mild systemic hypothermia to the head injury patients clearly had established a significant reduction in ICPs following cooling therapy [36]. The mechanisms of reduction in ICP values were postulated to be due to reduced cerebral edema, following an improvement of:


Reduction in ICP and improvement in CPP did not happen in our pilot study, perhaps, because decompressive craniectomy had been completed prior to direct hypothermia therapy. Hence, intracranial pressure and perfusion pressure effects might not be shown-up in this particular study. Nevertheless, future related study should be carried out with more homogenous patients to confirm this finding.

**133**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

*4.3.3 Effect of direct focal brain cooling on brain temperature*

There was no significant difference in brain temperature in all treatment groups as shown above in trend-results, thus showing that focal cooling did not seem to be effective in reducing focal brain temperature. This study was initially designed to reduce brain temperature; the mechanism of temperature reduction was thought to be achieved through two ways, which were direct cooling effect over the brain surface (via continuous irrigation of the cold Hartmann fluid) as well as through the indirect cooling effect (to the deeper part of the brain) via circulation and pulsation around the brain and cisterns. However, it seemed that the targeted effect was not achieved. This can be due to many factors including poor CSF circulation, and hence affecting the thermoregulation of the brain. It is worth mentioning that there is limitation of Licox probe as well. This device was specifically designed to detect the changes occurred around the area where it was inserted. Hence, it was unable to reflect accurately the whole brain temperature changes following head injury [41]. It was well documented in the literature that an injured brain might have significantly higher temperature compared to the core body temperature; ranging from 0.1°C to more than 2°C. The difference in the temperature gradient may be more significant in an injured brain as a result of destructive hyperactivity of the injured cells [42]. Numerous clinical studies have found that higher brain temperature is associated with adverse outcome and negative correlation with the prognosis of head injury patients. Hyperthermia increases the risk of ischemic area to become necrotic or apoptotic. In animal model, transient increase in core body temperature to 39–40°C led to 2.6-fold increase in the extent of neuronal injury in the hippocampus [43]. Since hyperthermia was an important independent factor of adverse neurological outcome and increase mortality in brain injury [44], accurate brain temperature reading was rather essential. For future reference, focal brain temperature reading with Licox may be combined with adjunct devices such as CT thermography as it can accurately measure the focal and whole brain temperature

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

for better comparison during treatment.

*4.3.4 Effect of direct focal brain cooling on the Glasgow Outcome Score (GOS)*

*4.3.5 Effect of direct focal brain cooling on immune responses*

Patients GOS was the most important factor to determine the outcome of the focal brain cooling treatment in this study. This classification system was specifically designed to help clinicians to determine the patients response following the treatment by assessing their functional status at discharge and at 6 months after the injury; score 1 reflects mortality, score 2 and 3 reflect significant morbidity, while score 4 and 5 reflect ability to function normally or near normal. The outcomes were promising as significant difference was noted, whereby the proportion of patients who received direct focal brain cooling treatment showed better GOS score of 4 and 5 at 6 months follow-up when compared to the no cooling group. However, no significant difference was established in GOS at day of discharge. The outcome of patient in severe head injury is actually multifactorial and could not just be attributed to a single factor. The age, other associated injuries, and hemodynamic instability will all contribute to the outcomes of the patients. The obvious contributing factor in our study is the increment in focal brain oxygenation during cooling therapy and it is markedly obvious in mild cooling group who received cold-fluid of 30–36°C.

In this study, the T-cell markers, pro-inflammatory cytokines, and total white cell count show reduction in values after cooling therapy; nonetheless, no *Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

)

**Pro-inflammatory cytokines (pg/ml)**

**Other immunological parameters**

**Table 5.**

*parameters.*

T-cell markers (cells/mm3

**Precooling (mean ± SD)**

CD 3 776.8 (407.5) 756.3 (339.9) 0.86 CD 4 443.1 (268.5) 429.7 (210.0) 0.64 CD 8 328.1 (183.6) 301.7 (135.7) 0.96 CD 19 284.4 (168.6) 261.5 (126.6) 0.62 CD 16 and 56 172.4 (113.8) 112.7 (80.8) 0.05

Interleukin-1 (IL-1) 45.34 (130.7) 5.7 (13.0) 0.33 Interleukin-6 (IL-6) 278.5 (221.1) 190.0 (208.4) 0.44 Tumor necrosis factor (TNF) 34.5 (37.6) 18.1 (14.2) 0.41

Total WBC 13.6 (5.0) 12.8 (4.0) 0.16

*Effect of regional brain cooling (both mild and deep cooling groups combined together) on immunological* 

**Postcooling (mean ± SD)**

**Wilcoxon signed Ranked test (p value)**

*4.3.2 Effect of direct focal brain cooling on ICP and CPP*

2.vascular permeability of microvascular endothelial cells [38],

1.the blood brain barrier [37],

tion within the brain, and

3. extravasation of hemoglobin [39],

4.membrane disintegration processes,

6.ion homeostasis including calcium [40].

The mean ICP did not show any significant difference amongst the studied groups as shown in the results above. There was also no evidence of refractory intracranial hypertension throughout the treatment period in all three groups, indicating that the focal cooling therapy used in this study was safe and not associated with risk of intracranial hypertension. The results seemed to contradict the effect of hypothermia, which supposed to have better control on ICPs, and hence, leading to better CPPs and mean brain oxygenation. Previous clinical study on the effect of mild systemic hypothermia to the head injury patients clearly had established a significant reduction in ICPs following cooling therapy [36]. The mechanisms of reduction in ICP values were postulated to be due to reduced cerebral edema, following an improvement of:

5. cytotoxic edema via decreased inflammatory reactions and free radical forma-

Reduction in ICP and improvement in CPP did not happen in our pilot study, perhaps, because decompressive craniectomy had been completed prior to direct hypothermia therapy. Hence, intracranial pressure and perfusion pressure effects might not be shown-up in this particular study. Nevertheless, future related study should be carried out with more homogenous patients to confirm this finding.

**132**

#### *4.3.3 Effect of direct focal brain cooling on brain temperature*

There was no significant difference in brain temperature in all treatment groups as shown above in trend-results, thus showing that focal cooling did not seem to be effective in reducing focal brain temperature. This study was initially designed to reduce brain temperature; the mechanism of temperature reduction was thought to be achieved through two ways, which were direct cooling effect over the brain surface (via continuous irrigation of the cold Hartmann fluid) as well as through the indirect cooling effect (to the deeper part of the brain) via circulation and pulsation around the brain and cisterns. However, it seemed that the targeted effect was not achieved. This can be due to many factors including poor CSF circulation, and hence affecting the thermoregulation of the brain. It is worth mentioning that there is limitation of Licox probe as well. This device was specifically designed to detect the changes occurred around the area where it was inserted. Hence, it was unable to reflect accurately the whole brain temperature changes following head injury [41].

It was well documented in the literature that an injured brain might have significantly higher temperature compared to the core body temperature; ranging from 0.1°C to more than 2°C. The difference in the temperature gradient may be more significant in an injured brain as a result of destructive hyperactivity of the injured cells [42]. Numerous clinical studies have found that higher brain temperature is associated with adverse outcome and negative correlation with the prognosis of head injury patients. Hyperthermia increases the risk of ischemic area to become necrotic or apoptotic. In animal model, transient increase in core body temperature to 39–40°C led to 2.6-fold increase in the extent of neuronal injury in the hippocampus [43]. Since hyperthermia was an important independent factor of adverse neurological outcome and increase mortality in brain injury [44], accurate brain temperature reading was rather essential. For future reference, focal brain temperature reading with Licox may be combined with adjunct devices such as CT thermography as it can accurately measure the focal and whole brain temperature for better comparison during treatment.

#### *4.3.4 Effect of direct focal brain cooling on the Glasgow Outcome Score (GOS)*

Patients GOS was the most important factor to determine the outcome of the focal brain cooling treatment in this study. This classification system was specifically designed to help clinicians to determine the patients response following the treatment by assessing their functional status at discharge and at 6 months after the injury; score 1 reflects mortality, score 2 and 3 reflect significant morbidity, while score 4 and 5 reflect ability to function normally or near normal. The outcomes were promising as significant difference was noted, whereby the proportion of patients who received direct focal brain cooling treatment showed better GOS score of 4 and 5 at 6 months follow-up when compared to the no cooling group. However, no significant difference was established in GOS at day of discharge. The outcome of patient in severe head injury is actually multifactorial and could not just be attributed to a single factor. The age, other associated injuries, and hemodynamic instability will all contribute to the outcomes of the patients. The obvious contributing factor in our study is the increment in focal brain oxygenation during cooling therapy and it is markedly obvious in mild cooling group who received cold-fluid of 30–36°C.

#### *4.3.5 Effect of direct focal brain cooling on immune responses*

In this study, the T-cell markers, pro-inflammatory cytokines, and total white cell count show reduction in values after cooling therapy; nonetheless, no significant statistical difference noted in each studied immune parameters. This may be due to our small sample size; therefore, future related study should consider to recruit more patients with better homogenous participants' population. Besides this drawback, another shortcoming is no level taken from non-cooling group for comparison, thus the true effect of regional brain cooling on immunological biomarkers cannot be truly ascertained. This initial result, however, might indicate that focal brain cooling treatment has little adverse effect onto immune responses, which often associated with induced systemic cooling. Following head injury, acute immunological responses to the trauma begin around 1 hour after the injury until several days. Pro inflammatory mediators such as tumor necrosis factors-alpha (TNF-α) and IL-1 are released from injured tissues and stimulate the migration of the leukocytes across the BBB. These lead to accumulation of the inflammatory cells in the injured brain within hours. Activation of the complement systems following head injury will stimulate the neutrophil and in later stages, also monocytes and macrophages. These initial stages are basically causing granulocytosis (up to 90%), increasing immunoglobulins (Ig)-E, slight increase or normal level of monocytes, B-lymphocytes as well as Ig-A, -G and -M. On the other hand, there is suppression of the other lymphocytes subsets particularly the CD3, CD4 and CD8 counts [45]. Some of these changes were found to be beneficial and associated with neuroprotective effects while some other inflammatory mediators were neurotoxic [46]. The CD3, CD4, and CD8 counts are normally suppressed after few hours following severe head injury. This level will remain low for the next 24–48 hours and generally normalized after 3 days. The CD8 count tends to normalize faster than the CD3 and CD4. Increased risk of infection had been attributed to the suppression of these cellular immunities. Besides these mechanisms in causing alterations in immune parameters, other possibilities should also be considered. Those possibilities include:


#### **5. Current innovation in direct focal brain cooling: D-Brain Cooling Machine™**

The internal cooling methods use central venous catheters to either infuse cold saline or directly to reduce the blood temperature by convection. By advancement in microelectronic industry, instrumentation system can be integrated on chip level that can miniaturize the system to micro dimension. One of the advancements is miniaturization of micro-controller that can be easier to interface with sensing instrumentation system. Thus in this project, simple and intelligent localized brain cooling instrument by using Programmable System on Chip (PSoC) is proposed. Advantages of this system are simple, can localize coolant area in brain and System on chip (SoC) based automation system. This project involves designing temperature chamber to place the sterile fluid that is connected with antibiotic piping directly to

**135**

**6. Conclusions**

*adjustable temperature chamber.*

**Figure 4.**

machine™ therapy.

