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12. Neuropharmacological Interventions Post ABI

Abbreviations

5-HT                       5-hydroxytryptophan

ABI                         Acquired Brain Injury

ADHD                    Attention Deficit Hyperactivity Disorder

BTX-A                    Botulinum Toxin Type A

CNS                        Central Nervous System

CPP                        Cerebral Perfusion Pressure

EBIC                       European Brain Injury Consortium

EDS                        Excessive Daytime Sleepiness

EEG                        Electroencephalogram

GABA                    Gamma-Aminobutyric Acid

GCS                        Glasgow Coma Scale

HAM-D                 Hamilton Rating Scale for Depression

HO                          Heterotopic Ossification

ICP                         Intracranial Pressure

MAP                      Mean Arterial Pressure

MABP                   Mean Arterial Blood Pressure

NE                          Norepinephrine

PCT                        Prospective Controlled Trial

PEDro                    Physiotherapy Evidence Database rating scale

PTA                        Post-traumatic Amnesia

RCT                        Randomized Controlled Trial

TBI                          Traumatic Brain Injury

Key Points


Different opioids may have different intracranial pressure effects post ABI; where morphine, sufentanil, and alfentanil may increase intracranial pressure, remifentanil may not affect intracranial pressure, and the effect of fentanyl on intracranial pressure post ABI is unclear.

Carbamazepine may decrease agitated behaviour post-traumatic brain injury.

Carbamazepine can maintain or improve seizure control in TBI compared to other anticonvulsants.

Intramuscular midazolam may be effective for acute seizure cessation.

Levetiracetam may be as effective as phenytoin in treating and preventing seizures in individuals in the intensive care unit post ABI.

Anticonvulsants provided immediately post ABI may reduce the occurrence of seizures only within the first week.

Anticonvulsants provided shortly post ABI may not reduce late seizures.

Anticonvulsants may have negative consequences on motor tasks.

Phenobarbital may not be effective in reducing the risk of late seizure development post ABI.

Phenobarbital paired with phenytoin may decrease rate of post-traumatic epilepsy compared to no treatment following a TBI.

Valproic acid and divalproex may be used to decrease the incidence of aggressive behaviour; however, more research is needed.

Lamotrigine may be successful in reducing pathologic laughing post-traumatic brain injury. More research is needed, with a greater number of subjects, to validate these findings.

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.

Donepezil may help to improve attention, short-term, long-term, and visual memory following brain injury.

Physostigmine may improve long-term memory in men with TBI.

The effectiveness of sertraline in treating depression post TBI is unclear.

Citalopram may be helpful in the reduction of depression post ABI.

Citalopram and carbamazepine may be effective in the treatment of mood disorders.

Desipramine may be effective in reducing depression.

Sertraline hydrochloride can be useful in reducing aggressive and irritable behaviours.

Amitriptyline can be used to decrease agitation.

Lithium may reduce behavioural problems but is associated with a high risk of neurotoxicity.

Although there is evidence to suggest that quetiapine can help reduce aggressive behaviour, more research is needed.

Ziprasidone in one small study has been shown to assist in the controlling of agitation; however more research is needed.

Haloperidol appears to have little negative effect on recovery following TBI.

Droperidol may be an effective agent for calming agitated patients.

Methotrimeprazine may be safe for controlling agitation following an acquired brain injury.

Phenol blocks of the musculocutaneous nerve may help decrease spasticity and improve range of motion temporarily up to five months post injection.

Oral baclofen appears to reduce lower extremity spastic hypertonia.

Oral baclofen may not improve tone, spasm frequency of reflexes in the upper extremity.

Botulinum toxin type A injections may reduce localized spasticity and improve range of motion following ABI.

Patients receiving botulinum toxin type A through a single motor point or through multisite distributed injections may both show a reduction in spasticity.

Botulinum toxin type A may effectively improve both upper and lower limb spasticity in children and adolescents following brain injury.

Bolus injections of intrathecal baclofen may produce short-term reductions in upper and lower extremity spasticity post ABI.

Prolonged intrathecal baclofen may reduce upper and lower extremity spasticity post ABI.

Intrathecal baclofen may cause short-term improvements in walking performance in ambulatory patients post ABI.

Intrathecal baclofen pumps may reduce upper and lower limb spasticity in children with hypoxia.

There are conflicting reports regarding the efficacy of pentobarbital and thiopental for controlling elevated intracranial pressure; however, thiopental may be more effective than pentobarbital for controlling elevated intracranial pressure.

Pentobarbital may be less effective than mannitol for controlling elevated intracranial pressure.

Barbiturate therapy should be avoided until all other measures for controlling elevated intra cranial pressure are exhausted; patients undergoing barbiturate therapy should have their immunological response monitored.

Disodium Etidronate may prevent the development of heterotopic ossification.

Dexanabinol in cremophor-ethanol solution may not be effective in controlling intracranial pressure or improving clinical outcomes post TBI; however, dual cannabinol agonists may be effective in increasing cerebral perfusion pressure and reducing mortality post TBI.

Pindolol can decrease aggressive behaviour following brain injury.

Propranolol may reduce the intensity of aggressive and agitated symptoms following brain injury.

Although the administration of chemical deep vein thrombosis prophylaxis within the first 72 hours post ABI has been shown to be effective in reducing the risk of developing deep vein thrombosis or pulmonary embolism without increasing the risk of intracranial bleeding, more research is needed to determine its true effectiveness.

Enoxaparin may be effective for the prevention of VTE after elective neurosurgery and has not been found to cause excessive bleeding.

Mannitol may effectively lower elevated intracranial pressure; furthermore, high doses may yield lower mortality rates and better clinical outcomes.

Mannitol may be equally effective as hypertonic saline and less effective than sodium lactate for reducing elevated intracranial pressure.

Amantadine may improve consciousness, cognitive function, and disability post ABI.

Amantadine and pramipexole may be effective in improving levels of consciousness in children post TBI.

Amantadine has been shown to be ineffective in improving attention and memory deficits. Its impact on executive functioning should be studied further.

Amantadine requires further research before conclusions can be drawn on its effects on aggression.

Dopamine enhancing drugs may accelerate the rate of recovery from a low response state post TBI in children.

Bromocriptine may improve some executive cognitive functions such as dual task performance and motivational deficits but it may not consistently improve memory. More research is needed before the benefits of using bromocriptine to enhance cognitive functioning are known.

Administration of dexamethasone may inhibit endogenous production of glucocorticoids in children.

Dexamethasone administration has no proven impact on recovery post brain injury in children.

Medroxyprogesterone intramuscularly may reduce sexual aggression.

Progesterone may improve Glasgow Outcome Scale scores and reduce mortality rates up to 6 months post injury, without an increased rate of adverse events.

Progesterone may not be effective in lowering intracranial pressure levels.

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear.

Methylphenidate may be effective in improving reaction time for working memory.

Response to methylphenidate may depend on genotype.

Methylphenidate may not have an adverse effect on the sleep-wake cycle of those who have sustained a TBI when given in commonly accepted dosages.

Methylphenidate may be effective in reducing anger following a brain injury.

Evidence regarding the efficacy of methylphenidate to improve cognitive and behavioural function is conflicting in children.

Modafinil has not been shown to be effective in treating fatigue.

Modafinil has been shown to be effective short-term in treating excessive daytime sleepiness, but may also cause insomnia.

Propofol, especially at higher doses may improve intracranial pressure and cerebral perfusion pressure; furthermore, propofol may reduce intracranial pressure and the need for other intracranial pressure interventions when used in conjunction with morphine.

Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on intracranial pressure.

Midazolam may have no effect on intracranial pressure, but may reduce mean arterial pressure, cerebral perfusion pressured, and systolic blood pressure.

Midazolam may not be different than propofol in its effect on intracranial pressure, cerebral perfusion pressure, or long-term outcomes.

Corticosteriods such as methylprednisolone, dexamethasone, and glucocorticoids may worsen outcomes, with no effect on intracranial pressure levels, and should not be used.

Triamcinolone may improve outcomes in patients with a Glasgow Coma Scale<8 and a focal lesion.

Introduction

For a number of years, it has been recognized that brain injury causes alterations in neurotransmitter levels through a number of pathways including direct neuronal trauma, changes in neuronal membranes, and through secondary injury such as alterations in cerebral perfusion. A number of both clinical and basic science researchers have attempted to find pharmacological treatments in an attempt to normalize neurotransmitter levels and enhance brain recovery.

The neurotransmitters of interest include serotonin (5-hydroxytryptophan), acetylcholine, gamma-aminobutyric acid (GABA), and catecholamines such as dopamine and norepinephrine (NE). There are many subtypes of serotonin receptors and medications that have affinity for 5-hydroxytryptophan1a, 1b, and 1c, which tend to reduce aggression in humans and have effects on sleep, mood, and behaviour. Acetylcholine is most associated with memory in the central nervous system (CNS), but may have other effects. It is synthesized from choline in neurons and is degraded mostly by acetylcholinesterase at the synapse. GABA and glycine are inhibitory neurotransmitters found throughout the CNS. GABAA receptors affect chlorine channels and hyperpolarize nerve cell membranes. Therefore, the neuron is less likely to activate. GABAB receptors enhance potassium or decrease calcium conductance across the cell membrane.

The catecholamines dopamine and NE tend to stimulate target receptors. Dopamine has diffuse effects on the CNS and is involved with motor control, arousal, procedural learning, and cognition. There are at least five dopamine receptor variants and abnormalities. The D2 variant is implicated in Parkinson’s disease and the D4 variant in schizophrenia. The effects of NE are associated with sleep regulation, mood, aggression, and perception of sensation. It results from the conversion of tyrosine into dopamine and then into NE.

This module provides an overview of the medications that have been used in brain injury to enhance recovery of a number of brain functions. Most of these medications’ effects are believed to be mediated through alterations in the neurotransmitters mentioned above. The module is organized to provide clinicians with evidence of pharmacological interventions for a number of clinically relevant problems after brain injury.

12.1 Analgesics

12.1.1 Opioids

Key Points

Different opioids may have different intracranial pressure effects post ABI; where morphine, sufentanil, and alfentanil may increase intracranial pressure, remifentanil may not affect intracranial pressure, and the effect of fentanyl on intracranial pressure post ABI is unclear.

Opioids are substances that produce morphine-like effects by binding to opioid receptors, found principally in the central nervous system and gastrointestinal tract. Each opioid has a distinct binding affinity to groups of opioid receptors that determines its pharmacodynamic response. Morphine has been the most commonly used opioid following ABI, while fentanyl and its derivatives have gained popularity owing to their more rapid onset and shorter duration of effect (Metz et al., 2000). However, controversy persists regarding the effect of opioids on ICP and CPP.  It has been reported that opioids can increase cerebral blood flow, which may lead to an increase in ICP (Bunegin et al., 1989; de Nadal et al., 2000; Marx et al., 1989; Werner et al., 1995) in the presence of intracranial pathology.

Discussion

Analgesic sedation with opioids is commonly used in conjunction with hypnotic agents (i.e., midazolam, propofol) to reduce nociceptive stimulation, which makes it difficult to evaluate the effects of opioids in isolation. Five studies reported increases in ICP after opioid administration (Albanese et al., 1993; Albanese et al., 1999; de Nadal et al., 2000; Sperry et al., 1992; Werner et al., 1995), while two found no increase in ICP (Engelhard et al., 2004; Karabinis et al., 2004; Lauer et al., 1997) and one reported a decrease (Scholz et al., 1994). However, the mode of administration has been suggested as a determining factor for increases in ICP (Albanese et al., 1993; Albanese et al., 1999). In the studies where patients received only bolus injections of opioids, significant increases in ICP were seen (de Nadal et al., 2000; Sperry et al., 1992; Werner et al., 1995).

Conclusions

There is level 1a evidence that morphine, sufentanil, and alfentanil may result in increased intracranial pressure post ABI.

There is conflicting evidence (level 1b) regarding the effects of fentanyl on intracranial pressure post ABI.

There is level 2 evidence that remifentanil may not affect intracranial pressure post ABI.

12.2 Anticonvulsant Medications

Following an ABI, seizures can occur rather quickly due to the increased metabolic demands on the brain, increased ICP and the excessive amounts of neurotransmitters released. Seizures can occur within hours of the initial head trauma (immediate seizures), within the first week of sustaining an injury (early seizures), or within several months post injury (late seizures) (Pagni & Zenga, 2005; Temkin et al., 1995). These seizures can further complicate the injury as they can lead to increased damage (Schierhout & Roberts, 2001). It has also been noted that the risk for developing or having late seizures post ABI is related to the severity of injury; those with a severe ABI are at greater risk (Ferguson et al., 2010; Temkin et al., 1995). For a more detailed discussion on seizures post ABI refer to Module 10.

Medications used to treat seizures post injury include carbamazepine (Tegretol), phenytoin (Dilantin), phenobarbital, primadone (Mysoline) and valporic acid (Depekane)/divalproex (Epival). These treatments have been used with both the adult and paediatric populations and have shown some success. Anticonvulsants have also shown some success in controlling or reducing the incidences of aggressive and agitated behaviours post ABI. For a more detailed discussion on the effects of anticonvulsants on aggression and agitation please refer to Module 8.

12.2.1 Carbamazepine

Key Points

Carbamazepine may decrease agitated behaviour post-traumatic brain injury.

Carbamazepine can maintain or improve seizure control in TBI compared to other anticonvulsants.

Carbamazepine has been proposed as an effective substitute for lithium in treating agitation and aggression following severe TBI. It has also been suggested as an alternative to anticonvulsants for controlling seizures without having harmful cognitive and behavioural side effects (Azouvi et al., 1999).

Discussion

Azouvi et al. (1999) in an 8-week open drug trial administered carbamazepine (Tegretol) to 10 individuals with severe brain injury who had significant behavioural challenges that were interfering with care and/or family integration. Results indicated improvement on the behavioural scales at the first assessment (2 weeks), which were maintained only for the scales of irritability and disinhibition by the end of the trial; although, overall neurobehavioural and social functioning had improved. It should be noted that drowsiness was a frequent adverse event which limited the dosage being increased in 40% of the participants.

A systematic review by Thompson et al. (2015) found that the traditional antiepileptic drugs, phenytoin or carbamazepine, decreased the risk of early seizures compared to controls (RR 0.42; 95% CI, 0.23 to 0.73, p=0.003); however, the evidence was low quality. In terms of seizure management, carbamazepine maintained or improved control when it replaced other anticonvulsants (Wroblewski et al., 1989). Particularly, carbamazepine monotherapy improved (50%) or maintained (50%) seizure control when it replaced combination therapy with carbamazepine and phenobarbital or phenytoin.

Conclusions

There is level 4 evidence that carbamazepine may decrease the incidence of aggressive behaviours following a traumatic brain injury.

There is level 4 evidence that carbamazepine may not decrease seizure control compared to other anticonvulsants following a traumatic brain injury.

12.2.2 Midazolam

Key Points

Intramuscular midazolam may be effective for acute seizure cessation.

Midazolam has been shown to be effective in controlling seizures post ABI.

Discussion

There appears to be very little research evaluating the efficacy of anticonvulsants given to treat seizures following onset. We identified only one such study in this review. Wroblewski et al. (1992) reported on a collection of 10 case studies of patients with TBI treated with intramuscular (IM) midazolam for acute seizure cessation after other benzodiazepine drugs had failed. The authors reported that in all patients, seizures ceased within minutes of midazolam administration, with slight to moderate sedation being the only reported side effects. Midazolam also prevented the onset of prolonged seizures or status epilepticus.

