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12. Neuropharmacological Interventions Post ABI

Mark Bayley MSc MD FRCPC, Amber Harnett Msc, Shannon Janzen MSc, Andrea Lee BSc(c), Robert Teasell MD FRCPC

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.

Remifentanil might not improve intracranial pressure, cerebral perfusion pressure, cerebral blood flow velocity, or mean arterial pressure post ABI

Sufentanil might decrease mean arterial pressure, cerebral perfusion pressure, heart rate and transiently increase intracranial pressure— especially in patients with low blood pressure.

Sufentanil used in combination with midazolam may decrease intracranial pressure and mean arterial pressure post ABI.

Propofol, especially at higher doses, likely improves favourable outcomes, intracranial pressure and cerebral perfusion pressure more effectively than morphine.

Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on morbidity outcomes, or intracranial, cerebral perfusion, and mean arterial pressure.

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.

Phenytoin may be an effective prophylactic drug for early post-traumatic seizures, however its effectiveness to treat late post-traumatic seizures has not been established.

Phenytoin is more effective than valproate as a prophylactic anti-seizure medication.

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

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 may be effective in reducing aggression following a TBI, although, additional research is needed.

Lamotrigine may be effective in reducing pathologic laughing and crying following a TBI. However, further research with larger sample sizes is needed to validate these findings.

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

It is unclear as to whether donepezil may improve attention in individuals with a moderate to severe ABI.

Physostigmine may improve long-term memory in men with TBI, however, more studies are required.

Rivastigmine may not be effective in treating attention deficits post ABI.

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.

Quetiapine may be effective in reducing aggression following a TBI, although additional research is needed.

Ziprasidone may be effective in reducing agitation following a TBI, although, additional research is needed.

Haloperidol appears to have no benefits, and possible negative effects on recovery, following a TBI.

Droperidol may be effective in reducing agitation following TBI, although additional research is required.

Methotrimeprazine may be safe and effective for controlling agitation following an ABI, although, additional research is required.

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.

Bolus injections of intrathecal baclofen likely produce short-term reductions in upper and lower extremity spasticity and improvements in walking performance post ABI.

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

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

There are conflicting reports regarding whether pentobarbital is superior to conventional management at improving intracranial pressure. The strongest evidence suggests there is no difference.

Thiopental may decrease intracranial pressure, cerebral perfusion pressure, and mean arterial pressure post ABI.

Thiopental may be more effective than pentobarbital at controlled refractory intracranial pressure, and less likely to develop adrenal insufficiency. However, thiopental may still be associated with leuko- and granulocytopenias. When used, combination with hypothermia may result in greater long-term outcomes.

Barbiturate therapy should be avoided until all other measures for controlling elevated intracranial pressure are exhausted; special attention should be paid to monitoring immunological function, adrenal function, and blood pressure status if used.

Pentobarbital might decrease energy expenditure and nitrogen metabolism in individuals with an ABI refractory to standard therapy.

Etidronate Disodium may prevent the development of heterotopic ossification in individuals with ABI.

It is unclear whether Dexanabinol in cremophor-ethanol solution is effective in controlling intracranial pressure and improving cerebral perfusion pressure, and clinical outcomes post TBI. The strongest evidence suggests no beneficial effects.

KN38-7271, a dual cannabinol agonist, is likely effective at improving intracranial pressure, cerebral perfusion pressure and survival post TBI at high doses.

Pindolol may be effective in reducing aggression following an ABI.

Propranolol may be effective in reducing the intensity of agitation and aggression following brain injury.

Administration of pharmacological thromboembolic prophylaxis within the first 72 hours post ABI may be effective for reducing the risk of developing venous thromboembolism.

Enoxaparin is effective for the prevention of venous thromboembolism development after elective neurosurgery and has not been found to cause excessive bleeding.

Mannitol may effectively improve intracranial pressure and cerebral perfusion pressure post ABI; however, this benefit may only be seen in hypertensive (intracranial pressure>20 mmHg) patients.