JEPeM/18010074).

**Conflict of interest**

None declared.

**Acknowledgements**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

the brain location. This chamber will be integrated with temperature controller, then, processed by PSoC microcontroller, as shown in **Figure 4A** and **B**. Subsequently, sensing and micro-controller will be interfaced to the system for temperature display.

*Direct brain cooling or D-brain cooling machine™. (A) Its principles; and (B) Illustration of final image of* 

This chapter highlights the fascinating result of our pilot study on direct focal brain cooling therapy in severe head injury patients. The significant clinical outcome results seem in mild cooling group is thought to be due to an elevation in oxygenation level of injured and decompressed brain tissues. Thus, direct brain cooling therapy seems as a promising treatment in severe head injuries, and should be considered by neurosurgeon and neurointensivist as an adjunctive method to decompressive craniectomy. Therefore, combination of both therapies may help many diffused and severely injured brains secondary to neurotrauma in gaining better clinical outcomes. Base on this initial and encouraging results, there is ongoing study by our group on direct focal brain cooling therapy in severely head injured patients by using newly invented cooling machine named D-Brain cooling

This chapter was funded by Research University (RUi) Grant (Grant No. USM/

This direct brain cooling machine is known as D-Brain Cooling Machine™.

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

*Direct Brain Cooling in Treating Severe Traumatic Head Injury DOI: http://dx.doi.org/10.5772/intechopen.84685*

#### **Figure 4.**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

be considered. Those possibilities include:

2.possibility of neuroendocrine changes,

3.the duration of the surgery,

mented, and

**Machine™**

1.blood product transfusion pre-, intra-, or postoperatively,

4.the incidence of pre- and intraoperative hypothermia, which were not docu-

5.the severity of trauma with consideration of the extend of tissues damaged [47].

The internal cooling methods use central venous catheters to either infuse cold saline or directly to reduce the blood temperature by convection. By advancement in microelectronic industry, instrumentation system can be integrated on chip level that can miniaturize the system to micro dimension. One of the advancements is miniaturization of micro-controller that can be easier to interface with sensing instrumentation system. Thus in this project, simple and intelligent localized brain cooling instrument by using Programmable System on Chip (PSoC) is proposed. Advantages of this system are simple, can localize coolant area in brain and System on chip (SoC) based automation system. This project involves designing temperature chamber to place the sterile fluid that is connected with antibiotic piping directly to

**5. Current innovation in direct focal brain cooling: D-Brain Cooling** 

significant statistical difference noted in each studied immune parameters. This may be due to our small sample size; therefore, future related study should consider to recruit more patients with better homogenous participants' population. Besides this drawback, another shortcoming is no level taken from non-cooling group for comparison, thus the true effect of regional brain cooling on immunological biomarkers cannot be truly ascertained. This initial result, however, might indicate that focal brain cooling treatment has little adverse effect onto immune responses, which often associated with induced systemic cooling. Following head injury, acute immunological responses to the trauma begin around 1 hour after the injury until several days. Pro inflammatory mediators such as tumor necrosis factors-alpha (TNF-α) and IL-1 are released from injured tissues and stimulate the migration of the leukocytes across the BBB. These lead to accumulation of the inflammatory cells in the injured brain within hours. Activation of the complement systems following head injury will stimulate the neutrophil and in later stages, also monocytes and macrophages. These initial stages are basically causing granulocytosis (up to 90%), increasing immunoglobulins (Ig)-E, slight increase or normal level of monocytes, B-lymphocytes as well as Ig-A, -G and -M. On the other hand, there is suppression of the other lymphocytes subsets particularly the CD3, CD4 and CD8 counts [45]. Some of these changes were found to be beneficial and associated with neuroprotective effects while some other inflammatory mediators were neurotoxic [46]. The CD3, CD4, and CD8 counts are normally suppressed after few hours following severe head injury. This level will remain low for the next 24–48 hours and generally normalized after 3 days. The CD8 count tends to normalize faster than the CD3 and CD4. Increased risk of infection had been attributed to the suppression of these cellular immunities. Besides these mechanisms in causing alterations in immune parameters, other possibilities should also

**134**

*Direct brain cooling or D-brain cooling machine™. (A) Its principles; and (B) Illustration of final image of adjustable temperature chamber.*

the brain location. This chamber will be integrated with temperature controller, then, processed by PSoC microcontroller, as shown in **Figure 4A** and **B**. Subsequently, sensing and micro-controller will be interfaced to the system for temperature display. This direct brain cooling machine is known as D-Brain Cooling Machine™.

#### **6. Conclusions**

This chapter highlights the fascinating result of our pilot study on direct focal brain cooling therapy in severe head injury patients. The significant clinical outcome results seem in mild cooling group is thought to be due to an elevation in oxygenation level of injured and decompressed brain tissues. Thus, direct brain cooling therapy seems as a promising treatment in severe head injuries, and should be considered by neurosurgeon and neurointensivist as an adjunctive method to decompressive craniectomy. Therefore, combination of both therapies may help many diffused and severely injured brains secondary to neurotrauma in gaining better clinical outcomes. Base on this initial and encouraging results, there is ongoing study by our group on direct focal brain cooling therapy in severely head injured patients by using newly invented cooling machine named D-Brain cooling machine™ therapy.

#### **Acknowledgements**

This chapter was funded by Research University (RUi) Grant (Grant No. USM/ JEPeM/18010074).

#### **Conflict of interest**

None declared.

#### **Author details**

Zamzuri Idris1 \*, Ang Song Yee1 , Regunath Kandasamy1 , Asrulnizam Abd Manaf<sup>2</sup> , Mohd Hasyizan Bin Hassan3 and Wan Nazaruddin Wan Hassan3

1 Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia

2 Collaborative Microelectronic Design Excellence Center (CEDEC), Engineering Campus Universiti Sains Malaysia, Nibong Tebal, Pulau Pinang, Malaysia

3 Neuroanaesthesia Division, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia

\*Address all correspondence to: neuroscienceszamzuri@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**137**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

[10] Jacobs S et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews. 2007;**4**:Cd003311

hypothermia for severe traumatic brain injury: A critically appraised topic. The

[11] Kramer C et al. Therapeutic

Neurologist. 2012;**18**(3):173-177

[12] Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality—Part 2: Practical aspects and side effects. Intensive Care Medicine.

[13] Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: Practical

considerations, side effects, and cooling methods. Critical Care Medicine.

[14] Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: A systematic review and meta-analysis. Journal of Neurotrauma.

[15] Andrews PJ et al. Hypothermia for intracranial hypertension after traumatic brain injury. The New England Journal of Medicine. 2015;**373**(25):2403-2412

[16] Clifton GL, Miller ER, Sung CC, et al. Lack of effect of induction of hypothermia after acute brain injury. New England Journal of Medicine.

[17] Shiozaki T et al. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia

Study Group in Japan. Journal of Neurosurgery. 2001;**94**(1):50-54

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*DOI: http://dx.doi.org/10.5772/intechopen.84685*

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**136**

**Author details**

Kelantan, Malaysia

Mohd Hasyizan Bin Hassan3

Malaysia, Kelantan, Malaysia

Zamzuri Idris1

provided the original work is properly cited.

\*, Ang Song Yee1

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Regunath Kandasamy1

1 Department of Neurosciences, School of Medical Sciences, Universiti Sains

Campus Universiti Sains Malaysia, Nibong Tebal, Pulau Pinang, Malaysia

\*Address all correspondence to: neuroscienceszamzuri@yahoo.com

2 Collaborative Microelectronic Design Excellence Center (CEDEC), Engineering

3 Neuroanaesthesia Division, School of Medical Sciences, Universiti Sains Malaysia,

and Wan Nazaruddin Wan Hassan3

, Asrulnizam Abd Manaf<sup>2</sup>

,

[1] Narayan RK et al. Clinical trials in head injury. Journal of Neurotrauma. 2002;**19**(5):503-557

[2] Maas AIR et al. Re-orientation of clinical research in traumatic brain injury: Report of an international workshop on comparative effectiveness research. Journal of Neurotrauma. 2012;**29**(1):32-46

[3] Nortje J, Menon DK. Traumatic brain injury: Physiology, mechanisms, and outcome. Current Opinion in Neurology. 2004;**17**(6):711-718

[4] Farag E, Manno EM, Kurz A. Use of hypothermia for traumatic brain injury: Point of view. Minerva Anestesiologica. 2011;**77**(3):366-370

[5] Kurland D et al. Hemorrhagic progression of a contusion after traumatic brain injury: A review. Journal of Neurotrauma. 2012;**29**(1):19-31

[6] Stiefel MF, Udoetuk JD, Spiotta AM, Gracias VH, Goldberg A, Maloney-Wilenskey E, et al. Conventional neurocritical care and cerebral oxygenation after traumatic brain injury. Journal of Neurosurgery. 2006;**105**:568-575

[7] Maloney-Wilensky E, Gracias V, Itkin A, Hoffman K, Bloom S, Yang W, et al. Brain tissue oxygen and outcome after severe traumatic brain injury: A systematic review. Critical Care Medicine. 2009;**37**(6):2057-2063

[8] Corry JJ et al. Hypothermia for refractory status epilepticus. Neurocritical Care. 2008;**9**(2):189-197

[9] Gluckman PD et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: Multicentre randomised trial. Lancet. 2005;**365**(9460):663-670

[10] Jacobs S et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews. 2007;**4**:Cd003311

[11] Kramer C et al. Therapeutic hypothermia for severe traumatic brain injury: A critically appraised topic. The Neurologist. 2012;**18**(3):173-177

[12] Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality—Part 2: Practical aspects and side effects. Intensive Care Medicine. 2004;**30**(5):757-769

[13] Polderman KH, Herold I. Therapeutic hypothermia and controlled normothermia in the intensive care unit: Practical considerations, side effects, and cooling methods. Critical Care Medicine. 2009;**37**(3):1101-1120

[14] Peterson K, Carson S, Carney N. Hypothermia treatment for traumatic brain injury: A systematic review and meta-analysis. Journal of Neurotrauma. 2008;**25**(1):62-71

[15] Andrews PJ et al. Hypothermia for intracranial hypertension after traumatic brain injury. The New England Journal of Medicine. 2015;**373**(25):2403-2412

[16] Clifton GL, Miller ER, Sung CC, et al. Lack of effect of induction of hypothermia after acute brain injury. New England Journal of Medicine. 2001;**344**:556-563

[17] Shiozaki T et al. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan. Journal of Neurosurgery. 2001;**94**(1):50-54

[18] O'Phelan KH et al. Therapeutic temperature modulation is associated with pulmonary complications in patients with severe traumatic brain injury. World Journal of Critical Care Medicine. 2015;**4**(4):296-301