Conclusions

There is level 4 evidence that intramuscular midazolam can be used for acute seizure cessation.

12.2.3 Phenytoin

Key Points

Levetiracetam may be as effective as phenytoin in treating and preventing seizures in individuals in the intensive care unit post ABI.

Anticonvulsants provided immediately post ABI may reduce the occurrence of seizures only within the first week.

Anticonvulsants provided shortly post ABI may not reduce late seizures.

Anticonvulsants may have negative consequences on motor tasks.

Early prevention of seizures has been attempted through administration of various anticonvulsants. It has been suggested that immediate administration of anticonvulsants, among them phenytoin, may be critical in reducing the risk of PTS developing (Pagni & Zenga, 2005).

Discussion

When it comes to seizure prophylaxis, phenytoin is the most commonly studied medication. When the administration of phenytoin is compared to a placebo, its effect on the occurrence of early seizures is inconclusive; Bhullar et al. (2014); Temkin et al. (1990), found it to be effective but Young et al. (1983) did not. A systematic review by Thompson et al. (2015) found that the traditional antiepileptic drugs, phenytoin or carbamazepine, decreased the risk of early seizures compared to controls (RR 0.42; 95% CI, 0.23 to 0.73, p=0.003); however, the evidence was low quality. Moreover, phenytoin was found to be no more effective than placebo in preventing late seizures (McQueen et al., 1983; Temkin et al., 1990; Young et al., 1983). In fact, Formisano et al. (2007) found that the occurrence of late seizures was significantly higher in patients treated with anti-epileptic medications than those who were not. It should be noted that phenytoin has been shown to have a negative impact on recovery. Dikmen et al. (1991) found that severely injured individuals receiving phenytoin performed more poorly on neuropsychological measures than controls at 1 month but no significant differences were found at 1 year. The following year (12 to 24 months), phenytoin was shown to have a small but negative effect on cognition (Dikmen et al., 1991). Further, those taking phenytoin had longer hospital stays and worse functional outcomes at discharge than individuals receiving no treatment (Bhullar et al., 2014). Overall, the evidence for the use of phenytoin for prevention of seizures is not favourable. There was no significant difference in mortality between those treated with antiepileptic drugs (phenytoin and carmazepam) and control subjects (RR 1.08; 95% CI, 0.79 to 1.46, p=0.64) (Thompson et al., 2015).

 

When phenytoin was compared to levetiracetam, the two drugs were comparable in terms of seizure rates (Inaba et al., 2013; Jones et al., 2008; Kruer et al., 2013; Radic et al., 2014), complications, adverse drug reactions, mortality rates (Inaba et al., 2013) and length of hospital stay (Kruer et al., 2013). A RCT by Szaflarski et al. (2010) found similar results in terms of there being no difference for early seizure rates, death or adverse events between the two drugs; however, the authors found that those on levetiracetam performed significantly better on the Disability Rating Scale at 3 and 6 months (p=0.042), and the Glasgow Outcome Scale at 6 months (p=0.039) post intervention compared to the phenytoin group. Furthermore, upon differentiation Radic et al. Radic et al. (2014) found that individuals with a midline shift greater than 0 millimeters were at a higher risk for electrographic seizures and a lower risk for adverse drug reactions on levetiracetam compared to phenytoin. Overall, a meta-analysis by Zafar et al. (2012) concluded that there was no superiority of either drug at preventing early seizures.

Conclusions

There is level 1b evidence to suggest that levetiracetam may be as safe and effective as phenytoin in the treatment and prevention of early seizures in individuals in the intensive care unit post ABI.

There is level 1b evidence that anticonvulsants given during the first 24 hours post ABI may reduce the occurrence of early seizures (within the first week post injury).

There is level 1a evidence that anticonvulsants given shortly after the onset of injury may not reduce mortality, persistent vegetative state, or the occurrence of late seizures (>1 week post injury).

There is level 1a evidence that seizure prophylactic treatment with either phenytoin or valproate may result in similar incidences of early or late seizures and similar mortality rates.

12.2.4 Phenobarbital

Key Points

Phenobarbital may not be effective in reducing the risk of late seizure development post ABI.

Phenobarbital paired with phenytoin may decrease rate of post-traumatic epilepsy compared to no treatment following a TBI.

Phenobarbital, a barbiturate, has been used to control seizures post ABI. It has also been used as a sedative to relieve anxiety.

Discussion

Individuals who were treated with a combination of phenytoin and phenobarbital as a seizure prophylaxis had a significantly lower incidence of post-traumatic epilepsy upon discontinuation of treatment compared to individuals who did not receive prophylaxis. This decrease was evident up to the two year follow-up. There were also no unfavourable or toxic side effects from either drug, which is important when discussing the risk of side effects versus the risk of post-traumatic epilepsy (Servit & Musil, 1981). Although a combination therapy, the effects of phenobarbital alone are not reported in this study. Manaka (1992) conducted an RCT examining the effects of phenobarbital for seizure control on those who had sustained a severe TBI. Those in the treatment group were administered phenobarbital at the end of the first month of study. Individuals receiving phenobarbital were given 10 to 25 ug/mL for a two year period, at which time individuals were tapered off the medication. All subjects in the study were monitored for the next five years. Study results indicate that phenobarbital did not have a prophylactic effect on post-traumatic epilepsy.

Conclusions

There is level 2 evidence indicating that phenobarbital given post ABI may not reduce the risk of late seizures.

There is level 2 evidence that phenobarbital combined with phenytoin prophylaxis may decrease rate of post-traumatic epilepsy compared to no prophylactic treatment.

12.2.5 Valporic Acid/Divalproex

Key Points

Valproic acid and divalproex may be used to decrease the incidence of aggressive behaviour; however, more research is needed.

Valproic acid, an antiepileptic, has been used to successfully treat seizure disorders in both adults and children. Moreover, it has been used to treat bipolar, post-traumatic stress disorder (PTSD) and mania (McElroy et al., 1987). It has also been found to reduce episodic explosiveness with an individual with TBI (Geracioti, 1994). Divalproex, another anticonvulsant, is believed to help reduce aggressive behaviours in individuals post TBI.

Discussion

Wroblewski et al. (1997b) examined the effects of valproic acid (Depakene) on reducing aggressive behaviour in a case series (n=5). Although the study reports that all patients showed a substantial reduction in challenging behaviour (i.e. outbursts, agitation, anger), no statistical analyses were performed. Researchers relied on visual inspection of data, and also presented graphs for only 3 of the 5 participants, rendering the interpretation of the findings difficult and potentially misleading. Further, patients were also part of a specialized neurobehavioural unit, which may have positively influenced the results.

Divalproex was used to treat symptoms of agitation in 29 patients with brain injuries (Chatham Showalter & Kimmel, 2000). Symptoms decreased in the majority of patients, indicating that divalproex may be an effective treatment to reduce agitation following brain injury.

Conclusions

There is level 4 evidence that valproic acid may decrease the incidence of aggressive behaviours.

There is level 4 evidence that divalproex may decrease the incidence of agitation post TBI.

12.2.6 Lamotrigine

Key Points

Lamotrigine may be successful in reducing pathologic laughing post-traumatic brain injury. More research is needed, with a greater number of subjects, to validate these findings.

The benefits of lamotrigine as an antiepileptic and mood stabilizer have been well established; however, its effectiveness as a mood stabilizer for patients with ABI has yet to be established (Gao & Calabrese, 2005; Tidwell & Swims, 2003).

Discussion

Results from a single study indicate that lamotrigine helps to reduce unwanted behaviours such as pathologic laughter but is not effective in reducing impulsivity (Chahine & Chemali, 2006). All four participants were on other medications to control for additional behaviours, however in each case these medications were eventually eliminated once lamotrigine was introduced. No formal outcome assessments were conducted making it challenging to draw conclusions from this study. Further research is needed.

Conclusions

There is Level 4 evidence to suggest that lamotrigine may help to reduce inappropriate behaviours post-traumatic brain injury.

12.3 Anti-Cholinesterase Inhibitors

12.3.1 Cerebrolysin and Cognitive Functioning

Key Points

Cerebrolysin may be beneficial for the improvement of clinical outcome and cognitive functioning following brain injury; however, controlled trials are needed to further evaluate its efficacy.

As explained by Alvarez et al. (2003), “Cerebrolysin (EBEWE Pharma, Unterach, Austria) is a peptide preparation obtained by standardized enzymatic breakdown of purified brain proteins, and comprises 25% low-molecular weight peptides and free amino acids” (pg. 272). Cerebrolysin has been demonstrated to have neuroprotective and neurotrophic effects, and has been linked to increased cognitive performance in an elderly population.

Discussion

In an open-label trial of 20 patients with TBI Alvarez et al. (2003) found that cerebrolysin was associated with improved brain bioelectrical activity, as evidenced by a significant increase in fast beta frequencies. A brief neuropsychological battery (Syndrome Kurztest) consisting of nine subtests was administered to evaluate memory and attentional functions in patients undergoing treatment with cerebrolysin. There was an overall significant improvement in performance post treatment, suggesting patients experienced cognitive benefits from cerebrolysin treatment. Improvements were also seen in terms of recovery, as measured by the GOS (Alvarez et al., 2003). Together these findings suggest that cerebroylsin may represent an effective neuroprotective therapy with tangible cognitive benefits for individuals living with an ABI. Controlled trials are necessary to further explore the efficacy of this drug.

Conclusions

There is level 4 evidence that cerebrolysin may improve attention and memory function post ABI, as well as clinical outcome.

12.3.2 Donepezil and Cognitive Functioning

Key Points

Donepezil may help to improve attention, short-term, long-term, and visual memory following brain injury.

The effectiveness of donepezil, a cholinesterase inhibitor, in improving cognitive and memory functions following brain injury has been assessed. Cognitive impairments affect one’s ability to return to work or school, as well as their ability to live alone (Masanic et al., 2001). When tested with individuals diagnosed with Alzheimer’s disease, donepezil has been found to be useful in treating memory problems (Morey et al., 2003; Walker et al., 2004). Its impact on cognitive function and memory in a TBI population is explored in the table below.

Discussion

In a RCT, Zhang et al. (2004) demonstrated that donepezil was associated with improvements in tasks of sustained attention and short-term memory, and that these improvements were sustained even after the washout period. Benefits associated with donepezil were also documented in an open-label study by Masanic et al. (2001) who found that the treatment tended to improve both short- and long-term memory of patients living with TBI. Improvements in memory were also reported by Morey et al. (2003) in their retrospective study who demonstrated that donepezil led to significant benefits in visual memory function.

Khateb et al. (2005) found only modest improvement on the various neuropsychological tests used to measure executive function, attention and learning and memory. Of note results from the learning phase of Rey Auditory Verbal Memory Test (RAVMT) showed significant improvement (p<0.05). To assess improvement in executive function, results from the Stroop-colour naming test showed significant changes (p<0.03). On the test for Attentional Performance (TAP) a significant change was noted on the divided attention (errors) subsection of the test.

Conclusions

There is level 1b evidence that donepezil may improve attention and short-term memory post ABI.

There is level 4 evidence that donepezil may be effective in improving short-, long-term, and visual memory post ABI.

12.3.3 Physostigmine

Key Points

Physostigmine may improve long-term memory in men with TBI.

Physostigmine is a cholinergic agonist that temporarily stops acetylcholinesterase which in turn slows the destruction of, and thereby increases the concentration of, acetylcholine at the synapse. Its use in Alzheimer’s disease has been examined at length. It has been proposed to improve memory in patients with head injury (McLean et al., 1987).

Discussion

In a double-blind, placebo-controlled randomized trial, oral physostigmine was administered to males with TBI as an active treatment (Cardenas et al., 1994). The authors found that physostigmine led to significant improvements in long-term memory scores in 44% (n=16) of study participants. Those who responded favourably to the treatment, as indicated by their performance on the Selective Reminding Test (SRT), also demonstrated improved balance compared to non-responders (Cardenas et al., 1994).

Conclusions

Based on a single RCT, there is level 1b evidence that oral physostigmine may improve long-term memory in men with TBI.

12.4 Anti-Depressants

Disorders of mood, including agitation, anxiety disorders, and major depression are all common following an ABI and are associated with suffering, worsening of other ABI sequelae, and poorer outcomes. The most common mood disorder after brain injury is a major depressive episode or depression (Jorge et al., 2004). A major depressive episode can result in hopelessness, feelings of grief or guilt, agitation, hopelessness, poor appetite, loss of libido and alterations in sleep. While ABI itself may also cause symptoms of sadness, grief, hopelessness, etc., a major depressive episode may slow the process of rehabilitation and may interfere with an individual’s ability to return to work or their relationships with family and friends (Jorge et al., 2004). For a more detailed discussion of anti-depressants and the effect on depression post ABI please refer to Module 8.

Depression is often treated pharmacologically following an ABI. Included among these Interventions are various antidepressants: serotonin selective re-uptake inhibitors such as sertraline, or citalopram; serotonin norepinephrine reuptake inhibitors such as duloxetine; and tricyclic antidepressants such as amitriptyline and desipramine. The following sections discuss the use of antidepressants following a brain injury.

Discussion

Two RCTs looked at the effects of sertraline on depression post ABI (Ashman et al., 2009; Lee et al., 2005). Ashman et al. (2009) compared sertraline to placebo and found improvements over time for both groups on all three outcomes (the Hamilton Rating Scale for Depression, the Beck Depression Inventory, and the Life-3 Quality of Life scales). No statistically significant differences were shown between the two groups; therefore the changes may not have been related to sertraline. The second RCT added a third arm to their trial. The authors randomized individuals with mild or moderate TBI to a sertraline, methylphenidate or placebo group (Lee et al., 2005). Similar to the first study, all participants improved on the depression measures (Beck Depression Inventory and the Hamilton Rating Scale for Depression). However, the study results indicated that those assigned to the sertraline and the methylphenidate groups reported significantly less depressive symptoms on these measures than the placebo group at study’s end (Lee et al., 2005). Further, fewer adverse events were reported for individuals receiving methylphenidate than those administered sertraline.

Conclusions

There is conflicting evidence that sertraline may be effective in the treatment of major depression post TBI.

12.4.1 Sertraline

Key Points

The effectiveness of sertraline in treating depression post TBI is unclear.

Discussion

Two RCTs looked at the effects of sertraline on depression post ABI (Ashman et al., 2009; Lee et al., 2005). Ashman et al. (2009) compared sertraline to placebo and found improvements over time for both groups on all three outcomes (the Hamilton Rating Scale for Depression, the Beck Depression Inventory, and the Life-3 Quality of Life scales). No statistically significant differences were shown between the two groups; therefore the changes may not have been related to sertraline. The second RCT added a third arm to their trial. The authors randomized individuals with mild or moderate TBI to a sertraline, methylphenidate or placebo group (Lee et al., 2005). Similar to the first study, all participants improved on the depression measures (Beck Depression Inventory and the Hamilton Rating Scale for Depression). However, the study results indicated that those assigned to the sertraline and the methylphenidate groups reported significantly less depressive symptoms on these measures than the placebo group at study’s end (Lee et al., 2005). Further, fewer adverse events were reported for individuals receiving methylphenidate than those administered sertraline.

Conclusions

There is conflicting evidence that sertraline may be effective in the treatment of major depression post TBI.

12.4.2 Citalopram

Key Points

Citalopram may be helpful in the reduction of depression post ABI.