It is unclear whether hypertonic saline is more effective than mannitol at lowering intracranial pressure or reducing hospital length of stay.

Hypertonic saline can improve cerebral perfusion pressure, cerebral blood flow, and brain tissue oxygenation more effectively than mannitol. However, hypertonic solution is not different than mannitol in terms of morbidity and mortality associated with treatment.

Hypertonic saline is superior to barbiturates, propofol, and fentanyl at lowering intracranial pressure post TBI.

Amantadine may improve consciousness, cognitive function, and disability post ABI; however, it might not affect emergence from coma post ABI. It is important to note that these benefits are only seen during amantadine administration, and so treatment must be continued to sustain the improvements made.

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

Amantadine is not effective at improving generalized cognition. Its impact on executive functioning should be studied further.

Amantadine requires further research before conclusions can be drawn regarding its effects on aggression and irritability following a TBI.

Bromocriptine does not appear to improve attention in those with an ABI.

(-)-OSU6162 treatment may not be effective for reducing fatigue post TBI.

Medroxyprogesterone intramuscularly may reduce sexual aggression.

Progesterone does not improve functional outcomes post TBI, with the potential exception of patients who are not severely ill upon admission (Glasgow coma scale score>5)

Progesterone is likely associated with the development of phlebitis and thrombophlebitis.

Progesterone has no effect on intracranial pressure, but does reduce mortality, and improves functional and neurological outcomes post ABI.

Growth hormone deficiency may be effectively treated with hormone replacement therapy and insulin growth like factor-1 therapy.

The administration of human growth hormones appears to have positive (although sometimes limited effects) on general and executive functioning in those with an ABI.

Melatonin treatment may improve sleep quality, sleep efficiency, and reduce fatigue in patients post TBI.

Melatonin treatment may not effect sleep onset latency or daytime sleepiness.

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

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

Response to methylphenidate may depend on the presence of the Met 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.

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. 

Dextroamphetamine is moderate evidence to suggest that dextroamphetamine is not effective for the remediation of general functioning.

Pramiracetam might improve memory in males post TBI, however, additional studies are required.

Propofol may improve intracranial pressure and cerebral perfusion pressure post ABI, without producing adverse outcomes.

Propofol and vasopressor treatment in combination, but not as monotherapy, might increase the risk of developing propofol infusion syndrome post ABI.

Propofol, especially at higher doses, likely improves favourable outcomes, intracranial pressure and cerebral perfusion pressure more effectively than morphine.

Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on morbidity outcomes, or intracranial, cerebral perfusion, and mean arterial pressure.

The combination of morphine and midazolam may confound the comparison between propofol and morphine, however, it is prudent to conclude propofol is at least as safe and effective as morphine.

Midazolam is likely not different than propofol at improving mortality, disability, or neurological outcomes.

High doses of midazolam might be associated with hypotension, specially following intubation.

Midazolam may have no effect on intracranial pressure but may reduce mean arterial pressure and cerebral perfusion pressure in patients, post-ABI.

Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on morbidity outcomes, or intracranial, cerebral perfusion, and mean arterial pressure.

Corticosteriods such as methylprednisolone, dexamethasone, and other glucocorticoids may worsen outcomes, and should not be used. However, methylprednisolone may be effective at improving mortality when specific complications, such as acute respiratory distress syndrome secondary to sepsis, arise.

Triamcinolone may improve outcomes in individuals post ABI with a Glasgow Coma Scale score less than 8 and a focal lesion.

Anatibant, regardless of dose, likely does not cause serious adverse events, affect morbidity, mortality or disability in patients post ABI.

It is unclear if a higher dose of anatibant is superior to a lower dose at improving intracranial pressure, however it may improve functional outcomes up to 6 months post injury.

Bradycor can prevent acute elevations in intracranial pressure and reduce therapeutic intensity levels post ABI; however, its effect on morbidity and mortality outcomes is not clear.