[19] Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nature Reviews. Neuroscience. 2012;**13**(4):267-278

[20] Tripathy S, Mahapatra AK. Targeted temperature management in brain protection: An evidence-based review. Indian Journal of Anaesthesia. 2015;**59**(1):9-14

[21] Idris Z et al. Better Glasgow outcome score, cerebral perfusion pressure and focal brain oxygenation in severely traumatized brain following direct regional brain hypothermia therapy: A prospective randomized study. Asian Journal of Neurosurgery. 2014;**9**(3):115-123

[22] Kuluz J et al. Selective brain cooling during and after prolonged global ischemia reduces cortical damage in rats. Stroke. 1992;**23**:1792-1796; discussion 1797

[23] Tadler SC, Callaway CW, Menegazzi JJ. Noninvasive cerebral cooling in a swine model of cardiac arrest. Academic Emergency Medicine. 1998;**5**(1):25-30

[24] Gelman B et al. Selective brain cooling in infant piglets after cardiac arrest and resuscitation. Critical Care Medicine. 1996;**24**(6):1009-1017

[25] Kuluz JW et al. Selective brain cooling increases cortical cerebral blood flow in rats. The American Journal of Physiology. 1993;**265**(3 Pt 2):H824-H827

[26] Pil WH et al. Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in

focal cerebral ischemia. Journal of Neurosurgery. 2000;**92**(1):91-99

[27] Thoresen M et al. Effective selective head cooling during posthypoxic hypothermia in newborn piglets. Pediatric Research. 2001;**49**(4):594-599

[28] Doll H et al. Pharyngeal selective brain cooling is associated with reduced CNS cortical lesion after experimental traumatic brain injury in rats. Journal of Neurotrauma. 2010;**27**(12):2245-2254

[29] King C et al. Brain temperature profiles during epidural cooling with the ChillerPad in a monkey model of traumatic brain injury. Journal of Neurotrauma. 2010;**27**(10):1895-1903

[30] Cheng G et al. Effects of selective head cooling on cerebral blood flow and metabolism in newborn piglets after hypoxia-ischemia. Early Human Development. 2011;**87**(2):109-114

[31] Yao C et al. Selective brain cooling in rats ameliorates intracerebral hemorrhage and edema caused by penetrating brain injury: Possible involvement of heme oxygenase-1 expression. Journal of Neurotrauma. 2011;**28**(7):1237-1245

[32] Kim J-H et al. Delayed and prolonged local brain hypothermia combined with decompressive craniectomy: A novel therapeutic strategy that modulates glial dynamics. Experimental Neurobiology. 2014;**23**(2):115-123

[33] Szczygielski J et al. Selective brain hypothermia mitigates brain damage and improves neurological outcome after post-traumatic decompressive craniectomy in mice. Journal of Neurotrauma. 2017;**34**(8):1623-1635

[34] Narotam PK, Morrison JF, Nathoo N. Brain tissue oxygen monitoring in traumatic brain injury and major

**139**

*Direct Brain Cooling in Treating Severe Traumatic Head Injury*

with bladder and rectal temperature in adults with severe head injury. Neurosurgery. 1998;**42**:1071-1075

[43] Baena RC, Busto R, Dietrich WD,

[44] Hajat C, Hajat S, Sharma P. Effect of post stroke pyrexia on stroke outcome: A meta-analysis of studies on patients.

[45] Smrcka M, Mrlian A, Klabusay M. Immune system status in the patients after severe brain injury. Bratislavské Lekárske Listy. 2005;**106**(3):144-146

[47] Salo M. Effect of anaesthesia and surgery on the immune response. Acta Anaesthesiologica Scandinavica.

Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischaemia. Neurology. 1997;**48**:768-773

Globus MY, Ginsberg MD.

Stroke. 2000;**31**:410-414

[46] Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: A double edgedsword. Current Opinion in Critical Care.

2002;**8**:101-105

1992;**36**:201-205

*DOI: http://dx.doi.org/10.5772/intechopen.84685*

trauma: Outcome analysis of a brain tissue oxygen-directed therapy. Journal of Neurosurgery. 2009;**111**:672-682

[35] Spiotta AM, Stiefel MF, Gracias VH, Garuffe AM, Kofke WA, Maloney-Wilensky E, et al. Brain tissue oxygendirected management and outcome in patients with severe traumatic brain injury. Journal of Neurosurgery.

2010;**113**:571-580

2008;**371**:1955-1969

1999;**26**:298-304

[36] Polderman KH. Induced hypothermia and fever control for prevention and treatment of

neurological injuries. Lancet Neurology.

[37] Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM. Biphasic opening of the blood-brain barrier following transient focal ischaemia: Effects of hypothermia. The Canadian Journal of Neurological Sciences.

[38] Jurkovich GJ, Pitt RM, Curreri PW, Granger DN. Hypothermia prevents increased capillary permeability following ischaemia - reperfusion injury. Journal of Surgical Research. 1988;**44**:514-521

[39] Kinoshita K, Chatzipanteli K, Alonso OF, Howard M, Dietrich WD. The effect of brain temperature on hemoglobin extravasation after traumatic brain injury. Journal of Neurosurgery. 2002;**97**:945-953

[40] Fischer S, Renz D, Wiesnet M,

[41] Rabinstein AA. Elucidating the value of continuous brain oxygen monitoring. Neurocritical Care.

[42] Henker RA, Brown SD, Marion DW. Comparison of brain temperature

Schaper W, Karliczek GF. Hypothermia abolishes hypoxiainduced hyperpermeability in brain microvessel endothelial cells. Brain Research. Molecular Brain Research.

1999;**74**:135-144

2010;**12**:144-145

*Direct Brain Cooling in Treating Severe Traumatic Head Injury DOI: http://dx.doi.org/10.5772/intechopen.84685*

trauma: Outcome analysis of a brain tissue oxygen-directed therapy. Journal of Neurosurgery. 2009;**111**:672-682

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

focal cerebral ischemia. Journal of Neurosurgery. 2000;**92**(1):91-99

[27] Thoresen M et al. Effective selective head cooling during posthypoxic hypothermia in newborn piglets. Pediatric Research. 2001;**49**(4):594-599

[28] Doll H et al. Pharyngeal selective brain cooling is associated with reduced CNS cortical lesion after experimental traumatic brain injury in rats. Journal of Neurotrauma.

[29] King C et al. Brain temperature profiles during epidural cooling with the ChillerPad in a monkey model of traumatic brain injury. Journal of Neurotrauma. 2010;**27**(10):1895-1903

[30] Cheng G et al. Effects of selective head cooling on cerebral blood flow and metabolism in newborn piglets after hypoxia-ischemia. Early Human Development. 2011;**87**(2):109-114

[31] Yao C et al. Selective brain cooling in rats ameliorates intracerebral hemorrhage and edema caused by penetrating brain injury: Possible involvement of heme oxygenase-1 expression. Journal of Neurotrauma.

2011;**28**(7):1237-1245

[32] Kim J-H et al. Delayed and prolonged local brain hypothermia combined with decompressive craniectomy: A novel therapeutic strategy that modulates glial dynamics.

Experimental Neurobiology.

[33] Szczygielski J et al. Selective brain hypothermia mitigates brain damage and improves neurological outcome after post-traumatic decompressive craniectomy in mice. Journal of Neurotrauma. 2017;**34**(8):1623-1635

[34] Narotam PK, Morrison JF, Nathoo N. Brain tissue oxygen monitoring in traumatic brain injury and major

2014;**23**(2):115-123

2010;**27**(12):2245-2254

[18] O'Phelan KH et al. Therapeutic temperature modulation is associated with pulmonary complications in patients with severe traumatic brain injury. World Journal of Critical Care

Medicine. 2015;**4**(4):296-301

Neuroprotective mechanisms of hypothermia in brain ischaemia. Nature Reviews. Neuroscience.

[21] Idris Z et al. Better Glasgow outcome score, cerebral perfusion pressure and focal brain oxygenation in severely traumatized brain following direct regional brain hypothermia therapy: A prospective randomized study. Asian Journal of Neurosurgery.

[20] Tripathy S, Mahapatra AK. Targeted temperature management in brain protection: An evidence-based review. Indian Journal of Anaesthesia.

[22] Kuluz J et al. Selective brain cooling during and after prolonged global ischemia reduces cortical damage in rats. Stroke. 1992;**23**:1792-1796;

[23] Tadler SC, Callaway CW, Menegazzi JJ. Noninvasive cerebral cooling in a swine model of cardiac arrest. Academic Emergency Medicine. 1998;**5**(1):25-30

[24] Gelman B et al. Selective brain cooling in infant piglets after cardiac arrest and resuscitation. Critical Care Medicine. 1996;**24**(6):1009-1017

[25] Kuluz JW et al. Selective brain cooling increases cortical cerebral blood flow in rats. The American Journal of Physiology. 1993;**265**(3 Pt 2):H824-H827

[26] Pil WH et al. Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in

[19] Yenari MA, Han HS.

2012;**13**(4):267-278

2015;**59**(1):9-14

2014;**9**(3):115-123

discussion 1797

**138**

[35] Spiotta AM, Stiefel MF, Gracias VH, Garuffe AM, Kofke WA, Maloney-Wilensky E, et al. Brain tissue oxygendirected management and outcome in patients with severe traumatic brain injury. Journal of Neurosurgery. 2010;**113**:571-580

[36] Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet Neurology. 2008;**371**:1955-1969

[37] Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM. Biphasic opening of the blood-brain barrier following transient focal ischaemia: Effects of hypothermia. The Canadian Journal of Neurological Sciences. 1999;**26**:298-304

[38] Jurkovich GJ, Pitt RM, Curreri PW, Granger DN. Hypothermia prevents increased capillary permeability following ischaemia - reperfusion injury. Journal of Surgical Research. 1988;**44**:514-521

[39] Kinoshita K, Chatzipanteli K, Alonso OF, Howard M, Dietrich WD. The effect of brain temperature on hemoglobin extravasation after traumatic brain injury. Journal of Neurosurgery. 2002;**97**:945-953

[40] Fischer S, Renz D, Wiesnet M, Schaper W, Karliczek GF. Hypothermia abolishes hypoxiainduced hyperpermeability in brain microvessel endothelial cells. Brain Research. Molecular Brain Research. 1999;**74**:135-144

[41] Rabinstein AA. Elucidating the value of continuous brain oxygen monitoring. Neurocritical Care. 2010;**12**:144-145

[42] Henker RA, Brown SD, Marion DW. Comparison of brain temperature with bladder and rectal temperature in adults with severe head injury. Neurosurgery. 1998;**42**:1071-1075

[43] Baena RC, Busto R, Dietrich WD, Globus MY, Ginsberg MD. Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischaemia. Neurology. 1997;**48**:768-773

[44] Hajat C, Hajat S, Sharma P. Effect of post stroke pyrexia on stroke outcome: A meta-analysis of studies on patients. Stroke. 2000;**31**:410-414

[45] Smrcka M, Mrlian A, Klabusay M. Immune system status in the patients after severe brain injury. Bratislavské Lekárske Listy. 2005;**106**(3):144-146

[46] Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: A double edgedsword. Current Opinion in Critical Care. 2002;**8**:101-105

[47] Salo M. Effect of anaesthesia and surgery on the immune response. Acta Anaesthesiologica Scandinavica. 1992;**36**:201-205

Chapter 7

Abstract

1. Introduction

(Tables 1 and 2) [1–3].

nursing caring.