Citalopram and carbamazepine may be effective in the treatment of mood disorders.

Discussion

Rapoport and colleagues Rapoport et al. (2008) administered 20 mg/day of citalopram for 6 weeks to one group while the second group began with 20 mg/day which was titrated to a maximum of 50 mg/day. The second group was studied for 10 weeks. For participants in both groups, their depression scores significantly decreased compared to baseline. In another study participants were randomly assigned to receive citalopram or placebo (Rapoport et al., 2010). Post-treatment relapse rates were calculated for each group and there were no significant differences noted between the groups with individuals relapsing (meeting criteria for major depressive disorder) 22 to 24 weeks post treatment; relapse occurred in 52.4% of patients. In both studies, adverse events were common (Rapoport et al., 2008; Rapoport et al., 2010). While citalopram on its own has shown potential to aid with depression, a study by Perino et al. (2001) found that when both citalopram and carbamazepine were given to patients diagnosed with post-TBI depression, scores on the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression  significantly improved after 12 weeks.

Conclusions

There is level 2 evidence that citalopram may aid in the reduction of depression post ABI.

There is level 4 evidence that citalopram and carbamazepine may be efficacious in the treatment of depression, anxiety and mood disorders.

12.4.3 Desipramine

Key Points

Desipramine may be effective in reducing depression.

Discussion

A single, small sample RCT found that desipramine was effective in treating long-standing depression (Wroblewski et al., 1996). Three of those in the treatment group and three in the control group had near complete resolution of depression; however, because the control group was crossed over to the treatment group, further studies are necessary before firm conclusions are drawn on this medication.

Conclusions

There is level 2 evidence to suggest that the administration of desipramine may assist in improving mood and reducing depression.

12.4.4 Sertraline and Amitriptyline

Key Points

Sertraline hydrochloride can be useful in reducing aggressive and irritable behaviours.

Amitriptyline can be used to decrease agitation.

Two studies examined the effect of antidepressants on reducing agitation and/or aggression in patients with brain injuries (Kant et al., 1998; Mysiw et al., 1988). Kant et al. (1998) examined the effect of sertraline, a serotonin selective reuptake inhibitors (SSRI), on reducing aggression and irritability in patients with brain injury, whereas Mysiw et al. (1988) examined the effect of amitriptyline (a tricyclic antidepressant (TCA) with both serotonergic and noradrenergic reuptake inhibition).

Discussion

Both studies showed potential to improve aggressive and agitated behaviour in patients with brain injuries. Kant et al. (1998) examined the effect of sertraline HCl (Zoloft) on reducing aggression and irritability in patients with closed head injuries of varying severities, two years post injury. The patients responded positively at both the four and eight week follow-ups, showing significant reduction in aggressive and irritable behaviour (Kant et al., 1998). The patients treated also had improvements in depression at week four. Mysiw et al. (1988) focused on 20 individuals who displayed agitation during their rehabilitation program and received amitriptyline. 70% of patients displayed significant reductions agitation within the first week (Mysiw et al., 1988). Both studies had similar limitations, those being small sample sizes and no true control groups.

Conclusions

There is level 4 evidence that sertraline hydrochloride can decrease the incidence of aggression and irritability.

There is level 4 evidence that amitriptyline can be useful in reducing the incidence of agitated behaviour.

12.5 Anti-Psychotics

12.5.1 Lithium Carbonate

Key Points

Lithium may reduce behavioural problems but is associated with a high risk of neurotoxicity.

Lithium carbonate has been used for many years in the treatment of mania and bipolar disorder (Kim, 2002). It has been suggested that mood disorders, such as mania, occurring after TBI, may contribute to the development of aggression (Kim, 2002; Wroblewski et al., 1997a). In the search for a pharmacological agent that reduces aggression following TBI with limited side effects in comparison to antipsychotics and benzodiazepines, lithium has been tried. Lithium carbonate also functions as a mood stabilizer.

Discussion

Lithium carbonate was used in a series of case reports with ten individuals with either TBI or stroke (Glenn et al., 1989). Glenn et al. (1989) reported favourable outcomes for the majority of patients (i.e., a decrease in observed aggressive, combative, or self-destructive behaviour or severe affective instability). However, this study highlights that there is a high risk of potential neurotoxicity among individuals with brain injuries, specifically in combination with neuroleptic drugs.

Conclusions

There is level 4 evidence to suggest that an antimanic agent (lithium carbonate) may reduce aggressive/agitated behaviour following a brain injury.

12.5.2 Quetiapine (Seroquel)

Key Points

Although there is evidence to suggest that quetiapine can help reduce aggressive behaviour, more research is needed.

Quetiapine has been used to reduce aggressive behaviour among those diagnosed with schizophrenia and Alzheimer’s disease (Volavka et al., 2004; Webb & Glueckauf, 1994). A closer examination of its impact within a brain injury population is discussed below.

Discussion

In one case series quetiapine assisted in helping to reduce aggressive behaviour in seven individuals (Kim & Bijlani, 2006). They also noted significant improvements in the Overt Aggression Scale-Modified, the Clinical Global Impression scores, and the overall scores of the Repeatable Battery for the Assessment of Neuropsychological Status. Quetiapine may be considered as an alternative to haloperidol or chlorpromazine if additional research finds it is just as effective in treating aggressive behaviours without the side effects (Kim & Bijlani, 2006).

Conclusions

There is Level 4 evidence (from one small study) to suggest that quetiapine may help reduce aggressive behaviour.

12.5.3 Ziprasidone

Key Points

Ziprasidone in one small study has been shown to assist in the controlling of agitation; however more research is needed.

Ziprasidone has been approved for acute agitation in those diagnosed with schizophrenia. It has also been found to work in the treatment of acute mania, often associated with bipolar disorder. For those who sustain a TBI, the period of post-traumatic amnesia (PTA) is defined as a period during which the individual is disorientated, have difficulty learning new concepts, and/or suffer from behaviour alterations (Brooke et al., 1992b). Researchers believe that these behaviour alternations may result from the individual’s lack of self-awareness which may be related to memory alterations that appear after the injury (Noé et al., 2007).

Discussion

Noé et al. (2007) studied individuals who were still in PTA stage at admission to rehabilitation. Within these participants, a decrease in agitation scores was reported during the first two weeks of ziprasidone administration. It was also noted that all who participated tolerated the medication with no clinical side effects observed. A larger RCT would be beneficial before any firm conclusions are made.

Conclusions

There is level 4 evidence from one study to suggest that ziprasidone can assist in the controlling of agitation post TBI.

12.5.4 Haloperidol

Key Points

Haloperidol appears to have little negative effect on recovery following TBI.

Haloperidol is a psychotropic drug found to reduce agitation. It also blocks or disrupts dopamine receptors. Thus, while it improves agitation, there is a theoretical concern that it may impede recovery by reducing arousal.

Discussion

In a retrospective chart review, agitation was managed in eleven patients with haloperidol and in fifteen patients without haloperidol (Rao et al., 1985). No significant differences were found between the two groups with regards to success of rehabilitation outcome; however, none of the patients in the treatment group obtained independence in intellectual skills (Rao et al., 1985).

Conclusions

There is level 4 evidence that haloperidol may not have a negative effect on the success of rehabilitation.

12.5.5 Droperidol (Inapsine)

Key Points

Droperidol may be an effective agent for calming agitated patients.

Droperidol is a butyrophenone antipsychotic agent that closely resembles haloperidol in structure. It has been used for the treatment of psychosis in Europe (Stanislav & Childs, 2000).

Discussion

When an individual is agitated, not only is the effectiveness of the medication administered important but also the time it takes to have a calming effect. One retrospective controlled trial found that a single-dose of droperidol calmed patients displaying agitated behaviour faster than other drugs such as haloperidol, lorazepam, and diphenhydramine (Stanislav & Childs, 2000). The study also found that droperidol calmed individuals without heavily sedating the patients like some of the comparative medications did. It is worth noting however that a large proportion of the sample had psychiatric co-morbidities; this should be kept in mind when generalizing the findings.

Conclusions

There is level 4 evidence that administration of a single-dose droperidol may calm agitated patients with ABI more quickly than other agents.

12.5.6 Methotrimeprazine

Key Points

Methotrimeprazine may be safe for controlling agitation following an acquired brain injury.

Methotrimeprazine (Nozinan) is a psychotropic medication. It has antipsychotic (mediated by dopamine blocking), tranquilizing, and analgesic properties. It appears to have an effect on opiate (pain) receptors as well (Maryniak et al., 2001).

Discussion

The oral administration of methotrimeprazine (MTZ) for agitation was evaluated in a retrospective chart review of 56 patients during inpatient rehabilitation (Maryniak et al., 2001). This was the first report on MTZ’s use in treating agitation after ABI and the authors found that in most cases MTZ was both safe and effective for controlling agitation. No standardized outcome measures were used within this study, and there was no control group; therefore, a more rigour study examining the safety and efficacy of MTZ within an ABI population is necessary before a level of evidence statement can be provided.

Conclusions

There is level 4 evidence that methotrimeprazine may be safe and effective for controlling agitation after an acquired brain injury.

12.6 Antispasticity Treatments

Spasticity is a common symptom encountered post ABI and is an element of the upper motor neuron syndrome. Spasticity has been formally defined as “a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon reflexes, resulting from excitability of the stretch reflex” (Lance, 1980). Common features of spasticity include increased muscle tone, exaggerated tendon jerks, and clonus.

Management of spasticity is not unique to brain injury survivors, since it is often associated with other conditions affecting the CNS such as spinal cord injury (SCI) and multiple sclerosis (MS). Spasticity may require intervention when it interferes with functional abilities such as mobility, positioning, hygiene, or when it is the cause of deformity or pain. Factors that must be taken into consideration when proposing treatment of spasticity include chronicity of the problem, the severity, the pattern of distribution (focal versus diffuse), and the locus of injury (Gormley et al., 1997), as well as comorbities. Some studies have found that spasticity of cerebral origin versus SCI respond differently to the same medications (Katz & Campagnolo, 1993). Typically, the clinical approach to spasticity is to first employ treatments that tend to be less interventional and costly; however, multiple strategies may need to be administered concurrently.

12.6.1 Nerve Block

Key Points

Phenol blocks of the musculocutaneous nerve may help decrease spasticity and improve range of motion temporarily up to five months post injection.

Local nerve blocks may be a potential management solution in circumstances where there is muscle spasticity affecting only a few muscle groups in a focal pattern.  Essentially, a nerve block involves the application of a chemical agent to impair nerve functioning.  The effect of the chemical agent may be temporary or permanent (Katz et al., 2000). Temporary acting agents include local anesthetic agents that block sodium ion channels, typically lasting only a few hours. Local anesthetic agents are used for diagnostic procedures or for assistance with activities such as casting (Gracies et al., 1997).  Agents used for permanent nerve blocks to treat spasticity include ethyl alcohol (>10%) and phenol (>3%). The duration of effect for these agents is between 2 and 36 months.  Complications of this type of block have included chronic dysesthesia, pain and permanent peripheral nerve palsies (Gracies et al., 1997).

Discussion

We identified two studies which evaluated the efficacy of nerve blocks as a treatment for spasticity.  Keenan et al. (1990) evaluated the effect of percutaneous phenol block of the musculocutaneous nerve to decrease elbow flexor spasticity.  The results indicated that there was improved range of motion of the elbow lasting a mean of five months.  In the second study, 11 closed head injury patients with spastic paralysis of the upper extremity were treated with percutaneous phenol injections into the spastic wrist and finger flexors (Garland et al., 1984).  The authors reported that relaxation of muscle tone persisted for up to two months following the injections.  Furthermore, there was a mean increase in resting wrist angle, active wrist extension, and passive wrist extension with finger flexed of 25, 30, and 5°, respectively (Garland et al., 1984). Evidently, these studies found that percutaneous phenol blocks are effective in temporarily controlling spasticity in patients post TBI.

Conclusions

There is level 4 evidence that phenol nerve blocks may reduce contractures and spasticity at the elbow, wrist and finger flexors for up to five months post injection.

12.6.2 Oral Antispasticity Drugs

Key Points

Oral baclofen appears to reduce lower extremity spastic hypertonia.

Oral baclofen may not improve tone, spasm frequency of reflexes in the upper extremity.

Oral agents are often used to manage spasticity particularly when a systemic agent to treat upper and lower extremity spasticity is required (Gracies et al., 1997). Although anti-spasticity agents may be used with other medical conditions such as spinal cord injury or multiple sclerosis (Gracies et al., 1997), the effectiveness should not be presumed to be similar for brain injury survivors.  Multiple medications have been evaluated to treat spasticity of both cerebral and spinal cord origin. The more common medications include GABA agonists that effect ion flux such as baclofen, benzodiazepines, dantrolene sodium, as well as agents that effect alpha-2 adreno receptors such as tizanidine and clonidine. The use of any of these drugs must be weighed against potential side effects, such as sedation, which are complicated by the cognitive and behavioural changes associated with brain injury.

Discussion

Oral Baclofen

Meythaler et al. (2004) completed a retrospective study evaluating the use of oral baclofen to manage spasticity in a mixed brain injury and stroke population. Pre and post testing revealed that oral baclofen improved spasticity in the lower extremity assessed using the Ashworth Rigidity Scale and Spasm Frequency Scale; however, no changes for tone, spasm frequency or reflexes were found for the upper extremity (Meythaler et al., 2004). The authors suggest that the lack of effect may be due in part to receptor specificity issues. Of note, a common adverse effect of the oral baclofen was the onset of considerable sleepiness in 17% of patients (Meythaler et al., 2004).

Oral Tizanidine

Meythaler et al. (2001) completed a randomized, double blinded placebo controlled cross over trial examining tizanidine for the management of spasticity. This study evaluated both stroke (53%) and TBI (47%) survivors. For both lower and upper extremity, there was a significant decrease in the Ashworth scores on the affected side with the active drug compared to placebo. However, significant differences between interventions were not found for upper and lower extremity spasm and reflex scores. Overall the authors felt that tizanidine was effective in decreasing the spastic hypertonia associated with ABI; however, a common side effect was increased somnolence (41%) Meythaler et al. (2001). Despite the study showing effectiveness, no level of evidence will be assigned for this drug due to more than 50% of the population being stroke.

Conclusions

There is level 4 evidence that oral baclofen may improve lower extremity spasticity but not upper extremity spasticity.

12.6.3 Botulinum Toxin Injections

Botulinum toxin type A (BTX-A) acts at pre-synaptic terminals to block acetylcholine released into the neuromuscular junction. When selectively injected into a specific muscle, BTX-A is thought to cause local muscle paralysis, thereby alleviating hypertonia caused by excessive neural activity (Jankovic & Brin, 1991). It has been suggested that BTX-A may be useful in the treatment of localized spasticity if oral treatments such as benzodiazepines, baclofen, dantrolene sodium, or tizanidine cause significant adverse effects (Gracies et al., 1997). The following sections review the use of botulinum toxin injections to remediate spasticity post-ABI in both the adult and paediatric population.

12.6.3.1 Botulinum Toxin Injections and the Adult Population

Key Points

Botulinum toxin type A injections may reduce localized spasticity and improve range of motion following ABI.

Patients receiving botulinum toxin type A through a single motor point or through multisite distributed injections may both show a reduction in spasticity.