Dimethyl sulfoxide may cause temporary improvements in intracranial pressure and cerebral perfusion pressure post ABI, however these improvements may not be sustained long-term.

DMSO might be able to transiently lower intracranial pressure; however, it is associated with the development of electrolyte imbalances. Both responses appear to be dose-dependent.

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.

Remifentanil might not improve intracranial pressure, cerebral perfusion pressure, cerebral blood flow velocity, or mean arterial pressure post ABI

Sufentanil might decrease mean arterial pressure, cerebral perfusion pressure, heart rate and transiently increase intracranial pressure— especially in patients with low blood pressure.

Sufentanil used in combination with midazolam may decrease intracranial pressure and mean arterial pressure post ABI.

Propofol, especially at higher doses, likely improves favourable outcomes, intracranial pressure and cerebral perfusion pressure more effectively than morphine.

Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on morbidity outcomes, or intracranial, cerebral perfusion, and mean arterial pressure.

 

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 Acquired Brain Injury (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 Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (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.

The American Association of Neurological Surgeons (AANS) and the European Brain Injury Consortium (EBIC) made no recommendations regarding opioids in acute ABI.

Discussion

One study researched the effects of IV remifentanil on patients with ABI. The remifentanil was administered first as a bolus, then as a continuous infusion, yet despite the different modes of application the study reported no differences in ICP, CPP, MAP, or cerebral blood flow velocity compared to baseline (Engelhard et al., 2004).

The effects of sufentanil on patients with ABI were researched by Werner et al. (1995) and Albanese et al. (1993). While both studies reported decreases in MAP, only Albanese at al. observed additional decreases in CPP and HR. Interestingly, both groups noted an increase in ICP following sufentanil treatment, albeit only transiently in one study (Albanese et al., 1993) or in patients with decreased MAP (Werner et al., 1995). Although the trials were small and not blinded, these results suggest that sufentanil is not an agent that should be considered when attempting to lower ICP post-ABI.

Several studies conducted RCTs comparing the efficacy of fentanyl to either morphine (de Nadal et al., 2000), sufentanil (Sperry et al., 1992), sufentanil and alfentanil (Albanese et al., 1999), morphine and sufentanil (Lauer et al., 1997) or remifentanil and morphine (Karabinis et al., 2004). Of the studies reviewed, 3 reported increases in ICP after opioid administration (Albanese et al., 1999; de Nadal et al., 2000; Sperry et al., 1992). The ICP increase was transient in Albanese et al. with the pressure returning to baseline 15 min after opiod administration. Of the aforementioned studies, all revealed a decrease in CPP and MAP after any type of opioid treatment. The remaining two studies found ICP did not change after opioid administration ((Engelhard et al., 2004; Karabinis et al., 2004; Lauer et al., 1997). Furthermore, CPP and MAP did not change, save for the sufentanil group in Lauer and colleagues’ study where a decrease in mean arterial pressure was found. 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).

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. However, it has been reported that using an opioid such as sufentanil with midazolam significantly improves ICP for a prolonged period of time (2 days), albeit at the expense of decreasing MAP (Scholz et al., 1994). 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. While, Kelly et al. (1999) noted propofol was significantly more effective than morphine at reducing ICP – especially at higher doses.  With respect to morbidity outcomes, one study reported no difference (Stewart et al., 1994) and the other an increase (Kelly et al., 1999) in favourable outcomes compared to the other treatment. Despite the disagreement in relationship directionality between studies, it can be concluded that propofol is at least as safe to use as morphine alone, or morphine with midazolam.

Conclusions

There is conflicting (level 1a and level 2) evidence as to whether fentanyl, morphine, or sufentanil increase intracranial pressure, and decrease cerebral perfusion pressure post ABI. The level 1a evidence suggests that it increases intracranial pressure and decreases cerebral perfusion pressure.

There is level 1b evidence that propofol is more effective than morphine at improving favourable outcomes and reducing intracranial pressure post TBI- specially at higher doses.