141

turate coma for refractory hypertension.

trauma.

Sedation in TBI Patients

based on the abovementioned new technologies.

Keywords: TBI, sedation, sedative agent

Lorenzo Peluso, Berta Monleon Lopez and Rafael Badenes

Sedation is an important topic in neurocritical patients. When compared with general intensive care unit and traumatic brain-injured patients, sedation has its therapeutic indications, such as management of intracranial pressure, treatment of status epilepticus, sedation for targeted temperature management patients and paroxysmal sympathetic activity. Nowadays, the assessment of sedation is done by neurological evaluation and new monitors based on electroencephalography signals that help the physician titrate the sedative agents. Therefore, the aim of this chapter is to discuss the main pharmacological properties of sedatives and analgesics, their proper indications related to pathophysiological issues and their titrations

Traumatic brain injury is an acquired brain injury which occurs after a sudden

TBI is a major socioeconomic problem. It is an important cause of death and hospital

admissions worldwide. The epidemiology in Europe is not well known, and more rigorous epidemiological studies are needed to fully quantify the effect of TBI society. There are primary and secondary injuries. The primary injury is the trauma suffered by the patient itself, while the secondary injuries develop afterwards due to hypoxia, alterations in cerebral hemodynamic and metabolism and disruption of the blood brain barrier. Our aim is to avoid the secondary insults. Examples which can lead to worsen primary injury are convulsions, fever or intracranial hypertension. TBI can be divided into different categories based on clinical examination or CT imaging. The most widely used is the Glasgow Coma Scale (GCS) based on neurological examination. Three categories can be found: mild, moderate, and severe. Other neurological scales used are based on time of loss of consciousness (LOC)

Many patients being admitted to the ICU are already under sedation due to neurological reasons. Nowadays, sedative agents are used either as a tool to apply other therapies (such as hypothermia) or as a treatment itself, for example, barbi-

affected by traumatic brain injury, have to face daily. These patients are usually excluded from randomized clinical trials, so the level of evidence in this setting is still low. The aims of sedation and analgesia can be divided into two main categories. Firstly, general objectives are to ensure the patients' comfort, reduction of pain and agitation, improvement of patient-ventilator synchrony and facilitation of the

Sedation and analgesia are practices that, all clinicians who provide care to patients

## Chapter 7 Sedation in TBI Patients

Lorenzo Peluso, Berta Monleon Lopez and Rafael Badenes

#### Abstract

Sedation is an important topic in neurocritical patients. When compared with general intensive care unit and traumatic brain-injured patients, sedation has its therapeutic indications, such as management of intracranial pressure, treatment of status epilepticus, sedation for targeted temperature management patients and paroxysmal sympathetic activity. Nowadays, the assessment of sedation is done by neurological evaluation and new monitors based on electroencephalography signals that help the physician titrate the sedative agents. Therefore, the aim of this chapter is to discuss the main pharmacological properties of sedatives and analgesics, their proper indications related to pathophysiological issues and their titrations based on the abovementioned new technologies.

Keywords: TBI, sedation, sedative agent

#### 1. Introduction

Traumatic brain injury is an acquired brain injury which occurs after a sudden trauma.

TBI is a major socioeconomic problem. It is an important cause of death and hospital admissions worldwide. The epidemiology in Europe is not well known, and more rigorous epidemiological studies are needed to fully quantify the effect of TBI society.

There are primary and secondary injuries. The primary injury is the trauma suffered by the patient itself, while the secondary injuries develop afterwards due to hypoxia, alterations in cerebral hemodynamic and metabolism and disruption of the blood brain barrier. Our aim is to avoid the secondary insults. Examples which can lead to worsen primary injury are convulsions, fever or intracranial hypertension.

TBI can be divided into different categories based on clinical examination or CT imaging. The most widely used is the Glasgow Coma Scale (GCS) based on neurological examination. Three categories can be found: mild, moderate, and severe. Other neurological scales used are based on time of loss of consciousness (LOC) (Tables 1 and 2) [1–3].

Many patients being admitted to the ICU are already under sedation due to neurological reasons. Nowadays, sedative agents are used either as a tool to apply other therapies (such as hypothermia) or as a treatment itself, for example, barbiturate coma for refractory hypertension.

Sedation and analgesia are practices that, all clinicians who provide care to patients affected by traumatic brain injury, have to face daily. These patients are usually excluded from randomized clinical trials, so the level of evidence in this setting is still low. The aims of sedation and analgesia can be divided into two main categories.

Firstly, general objectives are to ensure the patients' comfort, reduction of pain and agitation, improvement of patient-ventilator synchrony and facilitation of the nursing caring.


Control patients' level of sedation plays an important role in what recently has

In this chapter we will go over the basis of sedation in TBI patients, as well as the pharmacology of the different drugs used and the main indication for such patients.

The ideal sedative drug for a neurocritical patient should have different properties. It should have a rapid onset and recovery for a prompt neurologic evaluation, a predictable clearance independent of end-organ failure to avoid the accumulation of the drug, and it should be easily titrated. It has to reduce ICP by reducing cerebral blood flow (CBF) or cerebral vasoconstriction, however maintaining the coupling between cerebral blood flow and cerebral metabolic rate of oxygen consumption (CMRO2). Cerebral autoregulation should be preserved as well as normal vascular reactivity to changes in PaCO2. Finally, the hemodynamic depression should be

Propofol is a central nervous system depressant which directly activates GABA receptors and inhibits the NMDA receptor modulating calcium influx through slow calcium ion channels. It has a rapid onset (1–2 min) and a dose-related hypnotic effect. Its rapid onset is due to its high lipophilic property and a large volume of distribution, leading to a rapid recovery too (10–15 min). These characteristics made propofol one of the best alternatives for sedation in neurocritical patients allowing us to do wake-up test daily for neurologic evaluation. Some studies show that in patients requiring >48 h of mechanical ventilation [6], sedation with propofol results in significantly fewer ventilator days than intermittent lorazepam when sedatives are interrupted daily. Propofol has no active metabolites and does not produce significant drug interactions. It reduces ICP, CMRO2, CBF and cerebral electrical activity. CO2 vascular reactivity and cerebral autoregulation are also preserved. On the other hand, it has no analgesic effect, and it raises tolerance and tachyphylaxis. Side effects of propofol are dosedependent hypotension which can decrease cerebral perfusion pressure even if it induces a decrease in ICP [6] and dose-dependent respiratory depression. Thus, inva-

sive blood pressure and maybe cardiac output monitoring may be necessary.

hypoxia and progressive myocardial failure [7–9].

2.2 Benzodiazepines

143

Hypertriglyceridemia may appear after high-rate infusions; clinicians should also be aware of the propofol infusion syndrome (PRIS) to detect it as soon as possible. PRIS manifests as metabolic acidosis, hyperkalemia, rhabdomyolysis,

Benzodiazepines such as midazolam, lorazepam and diazepam are sedatives widely used in the ICU. They have anxiolytic, sedative and hypnotic properties. Midazolam is

been described as the "ABCDE bundle." An evidence-based clinical approach improves patients' outcome and recovery [5] such as duration of mechanical venti-

lation, brain dysfunction (i.e., delirium and coma), physical restraints, ICU

readmission rates, and discharge disposition of ICU survivors.

2. Pharmacology of sedatives and analgesics

minimal to avoid deleterious effects on brain circulation.

2.1 Propofol

Sedation in TBI Patients

DOI: http://dx.doi.org/10.5772/intechopen.85266

#### Table 1.

GCS classification


#### Table 2.

TBI classification: GCS and LOC time.

Specific objectives focused on "neurotreatment" are the reduction of intracranial pressure (ICP), the management of status epilepticus (SE), the control of targeted temperature management (TTM), the management of paroxysmal sympathetic activity and the decrease of cerebral oxygen consumption [1, 2].

A variety of studies show the positive outcomes of an adequate sedation and analgesia in the general critical care patient as, for example, reduce time on the ventilator and decrease the length of stay in ICU and prevention of neurologic deterioration, amongst others.

The best way to assess these patients is with the physical examination, allowing a clinical monitoring and timely detection of warning neurological signs; thus, the removal of the sedative agent is required. However, this can lead to a cerebral and hemodynamic derangement when sedation is abruptly stopped [3]. Cerebral hypoperfusion and raised ICP might result in an imbalance of energy supply and demand, especially for the injured brain and, therefore, aggravate the risk for metabolic distress and brain tissue hypoxia. It might lead to significant ICP elevation and cerebral perfusion pressure (CPP) reduction, but it has been shown that, in patients with a stable ICP and CPP readings, the wake-up tests remain the gold standard for clinical monitoring and detection of neurological changes [4].

Available drugs used for sedation are analgesics and sedatives. Evidence shows that combining them both in order to achieve the optimal level of sedation leads to a reduction in the appearance of adverse effects.

Control patients' level of sedation plays an important role in what recently has been described as the "ABCDE bundle." An evidence-based clinical approach improves patients' outcome and recovery [5] such as duration of mechanical ventilation, brain dysfunction (i.e., delirium and coma), physical restraints, ICU readmission rates, and discharge disposition of ICU survivors.

In this chapter we will go over the basis of sedation in TBI patients, as well as the pharmacology of the different drugs used and the main indication for such patients.

### 2. Pharmacology of sedatives and analgesics

The ideal sedative drug for a neurocritical patient should have different properties. It should have a rapid onset and recovery for a prompt neurologic evaluation, a predictable clearance independent of end-organ failure to avoid the accumulation of the drug, and it should be easily titrated. It has to reduce ICP by reducing cerebral blood flow (CBF) or cerebral vasoconstriction, however maintaining the coupling between cerebral blood flow and cerebral metabolic rate of oxygen consumption (CMRO2). Cerebral autoregulation should be preserved as well as normal vascular reactivity to changes in PaCO2. Finally, the hemodynamic depression should be minimal to avoid deleterious effects on brain circulation.