Discussion

Five studies examining the effects of BTX-A on spasticity following ABI were identified. Intiso et al. (2014) showed a reduction in spasticity for the upper extremity (elbow, wrist, and hand), as well as ankle joints at one and four months post intervention. Although pain was also significantly reduced, no significant improvements in function were shown, measured by the Glasgow Outcome Scale and the Frenchay Arm Test (Intiso et al., 2014). These findings were similar to those found by Yablon et al. (1996) who reported that BTX-A injections into the upper extremities improved range of motion and spasticity in 21 patients with ABI. These improvements were shown for patients who received the injections within one year of injury and also for those greater than one year post (Yablon et al., 1996). The time between injury and injection was also studied by Clemenzi et al. (2012). The results were similar to the previous study for pain and spasticity; however, the time between onset and injection did have an effect on functional outcomes. Patients with a shorter period of time between their injury and first injection had greater improvements on the Barthel Index (Clemenzi et al., 2012).

For the lower extremity, Fock et al. (2004) reported that BTX-A injections improved measures of walking performance including walking speed, stride length, cadence, dorsiflexion on contact with the ground and passive dorsiflexion. In terms of the administration of BTX-A, Mayer et al. (2008) found that a single motor point injection and multisite distributed injection resulted in similar outcomes, with both groups showing a clinical effect at three weeks post-intervention.

Conclusions

There is level 2 evidence that botulinum toxin type A injections can be effective in the management of localized spasticity following ABI.

There is level 1b evidence to suggest that patients receiving botulinum toxin type A through a single motor point or through multisite distributed injections may both show a reduction in spasticity regardless of the drug administration method.

12.6.3.2 Botulinum Toxin Injections and the Paediatric Population

Key Points

Botulinum toxin type A may effectively improve both upper and lower limb spasticity in children and adolescents following brain injury.

Discussion

Two studies evaluated the effectiveness of botulinum toxin type A (BTX-A) for the management of spasticity in children with an ABI. Overall, BTX-A improved spasticity and range of motion in children and adolescents that sustained an ABI (Guettard et al., 2009; van Rhijn et al., 2005). When BTX-A for both upper and lower extremities was paired with other therapies (physical, occupational and exercise therapy) there was also an improvement in voluntary motor control, in addition to the improvements seen in spasticity and range of motion. However, due to the lack of comparison group, conclusive statements cannot be made; it is difficult to determine if the effects were due to the combination of therapy, BTX-A alone, or the standard therapy. Future research should differentiate these groups to compare effectiveness (Guettard et al., 2009). Importantly, BTX-A treatment did not cause any adverse side effects for injection doses under 10 U/kg of botulinum toxin (Guettard et al., 2009; van Rhijn et al., 2005). Intra-muscular BTX-A injections may be considered an effective treatment for severely brain-injured children, especially in combination with orthotic devices and specific functional exercise programs. A review of the literature on botulinum toxin suggests that injections are effective for lower limb functional improvements, however future research is needed to determine the effects for the upper limb (Gordon & di Maggio, 2012).

Conclusions

There is level 2 evidence that botulinum toxin type A may be an effective treatment for children and adolescents with upper and lower limb spasticity.

12.6.4 Intrathecal Baclofen

A limitation of oral baclofen is the inability to achieve sufficient concentrations in the cerebrospinal fluid in order to modify spasticity without first causing significant sedation (Gracies et al., 1997). Intrathecal baclofen refers to direct administration of baclofen into the intrathecal space and cerebrospinal fluid at the lumbar level. For therapeutic treatment, a subcutaneously placed pump is required to provide continuous administration of the medication into the intrathecal space. This treatment procedure is more invasive and is associated with complications including infection, pump failure and tube complications such as kinking or disconnection (Gracies et al., 1997). The following sections review the current evidence for the use of intrathecal baclofen post-ABI in both the adult and paediatric population.

12.6.4.1 Intrathecal Baclofen and the Adult Population

Key Points

Bolus injections of intrathecal baclofen may produce short-term reductions in upper and lower extremity spasticity post ABI.

Prolonged intrathecal baclofen may reduce upper and lower extremity spasticity post ABI.

Intrathecal baclofen may cause short-term improvements in walking performance in ambulatory patients post ABI.

Discussion

Meythaler et al. (1996) confirmed the effectiveness of intrathecal baclofen in decreasing upper and lower extremity spasticity in a randomized, double blinded, placebo controlled cross-over trial. In subsequent studies, the same investigators went on to demonstrate the effectiveness of intrathecal baclofen for decreasing spasticity for up to three months (Meythaler et al., 1997) and 1 year (J. M. Meythaler et al., 1999). Investigations carried out by other research groups have reported similar findings regarding the efficacy of intrathecal baclofen for the management of spasticity post-ABI (Becker et al., 1997; Chow et al., 2015; Dario et al., 2002; Francisco et al., 2005; Hoarau et al., 2012b; Margetis et al., 2014; Posteraro et al., 2013; Stokic et al., 2005; Wang et al., 2016). However, a common limitation of these studies is the lack of a control group. Regardless, it appears that intrathecal baclofen is an effective treatment for spasticity; however, some adverse effects such as urinary hesitancy were reported. Hoarau et al. (2012a) conducted a 10-year follow up of individuals with dysautonomia and hypertonia treated with intrathecal baclofen therapy. The study found that 62.8% of participants had some type of complication; infections at the operative site was the most frequent complication (20.9%), followed by overdosed with profound flaccidity, sedation, and vomiting (16.3%) (Hoarau et al., 2012a).

Studies have also evaluated the functional consequences by assessing walking performance, gait speed and range of motion following a bolus injection of intrathecal baclofen (Chow et al., 2015; Horn et al., 2010; Horn et al., 2005). Horn et al. (2005) and Horn et al. (2010) found that although the injections produced changes in joint range of motion during gait, only ankles showed a significant result. Chow et al. (2015) similarly found an increase in ankle range of motion but found no significant differences in terms of gait speed, stride length, cadence or stance. Future studies should be conducted using a prospective controlled trial or RCT study design that includes control groups to further establish the efficacy of intrathecal baclofen for the management of spasticity post ABI.

Conclusions

There is level 1b evidence that bolus intrathecal baclofen injections may produce short-term (up to six hours) reductions in upper and lower extremity spasticity following ABI.

There is level 4 evidence to suggest that prolonged intrathecal baclofen may result in longer-term (three months, and one year) reductions in spasticity in both the upper and lower extremities following an ABI.

There is level 4 evidence, from two studies, to suggest that intrathecal baclofen can result in short-term improvements of walking performance in ambulatory patients, particularly gait velocity, stride length, and step width.

12.6.4.2 Intrathecal Baclofen and the Paediatric Population

Key Points

Intrathecal baclofen pumps may reduce upper and lower limb spasticity in children with hypoxia.

Discussion

An intrathecal baclofen injection pump improved spasticity in three young children (Walter et al., 2015). However, unlike botulinum toxin, baclofen side effects were more common. Two of the three patients had complications and five of the complications were related to the device. Two of these complications were due to skin protrusions. The pumps must be implanted in the skin and one child experienced problems with epifascial implantation. However these effects were minimized with subfascial implantation, which has become the sole technique for intrathecal baclofen pump implantations for children (Walter et al., 2015). Other complications were due to wound infection, cerebrospinal fluid leakage, and intractable spasticity. All complications were reversed with treatment or relocation of the pump.

Conclusions

There is level 4 evidence that intrathecal baclofen pumps may be effective at reducing spasticity in the upper and lower limbs for children with hypoxia.

12.7 Barbiturates

Key Points

There are conflicting reports regarding the efficacy of pentobarbital and thiopental for controlling elevated intracranial pressure; however, thiopental may be more effective than pentobarbital for controlling elevated intracranial pressure.

Pentobarbital may be less effective than mannitol for controlling elevated intracranial pressure.

Barbiturate therapy should be avoided until all other measures for controlling elevated intra cranial pressure are exhausted; patients undergoing barbiturate therapy should have their immunological response monitored.

Barbiturates have long been proposed as a useful intervention in the control of ICP. They are thought to reduce ICP by suppressing cerebral metabolism and reducing metabolic demands and cerebral blood volume (Roberts, 2000). Early reports indicated that barbiturates reduced ICP in patients reported to be unresponsive to rigorous treatments with conventional ICP management techniques, including mannitol and hyperventilation (Marshall et al., 1979; Rea & Rockswold, 1983; Rockoff et al., 1979). However, most of these early investigations provided only anecdotal or poor evidence, as they were conducted in very small cohorts of patients lacking control comparisons. Later studies explored the negative side effects associated with barbiturate coma, such as adrenal insufficiency (Llompart-Pou et al., 2007) and bone marrow suppression (Stover & Stocker, 1998).

The AANS made Level II B recommendations that high-dose barbiturates can be used to control elevated ICP that is refractory to maximum standard medical and surgical treatment (Carney et al., 2017). They also reported Level II evidence against the use of prophylactic barbiturates for inducing electroencephalogram burst suppression. The EBIC guidelines recommended barbiturate use to increase sedation only after previous sedation, analgesia, hyperventilation, osmotic therapy, and cerebrospinal fluid drainage have failed to control ICP (Maas et al., 1997).

Discussion

The findings of an RCT by Eisenberg et al. (1988) suggested that pentobarbital was an effective adjunctive therapy for the management of elevated ICP refractory to conventional therapeutic measures. However, this study only supported the use of the high dose barbiturate for a small subgroup of patients with severe ABI (GCS≤7). In contrast, the findings of an RCT by Ward et al. (1985) suggested that pentobarbital was no better than conventional ICP management measures, which was corroborated by Schwartz et al. (1984) in an RCT by Thorat et al. (2008) in a smaller case series.

While barbiturate use may decrease elevated ICP, it should be used with caution due to the many reports of adverse events. Schwartz et al. (1984) found that over half of those treated with pentobarbital developed arterial hypotension, an adverse effect that could worsen the condition of patients with severe ABI. Schalen et al. (1992) also noted that decreased ICP was associated with decreased CPP and MAP. More recently, Majdan et al. (2013) found that barbiturate administration was associated with a significant increase in the amount of time spent with low MAP, despite a decrease in the amount of time with elevated ICP. Furthermore, the authors reported that high doses of barbiturate were associated increased intubation days, days in the ICU, and did not improve clinical outcomes.

In accordance with recommendations made by the Brain Trauma Foundation, (Perez-Barcena et al., 2005; Perez-Barcena et al., 2008) compared the efficacy of pentobarbital and thiopental on the management of refractory ICP unmanageable by conventional measures. In two linked trials, they reported that thiopental was superior to pentobarbital in controlling refractory ICP. In the first report, thiopental was shown to help reduce refractory ICP in a greater number of patients, although these differences were not statistically different (Perez-Barcena et al., 2005). In a follow-up report, the authors found statistically significant results in favour of thiopental using multivariate logistic regression (Perez-Barcena et al., 2008).

Llompart-Pou et al. (2007) found thiopental less likely to induce adrenal insufficiency when compared to pentobarbital, further supporting its use when barbiturate coma is indicated. It should be noted that in an earlier study, Stover and Stocker (1998) reported that use of thiopental significantly reduced white blood cell production and could induce reversible leukopenia and granulocytopenia. The authors also noticed interactions with bone marrow suppressing antibiotics, which further exacerbated the problem. Thus, in instances where barbiturate coma is indicated, monitoring of immunological response is recommended.

There is little evidence that barbiturate therapy contributes to improvements in long-term clinical outcomes. In a prospective trial by Nordby and Nesbakken (1984), the authors reported that thiopental combined with mild hypothermia resulted in better clinical outcomes one year post injury when compared with conventional ICP management measures (including hyperventilation, steroids and mannitol).  However, since this study used a combination of thiopental and hypothermia, it is not possible to attribute the better clinical outcomes to thiopental alone.

A Cochrane review of seven trials involving 341 patients stated that there was no evidence that barbiturates decreased blood pressure or reduced mortality for one in four patients post TBI (Roberts & Sydenham, 2012). Therefore it was recommended that barbiturate coma be avoided until all other measures for controlling elevated ICP are exhausted.

Conclusions

There is conflicting (level 1b, level 2, level 3) evidence regarding the efficacy of pentobarbital in improving intracranial pressure over conventional management measures.

There is level 2 evidence that thiopental may be more effective than pentobarbital for controlling elevated intracranial pressure.

There is level 2 evidence that pentobarbital may not be more effective than mannitol for controlling elevated intracranial pressure.

There is level 3 evidence that high-dose barbiturate may result in increase length of stay and may not improve outcomes when compared to low-dose barbiturate.

There is level 4 evidence that barbiturate therapy may cause reversible leukopenia, granulocytopenia, and systemic hypotension, as well as supressed bone marrow production.

There is level 4 evidence that a combination barbiturate therapy and therapeutic hypothermia may result in improved clinical outcomes up to 1 year post injury.

12.8 Bisphosphonates

The evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) as prophylactic treatment for heterotopic ossification (HO) comes mostly from the use of indomethacin or ibuprofen as HO prophylaxis in patients following total hip arthroplasty (THA) (Kjaersgaard-Andersen & Schmidt, 1986; Ritter & Sieber, 1985). Although it has been reported that the prophylactic use of these medications significantly decreases HO formation following THA, it is not known if they have the same effect in the post ABI population.

12.8.1 Etidronate Disodium

Key Points

Disodium Etidronate may prevent the development of heterotopic ossification.

Ethylhydroxydiphosphonate (EHDP), or more commonly referred to as etidronate disodium, is a bisphosphonate that has been used in the prophylaxis and treatment of HO and remains controversial (Watanabe TK & MO., 2001). EHDP works by preventing the aggregation, growth and mineralization of calcium hydroxyapatite crystals which are essential for bone formation. EHDP may potentially delay fracture healing, as long-term use has been associated with osteomalacia.

Discussion

Although EHDP has been shown to be effective in reducing HO in other populations, such as spinal cord injury, its effectiveness among individuals with brain injury is less studied. In an ABI population, Spielman et al. (1983) found that patients treated with EHDP showed a significantly lower incidence of HO than the control group. However, due to the small sample size of the study and the research design, additional research assessing the benefit of EHDP for the intervention of HO following brain injury is needed.

Conclusions

There is level 2 evidence that Disodium Etidronate (EHDP) may reduce the development of heterotopic ossification in patients with severe head injury.

12.9 Cannabinoids

Key Points

Dexanabinol in cremophor-ethanol solution may not be effective in controlling intracranial pressure or improving clinical outcomes post TBI; however, dual cannabinol agonists may be effective in increasing cerebral perfusion pressure and reducing mortality post TBI.

Dexanabinol (HU-211) is a synthetic, non-psychotropic cannabinoid (Mechoulam et al., 1988). It is believed to act as a non-competitive N-methyl-D-aspartate receptor antagonist to decrease glutamate excitotoxicity (Feigenbaum et al., 1989). It is also believed to possess antioxidant properties (Eshhar et al., 1995) and has shown encouraging neuroprotective effects in animal models of TBI (Shohami et al., 1995).