There is level 2 evidence that alfentanil may result in a decrease in cerebral perfusion pressure and mean arterial pressure, and a transient increase in intracranial pressure, post ABI compared to controls.

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

There is level 2 evidence that propofol is similar to midazolam and morphine with regards to sedation, morbidity, changes in intracranial pressure, cerebral perfusion, and mean arterial pressure post ABI.

There is level 4 evidence that remifentanil may not improve intracranial pressure, cerebral perfusion pressure, mean arterial pressure, or cerebral blood flow velocity post ABI.

There is level 4 evidence that sufentanil may decrease mean arterial pressure, cerebral perfusion pressure, and heart rate post ABI.

There is level 4 evidence that sufentanil may transiently increases intracranial pressure post ABI.

There is level 4 evidence that sufentanil may increase intracranial pressure in patients with low mean arterial pressure post ABI.

There is level 4 evidence that sufentanil with midazolam decreases intracranial pressure and mean arterial pressure for 2 days 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 Midazolam given to treat seizures. 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

 

Phenytoin may be an effective prophylactic drug for early post-traumatic seizures, however its effectiveness to treat late post-traumatic seizures has not been established.

 

Phenytoin is more effective than valproate as a prophylactic anti-seizure medication.

 

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

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 the administration of phenytoin is compared to a placebo, its effect on the occurrence of early seizures is not encouraging; several studies did not find phenytoin to be effective (Bhullar et al., 2014; Temkin et al., 1990; Young et al., 1983). However, one RCT by Temkin et al., (1990) did find that phenytoin reduced the rate of early seizures only compared to placebo. 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. 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 the prevention of seizures is not favorable. 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, many studies have shown the two drugs to be comparable in terms of seizure rates (Inaba et al., 2013; Javed et al., 2016; 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 randomized controlled trial (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 GOS at 6 months (p=0.039) post intervention compared to the phenytoin group. A large RCT by Younus et al. (2018) found that individuals on levetiracetam has a significant decrease in seizure activity at follow-up, and fewer abnormal EEGs compared to those on phenytoin. Furthermore, upon differentiation Radic et al. (2014) found that individuals with any evidence of a midline shift 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.

When examining the effects of phenytoin compared to valproate Temkin et al. (1999) found no significant differences in rates of early seizures, late seizures, or mortality.  Dikmen et al. (1991) found that severely injured individuals receiving phenytoin performed no more poorly on neuropsychological measures than those taking valproic acid and valproate. The following year (12 to 24 months later), phenytoin was shown to have a small but negative effect on cognition (Dikmen et al., 1991).

Conclusions

There is level 1b evidence that phenytoin is effective in reducing the rate of only early onset post-traumatic seizures in patients with TBI.

 

There is conflicting evidence regarding whether or not phenytoin is effective in preventing post-traumatic seizure disorder long term compared to placebo treatment in patients with TBI. 

 

There is level 1a evidence that valproate is not more effective as a prophylactic anti-seizure medication compared to phenytoin in ABI populations.

 

There is level 1b evidence that levetiracetam and phenytoin do not show significant differences between them as prophylactic anti-seizure medication for individuals with ABI.

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 a 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 may be effective in reducing aggression following a TBI, although, additional research is needed.

Valproic acid, an antiepileptic, has been used to treat seizure disorders in both adults and children. It has also been used to treat mania, bipolar disorder, and PTSD (McElroy et al., 1987). A case study of an individual with TBI showed a reduction in episodic explosiveness (Geracioti Jr, 1994), and so it has been explored as an intervention for challenging behaviours post ABI.

Discussion

Wroblewski et al. (1997a) 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.

12.2.6 Lamotrigine

Key Points

Lamotrigine may be effective in reducing pathologic laughing and crying following a TBI. However, further research with larger sample sizes is needed to validate these findings.