#### 2.1 Propofol

Specific objectives focused on "neurotreatment" are the reduction of intracranial pressure (ICP), the management of status epilepticus (SE), the control of targeted temperature management (TTM), the management of paroxysmal sympathetic

Mild 14–15 0–30 min Moderate 9–13 30 min–24 h Severe 3–8 >24 h

Parameter Response Score Best eye-opening response -Spontaneously 4

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Best verbal response -Oriented and conversational 5

Best motor response -Obesity request 6




GCS LOC

A variety of studies show the positive outcomes of an adequate sedation and analgesia in the general critical care patient as, for example, reduce time on the ventilator and decrease the length of stay in ICU and prevention of neurologic

The best way to assess these patients is with the physical examination, allowing a clinical monitoring and timely detection of warning neurological signs; thus, the removal of the sedative agent is required. However, this can lead to a cerebral and hemodynamic derangement when sedation is abruptly stopped [3]. Cerebral hypoperfusion and raised ICP might result in an imbalance of energy supply and demand, especially for the injured brain and, therefore, aggravate the risk for metabolic distress and brain tissue hypoxia. It might lead to significant ICP elevation and cerebral perfusion pressure (CPP) reduction, but it has been shown that, in patients with a stable ICP and CPP readings, the wake-up tests remain the gold standard for clinical monitoring and detection of neurological changes [4].

Available drugs used for sedation are analgesics and sedatives. Evidence shows that combining them both in order to achieve the optimal level of sedation leads to a

activity and the decrease of cerebral oxygen consumption [1, 2].

deterioration, amongst others.

TBI classification: GCS and LOC time.

Table 1. GCS classification

Table 2.

142

reduction in the appearance of adverse effects.

Propofol is a central nervous system depressant which directly activates GABA receptors and inhibits the NMDA receptor modulating calcium influx through slow calcium ion channels. It has a rapid onset (1–2 min) and a dose-related hypnotic effect. Its rapid onset is due to its high lipophilic property and a large volume of distribution, leading to a rapid recovery too (10–15 min). These characteristics made propofol one of the best alternatives for sedation in neurocritical patients allowing us to do wake-up test daily for neurologic evaluation. Some studies show that in patients requiring >48 h of mechanical ventilation [6], sedation with propofol results in significantly fewer ventilator days than intermittent lorazepam when sedatives are interrupted daily. Propofol has no active metabolites and does not produce significant drug interactions. It reduces ICP, CMRO2, CBF and cerebral electrical activity. CO2 vascular reactivity and cerebral autoregulation are also preserved. On the other hand, it has no analgesic effect, and it raises tolerance and tachyphylaxis. Side effects of propofol are dosedependent hypotension which can decrease cerebral perfusion pressure even if it induces a decrease in ICP [6] and dose-dependent respiratory depression. Thus, invasive blood pressure and maybe cardiac output monitoring may be necessary.

Hypertriglyceridemia may appear after high-rate infusions; clinicians should also be aware of the propofol infusion syndrome (PRIS) to detect it as soon as possible. PRIS manifests as metabolic acidosis, hyperkalemia, rhabdomyolysis, hypoxia and progressive myocardial failure [7–9].

#### 2.2 Benzodiazepines

Benzodiazepines such as midazolam, lorazepam and diazepam are sedatives widely used in the ICU. They have anxiolytic, sedative and hypnotic properties. Midazolam is a GABA receptor agonist. Systemic effects of these drugs are anxiolysis, sedation, muscle relaxation, anterograde amnesia, respiratory depression and anticonvulsant activity. It decreases CMRO2 and CBF and has a slight effect on lowering ICP too. As with propofol, vascular reactivity to CO2 and cerebral autoregulation is preserved. Midazolam produces amnesia and has a rapid onset of action, and it produces less hemodynamic instability than propofol. However, they also produce tolerance and tachyphylaxis. Their metabolism is impaired when hepatic failure because of its oxidation via CYP450 enzyme system producing active metabolites excreted in the urine, leading to accumulation in renal dysfunction. It can prolong duration of mechanical ventilation, and the appearance of delirium in the ICU patients is increased. A continuous infusion of midazolam for more than 24 h will lose the rapid recovery properties due to the accumulation of active metabolites. Therefore, it is recommended only for short-term infusions. The Society of Critical Care Medicine consensus guidelines state that midazolam should be used only for short-term (<48 h) therapy [10]. High doses of benzodiazepines can cause respiratory depression and apnea, leading to an increase in ICP caused by hypercapnia. Benzodiazepines' reverser is flumazenil.

CYP450 enzyme system, and there are no active or toxic metabolites. Sedation with volunteers showed a decrease in regional and global cerebral blood flow, but the

neuroprotective effect in animal studies has also been studied, and they showed a preconditioning effect and attenuation of ischemia-reperfusion injury [26].

Nowadays, these drugs are used only for a specific goal. They are a GABA receptor agonist leading to a decrease in ICP and CBF that is proportional to the decrease in CMRO2 (up to 60%) during burst suppression. Barbiturates have been associated with a high incidence of systemic complications, such as hemodynamic instability and immune suppression with an increased risk of infections, such as pneumonia. Indication for barbiturates is limited to refractory intracranial hypertension and refractory status epilepticus [27]. They accumulate in the tissues after

Ketamine is an NMDA receptor antagonist with a relatively good hemodynamic stability. It has a fast onset and a short action. Sedation, analgesia and anesthesia can be induced with this drug, and it does not depress the respiratory system. Potential side effects of ketamine are increase of CMRO2, CBF and ICP (due to an increase in cerebral blood volume). However, some reports have shown to decrease CBF and ICP in head trauma patients sedated using both ketamine and propofol or with a PaCO2 maintained constant [28], and in an experimental setting ketamine even had neuroprotective properties [29]. Main advantages of using ketamine are the hemodynamic stability as well as CPP and the opportunity to reduce the excessive use of

In a recent study, the use of ketamine was associated with a lower incidence of cortical spreading depolarization (CSD) when compared with propofol, midazolam

Inhalative sedation in the ICU is starting to spread all over Europe and has been recommended as an alternative in a German consensus guideline [31]. However, it has historically been considered unsafe in the NICU around the world. Isoflurane, sevoflurane, and desflurane have shown some benefits compared with intravenous sedation. They have a low metabolism and, due to their low solubility, are eliminated quickly and offer shorter and more predictable wake-up times than intrave-

nous agents. They give also a better hemodynamic stability. Some volatile

intact, but it was impaired at MAC 2.0. They have also a dose-dependent neuroprotective effect; sevoflurane at MAC 0.5 does not have this effect [32]. In a prospective study, it was seen that sufficient sedation levels without clinically relevant ICP increases were achieved in 68% of the patients. However, MAP had to be maintained actively to preserve the CPP. Therefore, it was concluded that the neuroprotective effect did not outweigh the risk of adverse events, and sedation

with this agent should not be carry out in these patients [33]. A summary table can be found at the end of the chapter.

anesthetics abolish cerebral autoregulation at high doses; it has been reported that with sevoflurane at MAC 1.0, the autoregulation of cerebral blood flow remained

ratio with CMRO2 and flow metabolism coupling is maintained [25]. The

long-term infusions leading to slow recovery from sedation.

some sedative drugs as it reinforces them.

2.5 Barbiturates

Sedation in TBI Patients

DOI: http://dx.doi.org/10.5772/intechopen.85266

2.6 Ketamine

and opioids [30].

145

2.7 Inhalation sedatives

#### 2.3 Opioids

Morphine, fentanyl and remifentanil are the most frequently used opioids in the ICU [11]. These drugs stimulate mu, kappa and delta receptors, distributed all along the central nervous system (CNS). They have a fast onset when given intravenous (iv), and they are more easily titrated. Morphine and meperidine are not the ideal sedative agent for ICU because their active metabolite can precipitate seizures [12]. Moreover, morphine has a long-lasting effect. Fentanyl with its high lipid solubility has a very rapid onset and a short duration of action when given as a bolus; however, the pharmacokinetics change when administered in perfusion. It may increase ICP and decrease CPP (decrease in MAP) transiently after a bolus. Remifentanil is more powerful than morphine, and it is metabolized directly in the plasma by nonspecific esterases, thus avoiding drug accumulation. Due to its very short duration of action, it requires a continuous perfusion [13–17]. This makes this drug very suitable for neurocritical patients because it facilitates frequent awakening for the neurologic evaluation [18]. Remifentanil is eliminated by the kidneys, and it does not have to be adjusted if kidney failure. On the other side, as they act as respiratory depressants, they may cause hypercapnia with consequent increase in ICP. They can induce histamine release, causing urticaria and flushing, somnolence respiratory depression, chest wall and other muscle rigidity, dysphoria or hallucinations, nausea and vomiting, gastrointestinal dysmotility and vasodilation with hypotension. The reverser is naloxone, which should be given slowly and be titrated.

In order to reduce and minimize the use of opioids, it is possible to add other categories of analgesics as gabapentin and/or acetaminophen [19].

#### 2.4 Dexmedetomidine

Dexmedetomidine is an alpha-2 agonist which has been recently introduced into clinical practice. It has sedative, analgesic and anxiolytic properties, and it is widely starting to spread through the neurointensive care unit (NICU). It has a short-acting effect, and it does not accumulate, thus being very appropriate for frequently wakeup test for neurological evaluation. The respiratory depression is minimal, and it has been reported that it may reduce the incidence and severity of delirium. On the other side, it is a very expensive drug, and there have been reported cases of dosedependent bradycardia, hypotension, arrhythmias and hyperglycemia. Deep sedation is not possible with this drug [20–24]. The pharmacokinetics is influenced by liver rather than renal function. Dexmedetomidine is metabolized in the liver by

CYP450 enzyme system, and there are no active or toxic metabolites. Sedation with volunteers showed a decrease in regional and global cerebral blood flow, but the ratio with CMRO2 and flow metabolism coupling is maintained [25]. The neuroprotective effect in animal studies has also been studied, and they showed a preconditioning effect and attenuation of ischemia-reperfusion injury [26].

#### 2.5 Barbiturates

a GABA receptor agonist. Systemic effects of these drugs are anxiolysis, sedation, muscle relaxation, anterograde amnesia, respiratory depression and anticonvulsant activity. It decreases CMRO2 and CBF and has a slight effect on lowering ICP too. As with propofol, vascular reactivity to CO2 and cerebral autoregulation is preserved. Midazolam produces amnesia and has a rapid onset of action, and it produces less hemodynamic instability than propofol. However, they also produce tolerance and tachyphylaxis. Their metabolism is impaired when hepatic failure because of its oxidation via CYP450 enzyme system producing active metabolites excreted in the urine, leading to accumulation in renal dysfunction. It can prolong duration of mechanical ventilation, and the appearance of delirium in the ICU patients is increased. A continuous infusion of midazolam for more than 24 h will lose the rapid recovery properties due to the accumulation of active metabolites. Therefore, it is recommended only for short-term infusions. The Society of Critical Care Medicine consensus guidelines state that midazolam should be used only for short-term (<48 h) therapy [10]. High doses of benzodiazepines can cause respiratory depression and apnea, leading to an increase

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

in ICP caused by hypercapnia. Benzodiazepines' reverser is flumazenil.

reverser is naloxone, which should be given slowly and be titrated.

categories of analgesics as gabapentin and/or acetaminophen [19].