Discussion

In an early RCT, Knoller et al. Knoller et al. (2002) found that dexanabinol (50 mg or 150 mg) showed significant improvements in ICP and CPP over placebo for patients with TBI.  Despite showing significant improvements on the GOS and Disability Rating Scale at one month post treatment, these benefits progressively lost significance over the 6-month follow-up.  Maas et al. (2006) conducted a large-scale multicenter RCT to better establish the efficacy of dexanabinol in the treatment of TBI.  Patients admitted to 86 different centres from 15 countries were randomized to receive dexanabinol or placebo within six hours of injury. The authors reported that dexanabinol did not significantly improve outcomes on the GOSE, Barthel Index, or quality of life measures (SF-36, CIQ) at six months when compared to placebo.  Moreover, dexanabinol failed to provide any acute control of ICP or CPP. These findings suggest that the initial benefits reported by Knoller et al. (2002) may have been due to their small sample size. In a more recent RCT, Firsching et al. (2012) utilized a dual cannabinoid agonist as means of reducing ICP. When compared to placebo, the authors reported significant increases in CPP and greater survival at one month, but non-significant decreases in ICP. These results suggest that the dual cannabinoid agonist may an overall positive effect on patients post TBI and is worth exploring in future research.

Conclusions

There is conflicting (level 1b) evidence as to whether dexanabinol in cremophor-ethanol solution effectively lowers intracranial pressure, increases cerebral perfusion pressure, and improves long-term clinical outcomes post TBI when compared to placebo.

There is level 1b evidence that a dual cannabinoid agonist may significantly increase cerebral perfusion pressure and improves survival post TBI when compared to placebo.

12.10 Cardiovascular Medication

12.10.1 Beta-Blockers

It has been suggested that beta-blockers may improve agitation, anxiety and aggressive symptoms following brain injury, and reduce restlessness. Often the dosage is high, leaving patients susceptible to adverse effects such as sedation, depression and lethargy (Levy et al., 2005).

12.10.1.1 Pindolol

Key Points

Pindolol can decrease aggressive behaviour following brain injury.

Pindolol is a beta-blocker unlike many others in that it exerts a partial agonist effect, providing only a slight stimulation of the blocked receptor and maintaining a better resting sympathetic tone.

Discussion

Greendyke and Kanter (1986) investigated the effectiveness of a beta-blocker, pindolol, for the improvement of behavioural disturbances post ABI. A significant reduction in behaviours that led to assaults was demonstrated during treatment with pindolol, with the authors stating the optimal dose ranged between 40-60 mg per day. No therapeutic advantage was gained with doses beyond that but rather it led to adverse events (Greendyke & Kanter, 1986). Although the frequency of supplemented psychotropic medications was reduced in the pindolol group, these medications were still given and may have attributed to the reduction in assaultive episodes.

Conclusions

Based on a single RCT, there is level 1b evidence that pindolol may decrease aggression following brain injury.

12.10.1.2 Propranolol

Key Points

Propranolol may reduce the intensity of aggressive and agitated symptoms following brain injury.

Propranolol is a non-selective beta-blocker and has been used for the reduction of aggressive behaviours associated with compromised brain function. It is not known how this drug works to affect behaviour, however it appears to lack serious cognitive and affective side effects of other medications or physical restraints used to treat agitation post injury (Levy et al., 2005).

Discussion

Greendyke et al. (1986) investigated the effectiveness of a beta-blocker, propranolol, for the improvement of behaviour associated with brain disease in a randomized, crossover trial. Significantly fewer assaults and attempted assaults occurred during the 11-week propranolol treatment as compared to the placebo group. Of the nine patients, five showed marked improvement, two demonstrated moderate improvement, and two showed little or no improvement in assaultive behaviour. It should be noted that the participants also had severe dementia; therefore, this study was not used to draw conclusions for an ABI population as a whole. A later study by Brooke et al. (1992a) found that propranolol was effective in reducing the intensity of the agitation but was not significantly more effective in reducing the number of episodes compared to a placebo.

Conclusions

There is level 1b evidence that propranolol may reduce the intensity of agitated symptoms following brain injury.

12.11 Anti-Coagulants

Key Points

Although the administration of chemical deep vein thrombosis prophylaxis within the first 72 hours post ABI has been shown to be effective in reducing the risk of developing deep vein thrombosis or pulmonary embolism without increasing the risk of intracranial bleeding, more research is needed to determine its true effectiveness.

Enoxaparin may be effective for the prevention of VTE after elective neurosurgery and has not been found to cause excessive bleeding.

Subcutaneous heparin in low doses has been reported to be both safe and effective as prophylaxis against deep venous thrombosis (DVT) development post ABI (Watanabe & Sant, 2001). The route of delivery may also affect the efficacy of anticoagulant prophylaxis (Watanabe & Sant, 2001). For this reason, intravenously delivered heparin may be more effective in the prevention of thromboembolism compared with subcutaneous administration, although this method of delivery might increase the risk of bleeding (Green et al., 1988). Low-molecular weight heparins (LMWH), which are injected subcutaneously, have gained popularity due to the ease of administration and dosage adjustment. Of note, low-molecular weight variants of unfractionated heparin are significantly more expansive, and thus the risks, benefits, and costs need to be balanced out on an individual basis (Watanabe & Sant, 2001). Carlile et al. Carlile et al. (2006) found that 15 of the 16 rehabilitation centers surveyed reported routinely initiating treatment with either LMWH or low-dose unfractionated heparin. In a study with a mixed trauma population, low-dose heparin was compared to enoxaparin (LMWH) for the treatment of DVT (Geerts et al., 1996). Of those receiving low-dose heparin 44% suffered a DVT compared to 31% of patients receiving enoxaparin (p=0.014) (Geerts et al., 1996).

Discussion

The effect of administering chemical prophylaxis for DVT post ABI has been reviewed. Results indicate that early treatment (within the first 72 hours) may reduce the risk of developing DVT post injury (Byrne et al., 2016; Farooqui et al., 2013; Kim et al., 2002; Kim et al., 2014; Norwood et al., 2008; Salottolo et al., 2011; Scudday et al., 2011) without increasing the risk of intracranial hemorrhagic injury (Byrne et al., 2016; Koehler et al., 2011; Scudday et al., 2011) or deterioration on neurological examination (Kim et al., 2002).

Patients with ABI who were started on unfractionated heparin within three days of injury onset, compared to those who started after this time period, did not differ significantly in terms of the number of thromboembolic events (Kim et al., 2002; Kim et al., 2014). However, individuals who were administered heparin within three days of injury had slower progression of neurological impairments on computed tomography scans compared to late administration (Kim et al., 2014).

Norwood and colleagues conducted two studies examining the benefits of administering enoxaparin (LMWH) prophylaxis to those who sustain a severe ABI within the first 48 hours post injury (Norwood et al., 2008; Norwood et al., 2002). Results from both studies indicate that administering enoxaparin post ABI reduces the risk of developing DVT and PE, without increasing the risk of bleeding post injury. Scudday et al. (2011) also found that patients who received chemical prophylaxis within 72 hours of injury had a significantly lower incidence of developing VTE post ABI (p<0.019) compared to those not receiving chemical prophylaxis (Kim et al., 2014). Overall, a meta-analysis by Jamjoom and colleagues Jamjoom and Jamjoom (2013) conclude that individuals who begin pharmacological thromboprophylaxis within 72 hours of injury have half the risk of VTE without significant risk of intracranial hemorrhage progression, than those who start after 72 hours.

On the contrary, few studies have demonstrated these medications may not be beneficial or superior treatments. In one study with individuals who underwent a craniotomy post-ABI, no significant differences were reported for rate of DVT and PE when comparing those administered enoxaparin prophylaxis compared to those without (Daley et al., 2015). Further, Kwiatt et al. (2012) reported patients’ receiving LMWH were at higher risk for hemorrhage progression and the risk of using LMWH may exceed its benefit. Similarly for heparin, Lin et al. Lin et al. (2013) did not find a reduction in DVT or PE once individuals with a severe TBI were administered a heparin prophylaxis protocol.

In conclusion, a systematic review of twelve studies report that evidence is insufficient to determine effectiveness of these medications for VTE prevention; however despite the aforementioned studies without significant findings, overall evidence supports the use of enoxaparin for reduction of DVT and UFH for decreased mortality rates compared to no chemoprophylaxis (Chelladurai et al., 2013).

Conclusions

There is level 2 evidence supporting the administration of low molecular weight herapin within the first 72 hours post ABI to reduce the risk of developing deep vein thrombosis and pulmonary embolisms post injury.

There is level 2 evidence that administering low molecular weight herapin (enoxaparin) or heparin post ABI may not increase the risk of intracranial bleeding, compared to no treatment.

There is level 4 evidence that the use of chemoprophylaxis 24 hours after stable head computed tomography scan may decrease the rate of deep vein thrombosis formation post ABI.

12.11 Diuretics

12.11.1 Mannitol

Key Points

Mannitol may effectively lower elevated intracranial pressure; furthermore, high doses may yield lower mortality rates and better clinical outcomes.

Mannitol may be equally effective as hypertonic saline and less effective than sodium lactate for reducing elevated intracranial pressure.

Rapid administration of mannitol is among the first-line treatments recommended for the management of increased ICP.  However, this treatment is reported to be associated with significant diuresis and can cause acute renal failure, hyperkalemia, hypotension, and in some cases rebound increments in ICP (Battison et al., 2005; Doyle et al., 2001). For these reasons, the Brain Trauma Foundation recommends that mannitol only be used if a patient has signs of elevated ICP or deteriorating neurological status. Under such circumstances the benefits of mannitol for the acute management of ICP outweigh any potential complications or adverse effects. There is also some evidence that with prolonged dosage, mannitol may penetrate the blood brain barrier, thereby exacerbating the elevation in ICP (Wakai et al., 2013). Despite the effectiveness of mannitol in ICP management, recent evidence points to HTS as a potentially more effective hyperosmotic agent.

Although mannitol is commonly used in acute ABI, the AANS concluded that there was insufficient evidence available to support a formal recommendation (Carney et al., 2017). The EBIC recommended mannitol as the preferred osmotic therapy, with administration via repeated bolus infusions or as indicated by monitoring to a serum osmolarity of ≤315 (Maas et al., 1997).

Discussion

Overall, findings of single group interventions suggest that mannitol is effective in significantly reducing ICP following TBI (Diringer et al., 2012; Scalfani et al., 2012; Tang et al., 2015). Cruz and colleagues conducted three separate trials to investigate the effects of high dose mannitol on clinical outcomes in patients with ABI at six months post injury (Cruz et al., 2001, 2002; Cruz et al., 2004). All three trials reported that high dose mannitol (1.4 g/kg) was superior to conventional mannitol (0.7 g/kg) in lowering elevated ICP and improving clinical outcomes. In a retrospective study, Sorani et al. Sorani et al. (2008) found that for every 0.1 g/kg increase in mannitol dosage there was a 1.0 mmHg drop in ICP.

In a later trial, Francony et al. (2008) found that equimolar doses of mannitol and HTS were comparable in reducing ICP in stable patients with intact autoregulation post ABI. Mannitol was shown to improve brain circulation through possible improvements in blood rheology, but also significantly increased urine output. The authors suggested that both treatments may be effective, but patient pre-treatment factors should be considered before selection. In another trial, Ichai et al. (2009) reported that an equimolar dose of sodium lactate had a significantly greater effect on lowering elevated ICP that lasted longer than treatment with mannitol. Sodium lactate was also successful in reducing elevated ICP more frequently. Based on these results, further research into the effectiveness of sodium lactate in reducing ICP is warranted.

Most reports have recommended administering mannitol only when elevated ICP is proven or strongly suspected. Hartl et al. (1997) indicated that mannitol was only effective in diminishing ICP when the initial ICP was hypertensive (>20 mmHg). However, an RCT by Smith et al. (1986) reported that patients who received mannitol only after the onset of intracranial hypertension (>25 mmHg) were not significantly different from those who received mannitol irrespective of ICP measurements in terms of mortality rates or neurological outcomes. Thus it is unclear whether the use of mannitol as a prophylactic measure against potential elevations in ICP is appropriate.

Other reports have discouraged the use of mannitol before volume resuscitation and patient stabilization, due to potential osmotic diuresis and hypotension.  These adverse effects could further compromise CPP, but such an approach may deprive patients of the potential benefits of mannitol on ICP. With this in mind, Sayre et al. (1996) conducted an RCT to investigate the effects of early mannitol administration in an out-of-hospital emergency care setting. The authors reported that mannitol did not significantly affect blood pressure when compared to saline.

In a 2013 Cochrane review, Wakai et al. (2013) suggested that mannitol may have beneficial effects on mortality when compared to pentobarbital but detrimental effects when compared to HTS. However, there was a small benefit when mannitol treatment was monitored by a measurement of ICP when compared to standard care. The authors also reported that there was insufficient data on the effectiveness of pre-hospital administration of mannitol.

Conclusions

There is level 4 evidence that mannitol may be effective in controlling elevated intracranial pressure.

There is level 2 evidence that early administration of mannitol may not effectively lower elevated intracranial pressure, but may not adversely affect blood pressure.

There is level 2 evidence that high-dose mannitol may be more effective than conventional mannitol in reducing mortality rates and improving clinical outcomes.

There is level 1b evidence that mannitol may be no more effective than hypertonic saline in controlling elevated intracranial pressure.

There is level 1b evidence that mannitol may be less effective than sodium lactate in controlling elevated intracranial pressure.

12.12 Dopaminergic Medications

12.12.1 Amantadine

Amantadine is a dopamine agonist that acts both pre- and post-synaptically to enhance dopamine activity (Meythaler et al., 2002). Dopamine is thought to be involved in frontal lobe stimulation and plays a role in behavior, mood, language, motor control, hypothalamic function and arousal (Sawyer et al., 2008). Amantadine was initially developed for prophylactic use as an antiviral agent in the prevention of influenza A, but is now commonly used in the treatment of Parkinson’s disease. Amantadine’s properties as a potential neuro-active agent were quickly recognized (Zafonte et al., 2001). Researchers believe that amantadine could significantly improve arousal in comatose patients. Potential side effects include over-stimulation, peripheral edema, livedo reticularis, and lowering of the seizure threshold (Schneider et al., 1999a). The favourable risk-benefit profile of amantadine suggests that it may be an attractive treatment option for inducing arousal from coma (Hughes et al., 2005).

Discussion

Three retrospective studies that assessed amantadine were identified. In a case-control study, Hughes et al. (2005) found that patients receiving amantadine were no more likely to emerge from coma compared to those not receiving it. However, the authors mentioned that potential confounders may have affected the results, and that the point at which patients were considered to have emerged from the coma was arbitrarily assessed. In a chart review, Whyte et al. (2005) only selected patients who received amantadine 4-16 weeks post injury, in order to assess its potential in improving consciousness after medical stability was reached. The authors noted that patients who received amantadine showed significant improvements in disability one week after administration when compared to patients treated by other methods. They also reported no significant difference between groups in the time to first response to directions. In another chart review, patients who were treated with amantadine showed significant improvements in consciousness at discharge and decreased mortality rates when compared to those who did not receive it (Saniova et al., 2004). While the retrospective nature of these studies makes it difficult to draw conclusions, all authors recommended amantadine as a safe intervention with promising potential but suggested that further research was warranted.

Two RCTs have evaluated the effectiveness of amantadine in improving consciousness in adults. Using a crossover design, Meythaler et al. (2002) assessed patients for orientation, cognitive function, functional independence, and disability. The authors found that patients who received amantadine made significant gains on all outcome measures over six weeks, but made no further gains when switched to placebo for another six weeks. Patients initially receiving placebo made small gains, but went on to make further improvements after amantadine induction. While patients made some natural recovery on placebo, the authors noted that patients made more pronounced improvements on amantadine. They also suggested that amantadine aids in recovery regardless of the time of administration. Similarly, a trial by Giacino et al. (2012) found a significant improvement in disability in participants who received amantadine over four weeks when compared to placebo. However, following a two-week follow-up without amantadine treatment, their recovery slowed such that overall improvements were similar between the two groups (Giacino et al., 2012). The authors recommended that amantadine treatment may continue until recovery goals are reached, although it should be approached with caution.

When examining the use of Amantadine for children, two RCTs have been conducted. Amantadine was compared to a placebo in a cross-over study by McMahon et al. (McMahon et al., 2009). Although no significant differences were noted between the drugs in terms of recovery using standardized measures, physicians noted greater improvements in consciousness when amantadine was administered. It is possible the benefits of amantadine were not shown due to the small sample size of this study (n=7) and the fact two patients dropped out. A child was withdrawn due to medical complications and another was removed because the family requested unblinded administration of amantadine in the second three weeks.  In the second RCT, Patrick et al. Patrick et al. (2006) compared amantadine to pramipexole (both dopamine agonists) for children and adolescents who remained in a low-responsive state one month post injury. Patients in both groups made significant improvements on the Coma/ Near Coma Scale (CNCS), the Western NeuroSensory Stimulation Profile (WNSSP), and the DRS weekly gains. Patients also improved on Rancho Los Amigos Scale level. There were no significant side effects to treatment which, combined with the positive results, suggest that dopamine agonists may be a viable option for coma arousal in children and adolescents. However, the lack of control group and small sample size warrant further study before conclusions are drawn.

Green et al. (2004) evaluated the safety of amantadine in a paediatric population. In this study, five out of 54 patients experienced side effects which were all readily reversible. The significant change in Rancho Los Amigos Scale level in the treatment group was questionable due to differences in baseline. There were no significant differences in post-traumatic amnesia (PTA) or length of stay. The subjective improvements reported were difficult to distinguish from natural recovery.

Conclusions

There is level 1b evidence that pramipexole, and level 1a evidence that amantadine, may be effective in improving levels of consciousness in children with ABI.

There is level 1a evidence that amantadine may effectively improve consciousness, cognitive function, and disability when compared to placebo.

12.12.1.1 Amantadine in Acute Care

Amantadine is a dopamine agonist that acts both pre- and post-synaptically to enhance dopamine activity (Meythaler et al., 2002). Dopamine is thought to be involved in frontal lobe stimulation and plays a role in behavior, mood, language, motor control, hypothalamic function and arousal (Sawyer et al., 2008). Amantadine was initially developed for prophylactic use as an antiviral agent in the prevention of influenza A, but is now commonly used in the treatment of Parkinson’s disease. Amantadine’s properties as a potential neuro-active agent were quickly recognized (Zafonte et al., 2001). Researchers believe that amantadine could significantly improve arousal in comatose patients. Potential side effects include over-stimulation, peripheral edema, livedo reticularis, and lowering of the seizure threshold (Schneider et al., 1999a). The favourable risk-benefit profile of amantadine suggests that it may be an attractive treatment option for inducing arousal from coma (Hughes et al., 2005).

Discussion

Three retrospective studies that assessed amantadine were identified. In a case-control study, Hughes et al. (2005) found that patients receiving amantadine were no more likely to emerge from coma compared to those not receiving it. However, the authors mentioned that potential confounders may have affected the results, and that the point at which patients were considered to have emerged from the coma was arbitrarily assessed. In a chart review, Whyte et al. (2005) only selected patients who received amantadine 4-16 weeks post injury, in order to assess its potential in improving consciousness after medical stability was reached. The authors noted that patients who received amantadine showed significant improvements in disability one week after administration when compared to patients treated by other methods. They also reported no significant difference between groups in the time to first response to directions. In another chart review, patients who were treated with amantadine showed significant improvements in consciousness at discharge and decreased mortality rates when compared to those who did not receive it (Saniova et al., 2004). While the retrospective nature of these studies makes it difficult to draw conclusions, all authors recommended amantadine as a safe intervention with promising potential but suggested that further research was warranted.

Two RCTs have evaluated the effectiveness of amantadine in improving consciousness in adults. Using a crossover design, Meythaler et al. (2002) assessed patients for orientation, cognitive function, functional independence, and disability. The authors found that patients who received amantadine made significant gains on all outcome measures over six weeks, but made no further gains when switched to placebo for another six weeks. Patients initially receiving placebo made small gains, but went on to make further improvements after amantadine induction. While patients made some natural recovery on placebo, the authors noted that patients made more pronounced improvements on amantadine. They also suggested that amantadine aids in recovery regardless of the time of administration. Similarly, a trial by Giacino et al. (2012) found a significant improvement in disability in participants who received amantadine over four weeks when compared to placebo. However, following a two-week follow-up without amantadine treatment, their recovery slowed such that overall improvements were similar between the two groups (Giacino et al., 2012). The authors recommended that amantadine treatment may continue until recovery goals are reached, although it should be approached with caution.

When examining the use of Amantadine for children, two RCTs have been conducted. Amantadine was compared to a placebo in a cross-over study by McMahon et al. (McMahon et al., 2009). Although no significant differences were noted between the drugs in terms of recovery using standardized measures, physicians noted greater improvements in consciousness when amantadine was administered. It is possible the benefits of amantadine were not shown due to the small sample size of this study (n=7) and the fact two patients dropped out. A child was withdrawn due to medical complications and another was removed because the family requested unblinded administration of amantadine in the second three weeks.  In the second RCT, Patrick et al. Patrick et al. (2006) compared amantadine to pramipexole (both dopamine agonists) for children and adolescents who remained in a low-responsive state one month post injury. Patients in both groups made significant improvements on the Coma/ Near Coma Scale (CNCS), the Western NeuroSensory Stimulation Profile (WNSSP), and the DRS weekly gains. Patients also improved on Rancho Los Amigos Scale level. There were no significant side effects to treatment which, combined with the positive results, suggest that dopamine agonists may be a viable option for coma arousal in children and adolescents. However, the lack of control group and small sample size warrant further study before conclusions are drawn.

Green et al. (2004) evaluated the safety of amantadine in a paediatric population. In this study, five out of 54 patients experienced side effects which were all readily reversible. The significant change in Rancho Los Amigos Scale level in the treatment group was questionable due to differences in baseline. There were no significant differences in post-traumatic amnesia (PTA) or length of stay. The subjective improvements reported were difficult to distinguish from natural recovery.

Conclusions

There is level 1b evidence that pramipexole, and level 1a evidence that amantadine, may be effective in improving levels of consciousness in children with ABI.

There is level 1a evidence that amantadine may effectively improve consciousness, cognitive function, and disability when compared to placebo.

12.12.1.2 Amantadine and Cognitive Rehabilitation

Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist and has been used as an antiviral agent, as a prophylaxis for influenza A, for the treatment of neurological diseases such as Parkinson’s disease, and in the treatment of neuroleptic side-effects such as dystonia, akinthesia and neuroleptic malignant syndrome (Schneider et al., 1999a). It is also thought to work pre- and post-synaptically by increasing the amount of dopamine (Napolitano et al., 2005).

Discussion

In a small sample RCT by Schneider et al. (1999a) the effects of Amantadine on cognition and behaviours was assessed. In this six week cross-over study, patients received both placebo and amantadine. Although the study found that patients improved over the six week study period, statistical comparison of results evaluating the five subsets of attention, executive/flexibility, memory, behaviour and orientation did not demonstrate any significant effect for the use of Amantadine. Similarly, Kraus et al. (2005) demonstrated that the administration of amantadine over a 12-week treatment period does not improve memory deficits or attention; however, significant improvements in executive functioning were observed. Given the quality and sample size of the current studies, future studies exploring the efficacy of amantadine for learning and memory are warranted.

Conclusions

There is level 2 evidence that Amantadine may not help to improve learning and memory deficits.

12.12.1.3 Amantadine and Aggression

Amantadine is a non-competitive N-methyl-D-aspartate receptor antagonist that decreases glutamate levels, which may improve learning, memory, and behaviour deficits (Hammond et al., 2014). However, the effects of amantadine on reducing irritability and aggression have yet to be established among the TBI population.

Discussion

One placebo-controlled RCT compared the effects of amantadine on irritability and aggression. The frequency and severity of irritability were reduced when individuals were on Amantadine for 28 days, compared to placebo. However, Amantadine only significantly reduced aggression in individuals who had moderate-severe aggression at baseline (Hammond et al., 2014). A second RCT furthered Hammond et al. Hammond et al. (2014) findings by assessing the effects of Amantadine on irritability and aggression for up to 60 days. Amantadine produced a non-significant reduction in irritability compared to placebo at 28 and 60 days, according to the most problematic and aberrant items on the neuropsychiatric inventory (Hammond et al., 2015).

Conclusions

There is conflicting evidence of the effects of amantadine on reducing irritability and aggression in individuals with moderate-severe traumatic brain injury.

12.12.2 Dopamine Medications used in the Paediatric Population

Discussion

Patrick et al. (2003) examined the effect of a number of dopamine enhancing medications on improvement in arousal and awareness for individuals in a low response state. This study suggests a positive relationship between rate of recovery for children in a low response state and administration of dopamine-enhancing drugs. Limitations of this study include: a retrospective design, a small sample size (n=10), and multiple medications being studied.

Conclusions

There is level 4 evidence that dopamine-enhancing drugs may accelerate the rate of recovery from a low response state for children post TBI.

12.12.3 Bromocriptine

Bromocriptine is a dopaminergic agonist which primarily affects D2 receptors (Whyte et al., 2008). It has been suggested that dopamine is an important neurotransmitter for prefrontal function (McDowell et al., 1998). In a study looking at the effects of bromocriptine on rats, Kline et al. (2002) noted that the animals showed improvement in working memory and spatial learning; however, this improvement was not seen in motor abilities. Three studies have been identified investigating the use of bromocriptine as an adequate treatment for the recovery of cognitive impairments following brain injury.

Discussion

The question of whether bromocriptine improves cognitive function in patients with ABI was explored in two RCTs (McDowell et al., 1998; Whyte et al., 2008) and a case series (Powell et al., 1996). In an earlier investigation, low-dose bromocriptine (2.5 mg daily) improved functioning on tests of executive control including a dual task, Trail Making Test (TMT), the Stroop test, the Wisconsin Card Sorting Test (WCST) and the controlled oral word association test (COWAT) (McDowell et al., 1998). However, bromocriptine did not significantly influence working memory tasks. Further, a study by Whyte et al. (2008) found that bromocriptine had little effect on attention. It was noted that several participants did experience moderate to severe drug effects and withdrew or were withdrawn from the study.

Although McDowell et al. (1998) demonstrated some benefits following administration of bromocriptine, there was only a single administration of bromocriptine and the dose was considerably lower than that given by Whyte et al. (2008). Spontaneous recovery may have been a factor leading to the improved abilities in individuals receiving a single dose (2.5mg daily) of the medication; however, study results did not answer this question. Results from Whyte et al. (2008) noted that the placebo group demonstrated better (although not significant) trends in improvement on the various tasks administered. Powell et al. (1996) conducted a multiple baseline design on 11 patients with TBI or subarachnoid hemorrhage who received bromocriptine. Improvements were found on all measures assessed except mood.

Conclusions

Based on two RCTs, there is conflicting evidence supporting the use of bromocriptine to enhance cognitive functioning.

There is level 4 evidence that bromocriptine may improve all motivational deficits except mood.

12.13 Hormone Therapy

12.13.1 Dexamethasone and the Paediatric Population

In the past, literature with adult subjects investigating the use of steroids in severe TBI reported conflicting results. The following studies investigated the effects of dexamethasone on children with an ABI.

Discussion

The paediatric data highlights the fact that dexamethasone suppresses endogenous production of glucocorticoids (Fanconi et al., 1988; Kloti et al., 1987), therefore bringing into doubt any beneficial effect of exogenous glucocorticoids. This evidence, along with findings from Dearden et al. (1986) that dexamethasone failed to show difference in outcome in a mixed adult and paediatric sample, underscores the lack of firm data to support the use of these drugs in individuals with brain injury.

Conclusions

There is level 2 evidence that administration of dexamethasone may inhibit endogenous production of glucocorticoids and has no proven impact on recovery post brain injury.

12.13.2 Medroxyprogesterone

Sexual dysfunction following TBI has been reported to occur in at least 50% of patients (Emory et al., 1995). Hypersexuality is less common than hyposexuality (decreased libido) but results in a greater negative effect for the individual and results in a great burden of care by limiting independence. Hypersexual behaviour can encompass a range of behaviours, from indiscriminate sexual advances, promiscuity, and exhibitionism, to assault and/or rape (Mania et al., 2006). A recent study revealed inappropriate sexual talk to be the most common inappropriate sexual behaviour in a sample of TBI patients (Simpson et al., 2013). Treatment for sexual offenders without brain injuries has included pharmacological intervention and or counselling and education. Typically, medication is used to reduce the sexual drive, but it is unclear if it has effect on cognitive processing (i.e., preservative thoughts regarding sex).

Discussion

In a retrospective study, Depo-Provera, an anti-androgen drug, was evaluated in terms of its efficacy for controlling sexual aggression in eight males with TBI experiencing onset of sexual aggression three years post injury (Emory et al., 1995). Weekly IM injections of Depo-Provera (400 mg) in conjunction with monthly psychoeducational counseling resulted in a cessation of hypersexual behaviour and reduced testosterone levels. Three subjects re-offended when the drug was stopped, three remained on it and two stopped taking the drug and had maintained cessation of hypersexual behaviour.

Conclusions

There is level 4 evidence that Depo-Provera and counselling may reduce sexually aggressive behaviour.

12.13.3 Progesterone

Progesterone has drawn interest as a potential neuroprotective agent. Animal studies have suggested that progesterone reduces cerebral edema, regulates inflammation, reconstitutes the blood brain barrier, modulates excito-toxicity, and decreases apoptosis (Stein, 2008). In the human population, Groswasser et al. (1998) observed that female patients with TBI recovered better than male patients and suggested progesterone as a possible cause of this disparity. Trials have since been undertaken to accurately assess the effects of progesterone in the ABI population.

The AANS and the EBIC made no recommendations regarding progesterone in acute ABI.

Discussion

In an RCT, Wright et al. (2007) evaluated patients receiving the medication over three days and found no significant improvement in ICP levels over placebo. However, these patients showed a decreased 30-day mortality rate without an increased rate of complications. As well, less severe patients in this group also showed significantly greater rates of favourable outcomes on the GOSE. Noting limitations in group distribution within their study, the authors recommended a larger clinical trial. Xiao et al. (2008) conducted such a trial with patients receiving progesterone or placebo over five days. They similarly reported a lack of improvement in ICP over placebo, but significantly greater GOS and FIM scores at three months and six months, and lower mortality at six months. They also reported no complications associated with progesterone administration.

In contrast, more recent trials have reported no significant differences in outcomes between those receiving progesterone or placebo after three months  and six months (Shakeri et al., 2013; Skolnick et al., 2014; Wright et al., 2014). However, in a subgroup analysis of patients with initial GCS>5, Shakeri et al. (2013) found a significant improvement in GOS scores associated with progesterone. As well, one study reported that progesterone was not associated with increased rate of serious adverse events (Wright et al., 2014). Given the conflicting findings between studies, the evidence regarding progesterone in acute ABI should be taken with caution.

Conclusions

There is level 1a evidence that progesterone may not lower intracranial pressure levels post TBI when compared to placebo.