In order to reduce and minimize the use of opioids, it is possible to add other

Dexmedetomidine is an alpha-2 agonist which has been recently introduced into clinical practice. It has sedative, analgesic and anxiolytic properties, and it is widely starting to spread through the neurointensive care unit (NICU). It has a short-acting effect, and it does not accumulate, thus being very appropriate for frequently wakeup test for neurological evaluation. The respiratory depression is minimal, and it has been reported that it may reduce the incidence and severity of delirium. On the other side, it is a very expensive drug, and there have been reported cases of dosedependent bradycardia, hypotension, arrhythmias and hyperglycemia. Deep sedation is not possible with this drug [20–24]. The pharmacokinetics is influenced by liver rather than renal function. Dexmedetomidine is metabolized in the liver by

Morphine, fentanyl and remifentanil are the most frequently used opioids in the ICU [11]. These drugs stimulate mu, kappa and delta receptors, distributed all along the central nervous system (CNS). They have a fast onset when given intravenous (iv), and they are more easily titrated. Morphine and meperidine are not the ideal sedative agent for ICU because their active metabolite can precipitate seizures [12]. Moreover, morphine has a long-lasting effect. Fentanyl with its high lipid solubility has a very rapid onset and a short duration of action when given as a bolus; however, the pharmacokinetics change when administered in perfusion. It may increase ICP and decrease CPP (decrease in MAP) transiently after a bolus. Remifentanil is more powerful than morphine, and it is metabolized directly in the plasma by nonspecific esterases, thus avoiding drug accumulation. Due to its very short duration of action, it requires a continuous perfusion [13–17]. This makes this drug very suitable for neurocritical patients because it facilitates frequent awakening for the neurologic evaluation [18]. Remifentanil is eliminated by the kidneys, and it does not have to be adjusted if kidney failure. On the other side, as they act as respiratory depressants, they may cause hypercapnia with consequent increase in ICP. They can induce histamine release, causing urticaria and flushing, somnolence respiratory depression, chest wall and other muscle rigidity, dysphoria or hallucinations, nausea and vomiting, gastrointestinal dysmotility and vasodilation with hypotension. The

2.3 Opioids

2.4 Dexmedetomidine

144

Nowadays, these drugs are used only for a specific goal. They are a GABA receptor agonist leading to a decrease in ICP and CBF that is proportional to the decrease in CMRO2 (up to 60%) during burst suppression. Barbiturates have been associated with a high incidence of systemic complications, such as hemodynamic instability and immune suppression with an increased risk of infections, such as pneumonia. Indication for barbiturates is limited to refractory intracranial hypertension and refractory status epilepticus [27]. They accumulate in the tissues after long-term infusions leading to slow recovery from sedation.

#### 2.6 Ketamine

Ketamine is an NMDA receptor antagonist with a relatively good hemodynamic stability. It has a fast onset and a short action. Sedation, analgesia and anesthesia can be induced with this drug, and it does not depress the respiratory system. Potential side effects of ketamine are increase of CMRO2, CBF and ICP (due to an increase in cerebral blood volume). However, some reports have shown to decrease CBF and ICP in head trauma patients sedated using both ketamine and propofol or with a PaCO2 maintained constant [28], and in an experimental setting ketamine even had neuroprotective properties [29]. Main advantages of using ketamine are the hemodynamic stability as well as CPP and the opportunity to reduce the excessive use of some sedative drugs as it reinforces them.

In a recent study, the use of ketamine was associated with a lower incidence of cortical spreading depolarization (CSD) when compared with propofol, midazolam and opioids [30].

#### 2.7 Inhalation sedatives

Inhalative sedation in the ICU is starting to spread all over Europe and has been recommended as an alternative in a German consensus guideline [31]. However, it has historically been considered unsafe in the NICU around the world. Isoflurane, sevoflurane, and desflurane have shown some benefits compared with intravenous sedation. They have a low metabolism and, due to their low solubility, are eliminated quickly and offer shorter and more predictable wake-up times than intravenous agents. They give also a better hemodynamic stability. Some volatile anesthetics abolish cerebral autoregulation at high doses; it has been reported that with sevoflurane at MAC 1.0, the autoregulation of cerebral blood flow remained intact, but it was impaired at MAC 2.0. They have also a dose-dependent neuroprotective effect; sevoflurane at MAC 0.5 does not have this effect [32].

In a prospective study, it was seen that sufficient sedation levels without clinically relevant ICP increases were achieved in 68% of the patients. However, MAP had to be maintained actively to preserve the CPP. Therefore, it was concluded that the neuroprotective effect did not outweigh the risk of adverse events, and sedation with this agent should not be carry out in these patients [33].

A summary table can be found at the end of the chapter.


Mechanism

147

Rapid

Fast

Metabolism

 IV Bolus

Continuous IV

ICP

CBF

CMRO2

Map

Main advantages

 Main

Adverse effects

disadvantages

reduction

reduction

reduction

reduction

Sedation, anesthesia,

Increases secretions.

 Hallucinations. Nystagmus. Increases

IOP, IAP

Sedation in TBI Patients

analgesia. No

respiratory

depression. HD

stability.

Fast elimination.

Hypotension. MAC

Toxic metabolite

(compound A).

DOI: http://dx.doi.org/10.5772/intechopen.85266

Malignant hyperthermia

Increases CBF in

2 autoregulation

impairs.

cerebral ischemia.

infusion

dose

onset

recovery

of action

> Ketamine

NMDA R

+++ +++

 Liver

 1–4 mg/kg

 (0.5–2 mg/kg)

agonist

Sevorane

Not clear.

+++ ++

 5% Hepatic.

2% MAC

 0.5–3% of sevorane in May increase

after

increase

in CBF

95%

inhalatory

pathway

GABA R agonist +

glutamate

receptor

agonist


#### Sedation in TBI Patients DOI: http://dx.doi.org/10.5772/intechopen.85266

Mechanism

146

Rapid

Fast

Metabolism

 IV Bolus

Continuous IV

ICP

CBF

CMRO2

Map

Main advantages

 Main

Adverse effects

disadvantages

reduction

reduction

reduction

reduction

Clearance

No analgesia.

PRIS. Hypotension

> Tolerance and

tachyphylaxis.

Increases

triglycerides.

independent of renal

or hepatic function.

Rapid onset and fast

recovery

Amnesia. Rapid

Tolerance.

Hypotension. Apnea.

Delirium

Tachyphylaxis.

Accumulates in renal dysfunction.

Active metabolites

> Less peripheric

Hypotension

 Apnea. Hypotension.

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Pruritus. Nausea. Active

metabolite can produce

seizures. Muscle rigidity

accumulation than fentanyl. Analgesia

More potent

Accumulation

hepatic impairment.

Apnea

 with

Pruritus. Nausea.

Muscle rigidity. Hyperalgesia after

infusion. CV

depressant.

analgesic than

morphine

500 more potent

than morphine Sedative, anxiolytic,

Limited experience

Arrhythmias.

Hypotension.

Bradicardia.

in ABI.

analgesic. Minimal

respiratory

depression. Reduces

delirium

Second-line

Accumulates in

HD instability. Immunosuppression.

peripheral tissue.

Adjust dose in renal

failure.

treatment for

refractory

intracraneal

hypertension

onset

infusion

dose

onset

recovery

of action

> Propofol

GABA R

+++ +++

 Hepatic

 1.5–2.5 mg/kg 5–200 mg/kg/min

agonist

Midazolam

GABA R

+++ ++

 Hepatic

 0.02–

0.04–0.3 mg/kg/h

> 0.08 mg/kg

agonist

Morphine

Fentanyl Remifentanil MU-R agonist +++ +++

Dexdor

ALPHA 2

++

 ++

 Hepatic

 Not

0.2–1.4 mg/kg/h

recommended

agonist

Thiopental

GABA R

+++ +

 Hepatic

 2–5 mg/kg

 1–5 mg/kg/h

agonist

 Plasmatic

0.05–0.25 mg/kg/min

esterases

MU-R agonist +++ ++

 Hepatic

 25–125 mg

 10–100 mg/h

MU-R agonist +

 +

 Hepatic

 0.8–10 mg/h Max 80 mg/h

#### 3. Physiologic effects of sedatives on cerebral blood flow and cerebral metabolic rate of oxygen consumption

4.1 Control of intracranial pressure (ICP)

DOI: http://dx.doi.org/10.5772/intechopen.85266

better venous outflow.

Sedation in TBI Patients

The effect of sedatives on ICP is due mainly to reduction in CMRO2 that leads to a decrease in cerebral blood flow. This effect can be seen as a decrease in cerebral blood volume that leads to a decrease in ICP. As well, sedation reduces pain and agitation and improves the tolerance to the endotracheal tube. These effects lead to a decrease of sympathetic activity with a reduction of arterial pressure and less ventilation asynchronies leading to a decrease of jugular venous resistance and a

Sedation is a first-line therapy that should be integrated with other specific interventions as hyperventilation, osmotic agents and head-of-bed elevation. Bolus of opioids needs caution for the transient decrease in mean arterial pressure and increase in ICP due to autoregulatory cerebral vasodilation [36]. When compared with opioids, propofol showed an association with a lower ICP and less ICP treat-

The effects of hypothermia on the brain are multiple. First, the cerebral metabolic rate decreases leading to a decrease in CBF and, consequently, a reduction of cerebral volume. Moreover, cooling procedures suppress many of the pathways that lead to cell death, including apoptotic mechanisms (programmed cell death).

Sedation is recommended during TTM to prevent shivering, to reduce the stress response and to allow the patient-ventilator synchrony. To avoid shivering a lot of drugs are available, but they could engender side effects. One of the most used

An excess in sedation can lead to an increase of mechanical ventilation time and

Status epilepticus is a quite common neurologic condition with an overall inci-

The emergency therapy consists in benzodiazepines for the emergency, followed by one or more anti-epileptic drugs (AED). When both categories fail, it is necessary to begin a deep sedation with anesthetic agents for at least 24 h of

Different studies showed and reported the effectiveness of propofol or

The traditional barbiturate (phenobarbital), due to its side effects, is being

This syndrome has been recognized in a subgroup of survivors of severe acquired brain injury, characterized by simultaneous, paroxysmal transient

it has been associated with severe anoxia, subarachnoid and intracerebral

increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity. This syndrome has been observed for the last 60 years. It affects 8–10% of patients suffering from acute brain injury, and it is associated with greater morbidity, higher healthcare costs, longer hospitalization and poorer outcomes. However, it is a potentially treatable contributor to secondary brain injury. In patients surviving traumatic brain injury,

ments in patients with severe traumatic brain injury (TBI) [6].

drugs is propofol that has a dose-dependent antishivering effect.

4.2 Targeted temperature management (TTM)

a delay in neurological response [39].

effectiveness [41].

149

4.3 Treatment of status epilepticus (SE)

midazolam as therapy for refractory SE.

4.4 Paroxysmal sympathetic activity

replaced by the newest propofol and midazolam.

dence of 41–61 cases per 100,000 patients/year [40].

Sedation is one of the pillars in the management of patients with TBI. It is a treatment itself when used to prevent the secondary insult, and it allows other measures to be implemented which could not be applied otherwise, such as hypothermia.