There is level 1a evidence that progesterone may not be associated with adverse events when compared to placebo.

There is conflicting level 1a evidence as to whether progesterone improves long-term outcomes and reduces mortality post TBI when compared to placebo.

12.14 (a) Psychostimulants

12.14.1 Methylphenidate

12.14.1.1 Methylphenidate and Cognitive Functioning

Key Points

The effectiveness of methylphenidate treatment to improve cognitive impairment following brain injury is unclear.

Methylphenidate may be effective in improving reaction time for working memory.

Response to methylphenidate may depend on genotype.

Methylphenidate is a stimulant whose exact mechanism is unknown (Napolitano et al., 2005). One theory is that methylphenidate acts on the presynaptic nerve to prevent the reabsorption of serotonin and NE, thereby increasing their concentrations within the synaptic cleft. This in turn leads to increased neurotransmission of serotonin and NE (Kim et al., 2006). Methylphenidate has been extensively used as a treatment for attention deficit disorder, as well as narcolepsy (Glenn, 1998). A total of six RCTs examined the efficacy of methylphenidate as a treatment for the recovery of cognitive deficits post brain injury.

Discussion

In an RCT, Whyte et al. (2004) indicated that speed of processing, attentiveness during individual work tasks and caregiver ratings of attention were all significantly improved with methylphenidate treatment. No treatment related improvement was seen in divided or sustained attention, or in susceptibility to distraction. Similarly, Plenger et al. (1996) found methylphenidate significantly improved attention and concentration.

Speech et al. (1993) conducted a double blind placebo controlled trial evaluating the effects of methylphenidate following closed head injury. In contrast to the results noted by Whyte et al. (2004) and Plenger et al. (1996), methylphenidate did not demonstrate significant differences compared to placebo on measures of attention, information processing speed, or learning. Kim et al. (2006) examined the effects of a single-dose treatment of methylphenidate and, although a trend was found in favour of improved working and visuospatial memory for the treatment group, these results did not reach significance. Recently, Kim et al. (2012) found that reaction time improved significantly while on the methylphenidate. This is in line with Willmott and Ponsford (2009) who found that administering methylphenidate to a group of patients during inpatient rehabilitation, did significantly improve the speed of information processing.

In a recent RCT conducted by Willmott et al. (2013), the authors hypothesized that an individuals’ response to methylphenidate depends on their genotype. More specifically, that individuals possessing the methionine (Met) allele at the catechol-O-methyltransferase (COMT) gene would confer greater response to methylphenidate compared to those with the valine (Val) allele. While both Met/Met and Val/Val carriers performed more poorly in various attentional tasks compared to healthy controls, Met/Met carriers did show greater improvements in strategic control in attention than Val/Val carriers. As well, the authors were able to identify one significant drug and genetic interaction between Met/Met carriers and performance on the Symbol Digit Modalities Test (SDMT). These findings suggest Met/Met carriers may in fact be more responsive to methylphenidate than individuals with the Val genotype. However, further studies are needed to draw firm conclusions.

Conclusions

There is conflicting evidence regarding the effectiveness of the administration of methylphenidate following brain injury for the improvement of cognitive functioning.

There is level 1a evidence that methylphenidate may improve reaction time of working memory.

Based on a single RCT, there is level 1b evidence that an individual’s response to methylphenidate therapy may be dependent on his/her genotype of the catechol-O-methyltransferase gene.

12.14.1.2 Methylphenidate and Fatigue

Of the neurostimulants used in the post-acute care of TBI, methylphenidate is common, assisting with memory, attention, verbal fluency, and improving processing speed. While its use is heavily focused on the improvement of functional and cognitive deficits, methylphenidate has been reported to have unfavourable effects on sleep patterns of individuals with brain injuries. However, little has been written focusing directly on the effects of methylphenidate on the sleep-wake cycles of those with ABI (Al-Adawi et al., 2009).

Discussion

In the study by Al-Adawi et al. (2009) no significant differences were found between those who received methylphenidate and those who did not when looking at the scores of various assessment scales (e.g. activities of daily living, mobility and cognition). More importantly, sleep times between the two groups were not significantly different. Based on this study, methylphenidate does not seem to have adverse effects on the sleep-wake cycle.

Conclusions

There is level 3 evidence, based on a single study, that methylphenidate may not have an adverse effect on the sleep-wake cycle of those who have sustained a TBI.

12.14.1.3 Methylphenidate and Anger

Key Points

Methylphenidate may be effective in reducing anger following a brain injury.

One RCT examined the effect of methylphenidate on the control of anger following a brain injury (Mooney & Haas, 1993).

Discussion

In a RCT, Mooney and Haas (1993) demonstrated that methylphenidate helped to significantly reduce anger following brain-injury as demonstrated using several anger outcome measures. Despite the differences between the groups on one anger measure, a significant group main effect of the drug treatment was demonstrated.

Conclusions

There is level 2 evidence (from one randomized control trial) to suggest that treatment with methylphenidate following brain injury can significantly reduce anger.

12.14.1.3 Methylphenidate and the Paediatric Population

Key Points

Evidence regarding the efficacy of methylphenidate to improve cognitive and behavioural function is conflicting in children.

Methylphenidate, a psychomotor stimulant, is often used in the treatment of attention deficit hyperactivity disorder (ADHD) in children; however, it is also used with children who have sustained a brain injury. It is believed that those with ADHD and those who have sustained a brain injury have similar characteristics including: attention deficits, hyperactivity and impulsivity (Leonard et al., 2004). Methylphenidate has been shown to improve memory and attention in those with ADHD (Kempton et al., 1999).

Discussion

Two separate RCTs utilized a series of neurobehavioural tasks of attention, behaviour and concentration to assess children post brain injury. Mahalick et al. (1998) reported significantly improved performance on attention and concentration tasks with methylphenidate treatment, whereas Williams et al. (1998) did not report any significant benefits. As in many paediatric studies, the sample size was small, undermining the quality of the findings. Hornyak et al. (1997) suggest that the introduction of methylphenidate resulted in improved cognitive/behavioural function post TBI. This interpretation however, was based on qualitative data from a retrospective review of 10 charts. To date, no medication has proven to be effective in modifying outcome in the brain injured child. Investigators have studied the role of the psychostimulant methylphenidate and other dopamine enhancing medication including amantadine, pramipexole, bromocriptine, and levodopa.

Conclusions

Based on two small and conflicting RCTs, there is inconclusive evidence whether methylphenidate improves cognitive behavioural function in children post ABI.

12.14 (b) Stimulants

12.14.2 Modafinil

Key Points

Modafinil has not been shown to be effective in treating fatigue.

Modafinil has been shown to be effective short-term in treating excessive daytime sleepiness, but may also cause insomnia.

Modafinil, a wakefulness promoting agent, was approved to address excessive daytime sleepiness (EDS) (Jha et al., 2008). Additionally, the drug was approved for use to address narcolepsy and sleeping difficulties associated with shift work (“Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group,” 2000). Modafinil was found to enhance the quality of life for those with narcolepsy (Beusterien et al., 1999). Similar studies exploring the effectiveness of modafinil within the ABI population are limited.

Discussion

Two RCTs examined the effects of modafinil on fatigue and EDS for individuals with TBI (Jha et al., 2008; Kaiser et al., 2010). The two studies followed similar protocols with the initial administration of modafinil 100 mg daily, which was then titrated up to 100 mg twice per day, and both compared with a placebo control group. Both studies found no significant difference in fatigue, as measured by the FSS, between the intervention and control groups. Further, when Kaiser et al. (2010) compared those with fatigue at baseline (FSS ≥4) in both groups, the decreases shown in FSS scores remained non-significant between groups. The two studies also examined EDS using the Epworth Sleepiness Scale (ESS). The intervention groups both showed a significantly greater decrease in ESS scores when compared with controls, representing a greater improvement in EDS (Jha et al., 2008; Kaiser et al., 2010). It should be noted, however, that Jha et al. (2008) found the improvement to be significant at week 4 (p=0.02) but not at week 10 (p=0.56) highlighting that there was no clear temporal pattern of benefit. Of concern, those receiving modafinil reported more insomnia than controls (p=0.03). These studies suggest that modafinil may not be effective for improving fatigue.

Conclusions

There is level 1a evidence that modafinil may not be effective in treating fatigue but has been shown to be effective short-term in treating excessive daytime sleepiness post ABI.

12.15 Sedative Anaesthetic

12.15.1 Propofol

Key Points

Propofol, especially at higher doses may improve intracranial pressure and cerebral perfusion pressure; furthermore, propofol may reduce intracranial pressure and the need for other intracranial pressure interventions when used in conjunction with morphine.

Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on intracranial pressure.

Propofol is a fast acting sedative that is absorbed and metabolized quickly, leading to pronounced effects of short duration. Its beneficial effects occur via decreases in peripheral vascular tension resulting in potential neuroprotective effects, which may be beneficial in acute ABI care. Experimental results have shown positive effects on cerebral physiology including reductions in cerebral blood flow, cerebral oxygen metabolism, electroencephalogram activity, and ICP (Adembri et al., 2007). However, administration of high doses can result in propofol infusion syndrome, which has been characterized by severe metabolic acidosis, rhabdomyolosis, cardiac dysrhythmias, and potential cardiovascular collapse (Corbett et al., 2006).

The AANS reported Level II evidence for the recommendation of propofol in controlling of ICP, but not for improvement in mortality or long-term outcomes (Carney et al., 2017). They also indicated that high-dose propofol can produce significant morbidity. The EBIC recommended sedation as part of the treatment course for ABI but make no specific mention of propofol (Maas et al., 1997).

Discussion

In two earlier studies, propofol was reported to provide satisfactory sedation with few side effects. Farling et al. (1989) reported that propofol reduced ICP, increased CPP, and provided safe and effective sedation. Stewart et al. (1994) found that propofol provided sedation similar to a combination of midazolam and morphine with no differences in changes to ICP, CPP, and MAP or in outcomes at six months. However, both of these studies had small sample sizes and were lower quality. In a retrospective review, Smith et al. (2009) identified three patients with propofol infusion syndrome. The authors noted that each of these patients was receiving both propofol and vasopressors, and that no patient on either propofol or vasopressors alone developed propofol infusion syndrome.

An RCT by Kelly et al. (1999) compared propofol to morphine for safety and efficacy. Patients were randomly assigned to either a morphine group or a propofol group where they received three simultaneous injections: injection one had propofol or placebo, injection two had morphine or placebo, and injection three had low-dose morphine. This particular design allowed for the comparison of propofol dosing and its effectiveness while maintaining blinding, although all patients received propofol in conjunction with morphine. Propofol was found to reduce ICP when compared to morphine, and higher doses were shown to be more effective than lower doses. As well, patients in the propofol group showed less need for additional therapies for elevated ICP. At six months, there were no significant differences in mortality rates or GOS scores between the two groups. The authors suggested that propofol is a safe, acceptable, and possibly desirable alternative to opiate-based sedation (Kelly et al., 1999).

In a crossover RCT, patients with ABI received both propofol and dexmedetomidine, each over a six-hour period (James et al., 2012). The authors reported no significant differences between the groups after treatment in terms of ICP and CPP. As a result of these findings, they recommend that the “choice of sedative regimen be based on the profile of the sedative and the individual goals for a patient”.

Conclusions

There is level 1b evidence that propofol may reduce intracranial pressure and the need for other intracranial pressure interventions when used in conjunction with morphine compared to morphine alone.

There is level 1b evidence that a high dose of propofol may improve intracranial pressure and cerebral perfusion pressure compared to a low dose of propofol.

There is level 2 evidence that propofol may not be significantly different from dexmedetomidine in its effect on intracranial pressure.

There is level 2 evidence that propofol may not be significantly different from morphine and midazolam in its effect on intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and long-term outcomes.

There is level 4 evidence that propofol may improve intracranial pressure and cerebral perfusion pressure.

12.15.2 Midazolam

Key Points

Midazolam may have no effect on intracranial pressure, but may reduce mean arterial pressure, cerebral perfusion pressured, and systolic blood pressure.

Midazolam may not be different than propofol in its effect on intracranial pressure, cerebral perfusion pressure, or long-term outcomes.

Midazolam, another benzodiazepine, works by slowing activity in the brain to allow for relaxation and sleep. Midazolam has been found to reduce cerebrospinal fluid pressure in patients without intracranial mass lesions as well as decrease cerebral blood flow and cerebral oxygen consumption (McClelland et al., 1995). For a more detailed discussion of midazolam please refer to Modules 10 and Module 16.

Discussion

An early retrospective study by Papazian et al. (1993) reported that midazolam yielded non-significant reductions in ICP. In patients with severe TBI, those receiving midazolam had similar levels of ICP and CPP after treatment when compared to those receiving propofol, although was propofol associated with a shorter wake-up time (Sanchez-Izquierdo-Riera et al., 1998). The two medications were also found to provide similar long-term outcomes (Ghori et al., 2008). It should be noted that increased doses of midazolam have been associated with significant hypotension (Davis et al., 2001) and decreased levels of CPP and MAP (Papazian et al., 1993).

Conclusions

There is level 4 evidence that midazolam may reduce mean arterial pressure, cerebral perfusion pressure, and systolic blood pressure, but may have no effect on intracranial pressure.

There is level 2 evidence that midazolam may not be different from propofol in its effect on intracranial pressure or cerebral perfusion pressure.

There is level 1b evidence that midazolam may not be different than propofol in its effect on long-term outcomes.

12.17.1 Corticosteroids

Key Points

Corticosteriods such as methylprednisolone, dexamethasone, and glucocorticoids may worsen outcomes, with no effect on intracranial pressure levels, and should not be used.

Triamcinolone may improve outcomes in patients with a Glasgow Coma Scale<8 and a focal lesion.

Numerous corticosteroids have been used in brain injury care including dexamethasone, methylprednisolone, prednisolone, prednisone, betamethasone, cortisone, hydrocortisone, and triamcinolone (Alderson & Roberts, 2005). Using such a broad spectrum of agents within diverse patient groups has made understanding corticosteroid efficacy difficult. Adding to this difficulty is a lack of understanding regarding the mode of steroid action. Grumme et al. (1995) reported that laboratory studies have associated corticosteroid use with reductions in wet brain weight, facilitation of synaptic transmission, reduction of lipid peroxidation,  preservation of electrolyte distribution, enhanced blood flow, and membrane stabilization (Grumme et al., 1995). While it had been thought that the benefits of corticosteroids could arise from reductions in ICP, as well as neuroprotective activity, several studies have suggested limitations in their usage. Focal lesions seem to respond well to corticosteroid therapy, while diffuse intracerebral lesions and hematomas are less responsive (Cooper et al., 1979; Grumme et al., 1995).

In the wake of several large scale trials, questions regarding the safety of corticosteroid administration have been brought to light. Alderson and Roberts (1997) conducted a systematic review of corticosteroid literature and concluded that there was a 1.8% improvement in mortality associated with corticosteroid use. However, their 95% confidence interval ranged from a 7.5% reduction to a 0.7% increase in deaths. Roberts et al. (2004) studied corticosteroid use in acute brain injury with the goal of recruiting 20,000 patients with TBI; after 10,008 patients were recruited it became clear that corticosteroid use caused significant increases in mortality and the trial was halted.

The AANS stated that steroid use was not recommended for reducing ICP or improving outcomes, and that high-dose methylprednisolone was associated with increased mortality (Carney et al., 2017). The EBIC stated that there was no established indication for the use of steroids in acute head injury management (Maas et al., 1997).

Discussion

In light of a series of inconclusive studies into the effectiveness and safety of corticosteroid use, a very large multinational randomized collaboration for assessment of early methylprednisolone administration was initiated in 1999 (Roberts et al., 2004). To achieve 90% power, recruitment of 20,000 patients in the Corticosteroid Randomization after Severe Head Injury (CRASH) trial was the goal. After the random allocation of 10,008 patients, the experiment was halted. Of 4,985 patients allocated corticosteroids, 1052 died within two weeks compared to 893 of 4979 patients in the placebo group. This indicated a relative risk of death equal to 1.8 in the steroid group (p=0.0001). Further analysis showed no differences in outcomes between eight CT subgroups or between patients with major extracranial injury compared to those without. The authors also conducted a systematic review and meta-analysis of existing trials using corticosteroids for head injury. Before the CRASH trial, a 0.96 relative risk of death was seen in the corticosteroid group. Once the patients from the CRASH trial were added, the relative risk changed to 1.12. The authors suggest that based on this large multinational trial, corticosteroids should not be used in head injury care no matter what the severity of injury.

Two other studies assessed methylprednisolone in acute ABI management. Giannotta et al. (1984) conducted an RCT of patients with GCS≤8 treated with methylprednisolone. Patients were divided into one of three groups: a high dose, low dose or placebo group, then assessed at six months based on the GOS grading system. They reported no differences in mortality rates between groups. The authors then compressed the low dose and placebo groups and performed further analyses. They found that patients less than 40 years old in the high dose group showed significant decreases in mortality when compared to the low dose/ placebo group; further, they found no significant differences between these groups in beneficial outcomes. Saul et al. (1981) conducted another RCT where patients received methylprednisolone or no drug at all. They noted that there were no differences between the two groups in GOS scores at 6 months.

Four RCTs were found that assessed dexamethasone in ABI. Dearden et al. (1986) assessed consecutively admitted patients with ABI treated with dexamethasone. They noted that patients experiencing ICP levels >20 mmHg showed significantly poorer outcomes on the GOS at six months. Braakman et al. (1983) found no differences between patients treated with dexamethasone compared to placebo in one month survival rates or six month GOS scores. Similarly, Cooper et al. (1979) performed a double blind randomized controlled study of the effects of dexamethasone on outcomes in severe head injuries. Patients were divided into three groups and no significant differences were seen in outcomes. The authors performed several post-mortem examinations and indicate that often, patients initially diagnosed with focal lesions were in fact suffering from diffuse injuries which are not amenable to corticosteroid treatment. Finally, Kaktis and Pitts (1980) assessed the effects of low-dose (16mg/day) and high-dose (14mg/day) dexamethasone on ICP levels in patients with ABI. They noted no differences in ICP at any point during the 72 hour follow-up period.

In a cohort study conducted by Watson et al. (2004) patients receiving any form of glucocorticoid therapy (dexamethasone 98%, prednisone 2.4%, methylprednisone 1.6%, or hydrocortisone 1.6%) were compared two patients treated without corticosteroids for risk of development of post-traumatic seizures. Their inclusion criteria allowed for patients with only one of a list of complications to be included resulting in a diverse group of patients with TBI. They noted that patients receiving glucocorticoid treatment on the first day post injury were at increased risk of developing first late seizures compared to patients receiving no intervention. They also saw no improvement in patients receiving glucocorticoids after the first day. The authors suggest that this ads further strength to the argument against routine corticosteroid use in TBI (Watson et al., 2004).

Grumme et al. (1995) conducted an RCT in which GOS scores were assessed one year after injury in patients treated with the synthetic corticosteroid triamcinolone. While no overall effect between groups was found, further analysis was performed on subsets of patients. A significant increase in beneficial outcomes was seen in patients who had both a GCS<8 and a focal lesion. The authors suggest that in light of this evidence, patients with both GCS<8 and a focal lesion would benefit from steroid administration immediately after injury.

Conclusions

There is level 1a evidence that methylprednisolone may increase mortality rates in patients post ABI and should not be used.

Summary


There is level 1a evidence that morphine, sufentanil, and alfentanil may result in increased intracranial pressure post ABI.

There is conflicting evidence (level 1b) regarding the effects of fentanyl on intracranial pressure post ABI.

There is level 2 evidence that remifentanil may not affect intracranial pressure post ABI.

There is level 4 evidence that carbamazepine may decrease the incidence of aggressive behaviours following a traumatic brain injury.

There is level 4 evidence that carbamazepine may not decrease seizure control compared to other anticonvulsants following a traumatic brain injury.

There is level 4 evidence that intramuscular midazolam can be used for acute seizure cessation.

There is level 1b evidence to suggest that levetiracetam may be as safe and effective as phenytoin in the treatment and prevention of early seizures in individuals in the intensive care unit post ABI.

There is level 1b evidence that anticonvulsants given during the first 24 hours post ABI may reduce the occurrence of early seizures (within the first week post injury).

There is level 1a evidence that anticonvulsants given shortly after the onset of injury may not reduce mortality, persistent vegetative state, or the occurrence of late seizures (>1 week post injury).

There is level 1a evidence that seizure prophylactic treatment with either phenytoin or valproate may result in similar incidences of early or late seizures and similar mortality rates.

There is level 2 evidence indicating that phenobarbital given post ABI may not reduce the risk of late seizures.

There is level 2 evidence that phenobarbital combined with phenytoin prophylaxis may decrease rate of post-traumatic epilepsy compared to no prophylactic treatment.

There is level 4 evidence that valproic acid may decrease the incidence of aggressive behaviours.

There is level 4 evidence that divalproex may decrease the incidence of agitation post TBI.

There is Level 4 evidence to suggest that lamotrigine may help to reduce inappropriate behaviours post-traumatic brain injury.

There is level 4 evidence that cerebrolysin may improve attention and memory function post ABI, as well as clinical outcome.

There is level 1b evidence that donepezil may improve attention and short-term memory post ABI.

There is level 4 evidence that donepezil may be effective in improving short-, long-term, and visual memory post ABI.

Based on a single RCT, there is level 1b evidence that oral physostigmine may improve long-term memory in men with TBI.

There is conflicting evidence that sertraline may be effective in the treatment of major depression post TBI.

There is level 2 evidence that citalopram may aid in the reduction of depression post ABI.

There is level 4 evidence that citalopram and carbamazepine may be efficacious in the treatment of depression, anxiety and mood disorders.

There is level 2 evidence to suggest that the administration of desipramine may assist in improving mood and reducing depression.

There is level 4 evidence that sertraline hydrochloride can decrease the incidence of aggression and irritability.

There is level 4 evidence that amitriptyline can be useful in reducing the incidence of agitated behaviour.

There is level 4 evidence to suggest that an antimanic agent (lithium carbonate) may reduce aggressive/agitated behaviour following a brain injury.

There is Level 4 evidence (from one small study) to suggest that quetiapine may help reduce aggressive behaviour.

There is level 4 evidence from one study to suggest that ziprasidone can assist in the controlling of agitation post TBI.

There is level 4 evidence that haloperidol may not have a negative effect on the success of rehabilitation.

There is level 4 evidence that administration of a single-dose droperidol may calm agitated patients with ABI more quickly than other agents.

There is level 4 evidence that methotrimeprazine may be safe and effective for controlling agitation after an acquired brain injury.

There is level 4 evidence that phenol nerve blocks may reduce contractures and spasticity at the elbow, wrist and finger flexors for up to five months post injection.

There is level 4 evidence that oral baclofen may improve lower extremity spasticity but not upper extremity spasticity.

There is level 2 evidence that botulinum toxin type A injections can be effective in the management of localized spasticity following ABI.

There is level 1b evidence to suggest that patients receiving botulinum toxin type A through a single motor point or through multisite distributed injections may both show a reduction in spasticity regardless of the drug administration method.

There is level 2 evidence that botulinum toxin type A may be an effective treatment for children and adolescents with upper and lower limb spasticity.

There is level 1b evidence that bolus intrathecal baclofen injections may produce short-term (up to six hours) reductions in upper and lower extremity spasticity following ABI.

There is level 4 evidence to suggest that prolonged intrathecal baclofen may result in longer-term (three months, and one year) reductions in spasticity in both the upper and lower extremities following an ABI.

There is level 4 evidence, from two studies, to suggest that intrathecal baclofen can result in short-term improvements of walking performance in ambulatory patients, particularly gait velocity, stride length, and step width.

There is level 4 evidence that intrathecal baclofen pumps may be effective at reducing spasticity in the upper and lower limbs for children with hypoxia.

There is conflicting (level 1b, level 2, level 3) evidence regarding the efficacy of pentobarbital in improving intracranial pressure over conventional management measures.

There is level 2 evidence that thiopental may be more effective than pentobarbital for controlling elevated intracranial pressure.

There is level 2 evidence that pentobarbital may not be more effective than mannitol for controlling elevated intracranial pressure.

There is level 3 evidence that high-dose barbiturate may result in increase length of stay and may not improve outcomes when compared to low-dose barbiturate.

There is level 4 evidence that barbiturate therapy may cause reversible leukopenia, granulocytopenia, and systemic hypotension, as well as supressed bone marrow production.

There is level 4 evidence that a combination barbiturate therapy and therapeutic hypothermia may result in improved clinical outcomes up to 1 year post injury.

There is level 2 evidence that Disodium Etidronate (EHDP) may reduce the development of heterotopic ossification in patients with severe head injury.

There is conflicting (level 1b) evidence as to whether dexanabinol in cremophor-ethanol solution effectively lowers intracranial pressure, increases cerebral perfusion pressure, and improves long-term clinical outcomes post TBI when compared to placebo.

There is level 1b evidence that a dual cannabinoid agonist may significantly increase cerebral perfusion pressure and improves survival post TBI when compared to placebo.

Based on a single RCT, there is level 1b evidence that pindolol may decrease aggression following brain injury.

There is level 1b evidence that propranolol may reduce the intensity of agitated symptoms following brain injury.

There is level 2 evidence supporting the administration of low molecular weight herapin within the first 72 hours post ABI to reduce the risk of developing deep vein thrombosis and pulmonary embolisms post injury.

There is level 2 evidence that administering low molecular weight herapin (enoxaparin) or heparin post ABI may not increase the risk of intracranial bleeding, compared to no treatment.

There is level 4 evidence that the use of chemoprophylaxis 24 hours after stable head computed tomography scan may decrease the rate of deep vein thrombosis formation post ABI.

There is level 4 evidence that mannitol may be effective in controlling elevated intracranial pressure.

There is level 2 evidence that early administration of mannitol may not effectively lower elevated intracranial pressure, but may not adversely affect blood pressure.

There is level 2 evidence that high-dose mannitol may be more effective than conventional mannitol in reducing mortality rates and improving clinical outcomes.

There is level 1b evidence that mannitol may be no more effective than hypertonic saline in controlling elevated intracranial pressure.

There is level 1b evidence that mannitol may be less effective than sodium lactate in controlling elevated intracranial pressure.

There is level 1b evidence that pramipexole, and level 1a evidence that amantadine, may be effective in improving levels of consciousness in children with ABI.

There is level 1a evidence that amantadine may effectively improve consciousness, cognitive function, and disability when compared to placebo.

There is level 2 evidence that Amantadine may not help to improve learning and memory deficits.

There is conflicting evidence of the effects of amantadine on reducing irritability and aggression in individuals with moderate-severe traumatic brain injury.

There is level 4 evidence that dopamine-enhancing drugs may accelerate the rate of recovery from a low response state for children post TBI.

Based on two RCTs, there is conflicting evidence supporting the use of bromocriptine to enhance cognitive functioning.

There is level 4 evidence that bromocriptine may improve all motivational deficits except mood.

There is level 2 evidence that administration of dexamethasone may inhibit endogenous production of glucocorticoids and has no proven impact on recovery post brain injury.

There is level 4 evidence that Depo-Provera and counselling may reduce sexually aggressive behaviour.

There is level 1a evidence that progesterone may not lower intracranial pressure levels post TBI when compared to placebo.

There is level 1a evidence that progesterone may not be associated with adverse events when compared to placebo.

There is conflicting level 1a evidence as to whether progesterone improves long-term outcomes and reduces mortality post TBI when compared to placebo.

There is conflicting evidence regarding the effectiveness of the administration of methylphenidate following brain injury for the improvement of cognitive functioning.

There is level 1a evidence that methylphenidate may improve reaction time of working memory.

Based on a single RCT, there is level 1b evidence that an individual’s response to methylphenidate therapy may be dependent on his/her genotype of the catechol-O-methyltransferase gene.

There is level 3 evidence, based on a single study, that methylphenidate may not have an adverse effect on the sleep-wake cycle of those who have sustained a TBI.

There is level 2 evidence (from one randomized control trial) to suggest that treatment with methylphenidate following brain injury can significantly reduce anger.

Based on two small and conflicting RCTs, there is inconclusive evidence whether methylphenidate improves cognitive behavioural function in children post ABI.

There is level 1a evidence that modafinil may not be effective in treating fatigue but has been shown to be effective short-term in treating excessive daytime sleepiness post ABI.

There is level 1b evidence that propofol may reduce intracranial pressure and the need for other intracranial pressure interventions when used in conjunction with morphine compared to morphine alone.

There is level 1b evidence that a high dose of propofol may improve intracranial pressure and cerebral perfusion pressure compared to a low dose of propofol.

There is level 2 evidence that propofol may not be significantly different from dexmedetomidine in its effect on intracranial pressure.

There is level 2 evidence that propofol may not be significantly different from morphine and midazolam in its effect on intracranial pressure, cerebral perfusion pressure, mean arterial pressure, and long-term outcomes.

There is level 4 evidence that propofol may improve intracranial pressure and cerebral perfusion pressure.

There is level 4 evidence that midazolam may reduce mean arterial pressure, cerebral perfusion pressure, and systolic blood pressure, but may have no effect on intracranial pressure.

There is level 2 evidence that midazolam may not be different from propofol in its effect on intracranial pressure or cerebral perfusion pressure.

There is level 1b evidence that midazolam may not be different than propofol in its effect on long-term outcomes.

There is level 1a evidence that methylprednisolone may increase mortality rates in patients post ABI and should not be used.

There is level 1b evidence that dexamethasone may not lower elevated intracranial pressure levels and may worsen outcomes.

There is level 2 evidence that triamcinolone may improve outcomes in patients with a Glasgow Coma Scale<8 and a focal lesion.

There is level 3 evidence that glucocorticoid administration may increase the risk of developing first late seizures.

References

Adembri, C., Venturi, L., & Pellegrini-Giampietro, D. E. (2007). Neuroprotective effects of propofol in acute cerebral injury. CNS Drug Rev, 13(3), 333-351.

Al-Adawi, S., Hoaglin, H., Vesali, F., Dorvlo, A. S., & Burke, D. T. (2009). Effect of amantadine on the sleep-wake cycle of an inpatient with brain injury. Brain Inj, 23(6), 559-565.

Albanese, J., Durbec, O., Viviand, X., Potie, F., Alliez, B., & Martin, C. (1993). Sufentanil increases intracranial pressure in patients with head trauma. Anesthesiology, 79(3), 493-497.

Albanese, J., Viviand, X., Potie, F., Rey, M., Alliez, B., & Martin, C. (1999). Sufentanil, fentanyl, and alfentanil in head trauma patients: a study on cerebral hemodynamics. Crit Care Med, 27(2), 407-411.

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