The physiologic effects of sedatives are different, and they can be divided into effects on CBF and CMRO2.

#### 3.1 Effects on cerebral blood flow (CBF)

One of the main goals when treating these patients is to maintain a sufficient cerebral blood flow. Therefore, our drugs should have little or no effect on this matter.

The effects of intravenous sedatives on CBF have been investigated for diazepam, midazolam and propofol. All these iv agents cause a dose-dependent decrease in CMRO2 and CBF. CBF reduction is an adaptative phenomenon to minimize brain metabolism. They usually have a systemic effect decreasing mean arterial pressure (MAP), inducing myocardial depression and peripheral vasodilation. Therefore, in patients with impaired autoregulation, such as those with TBI, decreasing the MAP can lead to a critical lowering in cerebral perfusion pressure and oxygen delivery to the brain. This can lead or worsen the secondary brain insult (ischemia/hypoxia) [34, 35]. If autoregulation is intact, this reduction on MAP will produce reflex cerebral vasodilation and may lead to an increase in intracranial pressure [36]. The hemodynamic effects are usually dose dependent, so it is important to assess the preload status of the patient in order to predict the hemodynamic response to the sedative agent, particularly in those with previous cardiac dysfunction.

#### 3.2 Effects on the cerebral metabolic rate of oxygen consumption (CMRO2)

The CMRO2 and CBF are nicely connected. In TBI patients, our target is to maintain an adequate oxygen availability and energy balance; thus, we aim to increase oxygen delivery by optimizing cerebral and systemic hemodynamic, as well as attenuating metabolic demands [2, 37, 38].

Patients in coma or suffering from secondary brain insults have their cerebral metabolism decreased globally by one-third to one-half of normal levels.

Sedative agents act by reducing CMRO2, improving cerebral tolerance to ischemia and limiting the supply/demand mismatch in conditions of impaired autoregulation [34, 35]. Beyond the level of isoelectric EEG, no further suppression of cerebral oxygen consumption can take place; a minimal oxygen consumption is, indeed, due to cells' homeostasis.

#### 4. Neurological indications for sedation

Continuous infusion of sedative agents is contemplated during the first 48 h, in order to prevent secondary brain injury by decreasing oxygen consumption, as well as to reduce pain, anxiety and agitation to tolerate mechanical ventilation.

Apart from the general indications due to patient's agitation and pain control, there are specific situations in these patients that require sedation as therapy.

3. Physiologic effects of sedatives on cerebral blood flow and cerebral

Sedation is one of the pillars in the management of patients with TBI. It is a treatment itself when used to prevent the secondary insult, and it allows other measures to be implemented which could not be applied otherwise, such as hypothermia. The physiologic effects of sedatives are different, and they can be divided into

One of the main goals when treating these patients is to maintain a

sufficient cerebral blood flow. Therefore, our drugs should have little or no effect

The effects of intravenous sedatives on CBF have been investigated for diazepam, midazolam and propofol. All these iv agents cause a dose-dependent decrease in CMRO2 and CBF. CBF reduction is an adaptative phenomenon to minimize brain metabolism. They usually have a systemic effect decreasing mean arterial pressure (MAP), inducing myocardial depression and peripheral vasodilation. Therefore, in patients with impaired autoregulation, such as those with TBI, decreasing the MAP can lead to a critical lowering in cerebral perfusion pressure and oxygen delivery to the brain. This can lead or worsen the secondary brain insult (ischemia/hypoxia) [34, 35]. If autoregulation is intact, this reduction on MAP will produce reflex cerebral vasodilation and may lead to an increase in intracranial

pressure [36]. The hemodynamic effects are usually dose dependent, so it is important to assess the preload status of the patient in order to predict the hemodynamic response to the sedative agent, particularly in those with previous

3.2 Effects on the cerebral metabolic rate of oxygen consumption (CMRO2)

The CMRO2 and CBF are nicely connected. In TBI patients, our target is to maintain an adequate oxygen availability and energy balance; thus, we aim to increase oxygen delivery by optimizing cerebral and systemic hemodynamic, as

Patients in coma or suffering from secondary brain insults have their cerebral

Sedative agents act by reducing CMRO2, improving cerebral tolerance to ische-

Continuous infusion of sedative agents is contemplated during the first 48 h, in order to prevent secondary brain injury by decreasing oxygen consumption, as well

autoregulation [34, 35]. Beyond the level of isoelectric EEG, no further suppression of cerebral oxygen consumption can take place; a minimal oxygen consumption is,

metabolism decreased globally by one-third to one-half of normal levels.

mia and limiting the supply/demand mismatch in conditions of impaired

as to reduce pain, anxiety and agitation to tolerate mechanical ventilation. Apart from the general indications due to patient's agitation and pain control, there are specific situations in these patients that require sedation

well as attenuating metabolic demands [2, 37, 38].

4. Neurological indications for sedation

indeed, due to cells' homeostasis.

as therapy.

148

metabolic rate of oxygen consumption

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

3.1 Effects on cerebral blood flow (CBF)

effects on CBF and CMRO2.

on this matter.

cardiac dysfunction.

#### 4.1 Control of intracranial pressure (ICP)

The effect of sedatives on ICP is due mainly to reduction in CMRO2 that leads to a decrease in cerebral blood flow. This effect can be seen as a decrease in cerebral blood volume that leads to a decrease in ICP. As well, sedation reduces pain and agitation and improves the tolerance to the endotracheal tube. These effects lead to a decrease of sympathetic activity with a reduction of arterial pressure and less ventilation asynchronies leading to a decrease of jugular venous resistance and a better venous outflow.

Sedation is a first-line therapy that should be integrated with other specific interventions as hyperventilation, osmotic agents and head-of-bed elevation. Bolus of opioids needs caution for the transient decrease in mean arterial pressure and increase in ICP due to autoregulatory cerebral vasodilation [36]. When compared with opioids, propofol showed an association with a lower ICP and less ICP treatments in patients with severe traumatic brain injury (TBI) [6].

#### 4.2 Targeted temperature management (TTM)

The effects of hypothermia on the brain are multiple. First, the cerebral metabolic rate decreases leading to a decrease in CBF and, consequently, a reduction of cerebral volume. Moreover, cooling procedures suppress many of the pathways that lead to cell death, including apoptotic mechanisms (programmed cell death).

Sedation is recommended during TTM to prevent shivering, to reduce the stress response and to allow the patient-ventilator synchrony. To avoid shivering a lot of drugs are available, but they could engender side effects. One of the most used drugs is propofol that has a dose-dependent antishivering effect.

An excess in sedation can lead to an increase of mechanical ventilation time and a delay in neurological response [39].

#### 4.3 Treatment of status epilepticus (SE)

Status epilepticus is a quite common neurologic condition with an overall incidence of 41–61 cases per 100,000 patients/year [40].

The emergency therapy consists in benzodiazepines for the emergency, followed by one or more anti-epileptic drugs (AED). When both categories fail, it is necessary to begin a deep sedation with anesthetic agents for at least 24 h of effectiveness [41].

Different studies showed and reported the effectiveness of propofol or midazolam as therapy for refractory SE.

The traditional barbiturate (phenobarbital), due to its side effects, is being replaced by the newest propofol and midazolam.

#### 4.4 Paroxysmal sympathetic activity

This syndrome has been recognized in a subgroup of survivors of severe acquired brain injury, characterized by simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity. This syndrome has been observed for the last 60 years. It affects 8–10% of patients suffering from acute brain injury, and it is associated with greater morbidity, higher healthcare costs, longer hospitalization and poorer outcomes. However, it is a potentially treatable contributor to secondary brain injury. In patients surviving traumatic brain injury, it has been associated with severe anoxia, subarachnoid and intracerebral

hemorrhage and hydrocephalus. There are many theories dealing with the pathophysiology of this entity. Disconnection of the inhibitory efferent pathways (malfunctioning pathways) from cortical areas of the brain is one of the possible theories. It is also thought that alterations in the excitatory nucleus of the brainstem can cause this syndrome; excitatory centers are then upregulated, increasing sympathetic activity. There is no accepted treatment for this entity. The objective is to mitigate signs and symptoms to avoid the adverse effects such as dehydration, muscle wasting or delayed recovery. Dopaminergic agents have shown to decrease body temperature and sweating. Alpha agonists can decrease heart rate and blood pressure. When medication fails, the use of hyperbaric oxygen therapy (HBOT) to control autonomic discharges and posturing in the subacute TBI phase has been reported. In this condition, sedation should be considered to reduce sympathetic activation [42].

Propofol and midazolam seem to be the most used drugs in such patient due to their security profile; ketamine appears to be interesting for its neuroprotective

To target sedation properly, it is possible to use different approaches; the use of score (RASS, SAS) in the awake patient remains a good tool that can be integrated in comatose patient, knowing their limits, with the newest EEG-derived methods.

, Berta Monleon Lopez<sup>2</sup> and Rafael Badenes<sup>2</sup>

2 Department of Anesthesiology and Surgical-Trauma Intensive Care, Hospital

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Intensive Care Hôpital Erasme, Brussels, Belgium

\*Address all correspondence to: rafaelbadenes@gmail.com

\*

role.

Conflict of interest

Sedation in TBI Patients

Author details

Lorenzo Peluso<sup>1</sup>

151

Clìnico Universitario, Valencia, Spain

provided the original work is properly cited.

We declare no conflict of interest.

DOI: http://dx.doi.org/10.5772/intechopen.85266

#### 5. Monitoring sedation in the neuro-ICU

Monitoring the depth of sedation is essential in the management of the patient in the ICU, and it influences their outcomes. Oversedation increases the risk of infections by delaying weaning from mechanical ventilation and increases length of stay and, thus, costs. On the other side, undersedation can cause agitation and anxiety of the patient, increase the risk of self-extubating and develop asynchronies between the patient and the ventilator. In NICU patients, assessing routine level of sedation is really important both for the daily wake-up tests that should be done for neurologic evaluation and, in comatose patients, to avoid oversedation.

There are various scales available for ICU patients. The Ramsay Sedation Scale evaluates consciousness, while the Richmond Agitation-Sedation Scale (RASS) examines cognition. The Motor Activity Assessment Scale (MAAS) and the Sedation-Agitation Scale (SAS) monitor sedation and arousal. Both RASS and SAS are reasonable to use in TBI patients [43]. Moreover, RASS is usually integrated with a delirium assessment performed with Confusion Assessment Method for the ICU (CAM-ICU). However, in deeply sedated patients and with muscular blockade, these scales become useless. EEG monitoring has therefore become a very investigated topic to titrate sedation in these patients. Simplified EEG tools like BIS, based on Fourier transform, have shown significant correlation with RASS and SAS in ABI [44]. However, BIS was developed to monitor sedation in the operating room (OR) setting in patients with no acute brain injury (ABI) due to the possible changes in EEG because of the brain lesion; it is often used in the ICU setting.

The possible confounders of such method are shivering, temperature fluctuation, increased muscle tone, grimacing and catecholamine levels. To assess the adequacy of pain relief, it is useful to assess autonomic signs of activation such as tachycardia, hypertension, ICP increase and diaphoresis.

#### 6. Conclusions

Sedation and analgesia are widely used in NICU and all clinicians who provide care to neuropatients' face daily with such practice. The indication for sedation in NICU could be general or properly neurologic that is considered as a therapy in the acute brain injury patient. Sedation, indeed, allows a better control of cerebral hemodynamic and is part of control of intracranial pressure.

The knowledge of basic principles of pharmacology, neurophysiology, and neuropathology remains, therefore, essential to manage such kind of therapy.

Sedation in TBI Patients DOI: http://dx.doi.org/10.5772/intechopen.85266

Propofol and midazolam seem to be the most used drugs in such patient due to their security profile; ketamine appears to be interesting for its neuroprotective role.

To target sedation properly, it is possible to use different approaches; the use of score (RASS, SAS) in the awake patient remains a good tool that can be integrated in comatose patient, knowing their limits, with the newest EEG-derived methods.

### Conflict of interest

hemorrhage and hydrocephalus. There are many theories dealing with the pathophysiology of this entity. Disconnection of the inhibitory efferent pathways (malfunctioning pathways) from cortical areas of the brain is one of the possible theories. It is also thought that alterations in the excitatory nucleus of the brainstem can cause this syndrome; excitatory centers are then upregulated, increasing sympathetic activity. There is no accepted treatment for this entity. The objective is to mitigate signs and symptoms to avoid the adverse effects such as dehydration, muscle wasting or delayed recovery. Dopaminergic agents have shown to decrease body temperature and sweating. Alpha agonists can decrease heart rate and blood pressure. When medication fails, the use of hyperbaric oxygen therapy (HBOT) to control autonomic discharges and posturing in the subacute TBI phase has been reported. In this condition, sedation should be considered to reduce sympathetic

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Monitoring the depth of sedation is essential in the management of the patient in the ICU, and it influences their outcomes. Oversedation increases the risk of infections by delaying weaning from mechanical ventilation and increases length of stay and, thus, costs. On the other side, undersedation can cause agitation and anxiety of the patient, increase the risk of self-extubating and develop asynchronies between the patient and the ventilator. In NICU patients, assessing routine level of sedation is really important both for the daily wake-up tests that should be done for neuro-

There are various scales available for ICU patients. The Ramsay Sedation Scale evaluates consciousness, while the Richmond Agitation-Sedation Scale (RASS) examines cognition. The Motor Activity Assessment Scale (MAAS) and the Sedation-Agitation Scale (SAS) monitor sedation and arousal. Both RASS and SAS are reasonable to use in TBI patients [43]. Moreover, RASS is usually integrated with a delirium assessment performed with Confusion Assessment Method for the ICU (CAM-ICU). However, in deeply sedated patients and with muscular blockade, these scales become useless. EEG monitoring has therefore become a very investigated topic to titrate sedation in these patients. Simplified EEG tools like BIS, based on Fourier transform, have shown significant correlation with RASS and SAS in ABI [44]. However, BIS was developed to monitor sedation in the operating room (OR) setting in patients with no acute brain injury (ABI) due to the possible changes in

The possible confounders of such method are shivering, temperature fluctuation, increased muscle tone, grimacing and catecholamine levels. To assess the adequacy of pain relief, it is useful to assess autonomic signs of activation such as

Sedation and analgesia are widely used in NICU and all clinicians who provide care to neuropatients' face daily with such practice. The indication for sedation in NICU could be general or properly neurologic that is considered as a therapy in the acute brain injury patient. Sedation, indeed, allows a better control of cerebral

The knowledge of basic principles of pharmacology, neurophysiology, and neu-

ropathology remains, therefore, essential to manage such kind of therapy.

activation [42].

6. Conclusions

150

5. Monitoring sedation in the neuro-ICU

logic evaluation and, in comatose patients, to avoid oversedation.

EEG because of the brain lesion; it is often used in the ICU setting.

tachycardia, hypertension, ICP increase and diaphoresis.

hemodynamic and is part of control of intracranial pressure.

We declare no conflict of interest.

### Author details

Lorenzo Peluso<sup>1</sup> , Berta Monleon Lopez<sup>2</sup> and Rafael Badenes<sup>2</sup> \*

1 Department of Intensive Care Hôpital Erasme, Brussels, Belgium

2 Department of Anesthesiology and Surgical-Trauma Intensive Care, Hospital Clìnico Universitario, Valencia, Spain

\*Address all correspondence to: rafaelbadenes@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

[10] Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of Pain,

[11] Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients. Critical Care Medicine. 2006;34(2):374-380

Normeperidine toxicity. Anesthesia and

[13] Pitsiu M, Wilmer A, Bodenham A, et al. Pharmacokinetics of remifentanil and its major metabolite, remifentanil acid, in ICU patients with renal impairment. British Journal of Anaesthesia. 2004;92:493-503

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[15] Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new shortacting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology. 1993;79(5):881-892

[16] Delvaux B, Ryckwaert Y, Van Boven M, et al. Remifentanil in the intensive

withdrawal syndrome after prolonged sedation. Anesthesiology. 2005;102(6):

care unit: Tolerance and acute

[17] Karabinis A, Mandragos K, Stergiopoulos S, et al. Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: A

randomised, controlled trial

1281-1282

agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care

Medicine. 2018;46:e825-e873

[12] Armstrong PJ, Bersten A.

Analgesia. 1986;65(5):536-538

undergoing mechanical ventilation. The New England Journal of Medicine.

[2] A Villa F, Citerio G. Sedation and analgesia in neurointensive care. In: Textbook of Neurointensive Care. 2nd ed. London: Springer; 2013.

[3] Oddo M, Crippa IA, Mehta S, Menon

[4] Marklund N. The neurological wakeup test-A role in neurocritical care monitoring of traumatic brain injury patients? Frontiers in Neurology. 2017;8:

[5] Morandi A, Brummel NE, Ely EW. Sedation, delirium and mechanical ventilation: The "ABCDE" approach. Current Opinion in Critical Care. 2011;

[6] Kelly DF, Goodale DB, Williams J, et al. Propofol in the treatment of moderate and severe head injury: A randomized, prospective, doubleblinded pilot trial. Journal of Neurosurgery. 1999;90:1042-1052

[7] Cannon ML, Glazier SS, Bauman LA. Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged

propofol infusion. Journal of Neurosurgery. 2001;95:1053-1056

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2001;95:925-926

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[20] Bloor BC, Ward DS, Belleville JP, et al. Effects of intravenous dexmedetomidine in humans: Part II: Hemodynamic changes. Anesthesiology. 1992;77:1134-1142

[21] Talke P, Richardson CA, Scheinin M, et al. Postoperative pharmacokinetics and sympatholytic effects of dexmedetomidine. Anesthesia and Analgesia. 1997;85:1136-1142

[22] Triltsch AE, Welte M, von Homeyer P, et al. Bispectral index—Guided sedation with dexmedetomidine in intensive care: A prospective, randomized, double blind, placebocontrolled phase II study. Critical Care Medicine. 2002;30:1007-1014

[23] Venn RM, Bryant A, Hall GM, et al. Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in postoperative patients needing sedation in the intensive care unit. British Journal of Anaesthesia. 2001;86:650-656

[24] Drummond JC, Dao AV, Roth DM, et al. Effect of dexmedetomidine on cerebral blood flow velocity, cerebral metabolic rate, and carbon dioxide response in normal humans. Anesthesiology. 2008;108:225-232

[25] Dahmani S, Rouelle D, Gressens P, et al. Effects of dexmedetomidine on

hippocampal focal adhesion kinase tyrosine phosphorylation in physiologic and ischemic conditions. Anesthesiology. 2005;103:969-977

[26] Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the m anagement of severe traumatic brain injury XI. Anesthetics, analgesics, and sedatives. Journal of Neurotrauma. 2007;24 (Supp. 1):S71-S76

[27] Albanèse J, Arnaud S, Rey M, et al. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology. 1997;87(6):1328-1334

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Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

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[42] Perkes I, Baguley IJ, Nott MT, et al. A review of paroxysmal sympathetic hyperactivity after acquired brain injury. Annals of Neurology. 2010;68:

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126-135

21-26

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[35] Van Hemelrijck J, Fitch W, Mattheussen M, Van Aken H, Plets C, Lauwers T. Effect of propofol on cerebral circulation and autoregulation

in the baboon. Anesthesia and Analgesia. 1990;71:49-54

patients: A study on cerebral

1999;27:407-411

2002;166:1024-1028

University Press; 2016

154

[39] Samaniego EA, Mlynash M, Caulfield AF, et al. Sedation confounds outcome prediction in cardiac arrest survivors treated with hypothermia. Neurocritical Care. 2011;15:113-119

[40] De Lorenzo RJ, Hauser WA, Towne AR, et al. A prospective, populationbased epidemiologic study of status epilepticus in Richmond, Virginia. Neurology. 1996;46(4):1029-1035

[36] Albanese J, Viviand X, Potie F, Rey M, Alliez B, Martin C. Sufentanil, fentanyl, and alfentanil in head trauma

hemodynamics. Critical Care Medicine.

Respiratory and Critical Care Medicine.

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care unit. American Journal of

21(Supp. 2):S27-S37

### *Edited by Yongxia Zhou*

Traumatic brain injury (TBI) is a significant public health problem. There are several advanced techniques available for the investigation of disease neurobiology, diagnosis, and treatment. This book covers many topics in the active TBI research field such as cumulative mild head injury review, brain changes, and risk factors, as well as post-concussion syndrome (PCS) definition, classification, and association with brain dysfunction. Brain changes, including blood flow, intracranial pressure, and neuroinflammation, the neurobiological basis of neuroprotective activation, as well as correlation with PCS, including sleep, are illustrated further. Furthermore, multiple biomarkers, including S-100β, UCH-L1, and GFAP for blood–brain barrier breakdown and neuronal injury, are reviewed thoroughly. Lastly, well-evaluated neuroprotective agents, hypothermia as a neuroprotective effect in TBI, and effects investigation, as well as sedation in TBI as a neurocritical and therapeutic strategy with different assessments, are reported.

This book introduces readers to a number of perspectives, including TBI disease pathophysiology and post-concussion syndrome classification, associated brain changes, imaging diagnosis, and several useful biomarkers with high sensitivities, as well as multiple therapeutic strategies. Various advanced technical developments, upfront neuroimaging, and clinical data are presented together with comprehensive, up-todate, and interesting examples. Detailed reviews and accurate illustrations together with objective and informative discussions of several challenging problems such as PCS and neuroprotective treatments are the advantages of this book. Finally, this book will hopefully convey the clinical aspects of TBI and help guide diagnosis and therapeutic research in this field.

Published in London, UK © 2019 IntechOpen © Iaremenko / iStock

Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment

Traumatic Brain Injury

Neurobiology, Diagnosis and Treatment

*Edited by Yongxia Zhou*