Lamotrigine has demonstrated effectiveness as an antiepileptic (Brandt & May, 2018) and mood stabilizer (Baldessarini et al., 2018). Among individuals with ABI, however, its effectiveness as a mood stabilizer 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 and crying but did not address impulsivity (Chahine & Chemali, 2006b). All four participants were on other medications to control for additional behaviours, but these medications were eventually eliminated once lamotrigine was introduced. No formal outcome assessments were conducted, which makes it difficult to draw conclusions from this study.

Conclusions

There is level 4 evidence that lamotrigine may reduce inappropriate behaviours post TBI.

12.3 Anti-Cholinesterase Inhibitors

12.3.1 Cerebrolysin and Cognitive Functioning

Key Points

Cerebrolysin may be beneficial for improving clinical outcomes 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 neurological recovery, as measured by the Glasgow Outcome Scale (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. However, controlled trials are necessary to further explore the efficacy of this drug.

Conclusions

There is level 4 evidence that cerebrolysin may improve attention scores post ABI.

12.3.2 Donepezil and Cognitive Functioning

Key Points

It is unclear as to whether donepezil may improve attention in individuals with a moderate to severe ABI.

Originally developed for improving cognitive function and memory in people with Alzheimer’s disease, donepezil is an acetylcholinesterase inhibitor (Cacabelos, 2007). Donepezil has been found to be effective at delaying cognitive impairment in people with Alzheimer’s disease (Takeda et al., 2006). Since evidence suggests that cholinergic dysfunction may contribute to persistent cognitive deficits for people after traumatic brain injury, improvements in attention, memory, and other aspects of cognition related to the acetylcholine system are expected when cholinergic function is reduced (Arciniegas, 2003).

Discussion

In an RCT, Zhang et al. (2004) demonstrated that donepezil was associated with significantly more improvement in tasks of sustained attention compared to placebo. These improvements were sustained even after the washout period. Once both groups had completed donepezil treatment there were no significant differences between groups on any measures of attention. Khateb et al. (2005) found that individuals did perform significantly better on measures of divided attention after donepezil treatment, however 4/15 participants stopped treatment due to negative side-effects. In contrast to the positive effects found by these studies, one prospective controlled trial found no significant effects of donepezil on any measures of cognition, including attention (Campbell et al., 2018). In both the Campbell et al. (2018) and Zhang et al. (2004) studies, individuals received donepezil for approximately the same duration.

Conclusions

There is conflicting level 1b (positive) and level 2 (negative) evidence that donepezil may improve attention compared to placebo post ABI.

12.3.3 Physostigmine

Key Points

Physostigmine may improve long-term memory in men with TBI, however, more studies are required.

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

There is level 1b evidence that oral physostigmine may improve long-term memory compared to placebo in men with TBI, however more recent studies are required.

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., 1997b). 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

Quetiapine may be effective in reducing aggression following a TBI, although additional 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 that quetiapine may reduce aggressive behaviour.

12.5.3 Ziprasidone

Key Points

Ziprasidone may be effective in reducing agitation following a TBI, although, additional research is needed.

Ziprasidone is an atypical antipsychotic has been approved for the treatment of acute agitation in schizophrenia as well as acute mania associated with bipolar disorder. Following a TBI, ziprasidone may be similarly effective in reducing agitation.

Discussion

The period of post traumatic amnesia has been defined as a period where the individual is disorientated and may suffer from behaviour alterations (Brooke et al., 1992). Researchers have suggested that these changes in behaviour result from a lack of self-awareness, which may be associated with memory alterations that appear after injury (Noé et al., 2007). One study examined individuals who were still suffering from post-traumatic amnesia upon admission to rehabilitation. These patients showed a decrease in agitation during the first two weeks of ziprasidone administration. As well, it was noted that all patients tolerated the medication, with no clinical side effects observed (Noe et al. 2007).

Conclusions

There is level 4 evidence that ziprasidone may reduce agitation post TBI.

12.5.4 Haloperidol

Key Points

Haloperidol appears to have no benefits, and possible negative effects on recovery, following a TBI.

Haloperidol is a butyrophenone antipsychotic agent that acts as a dopamine receptor antagonist. It is a typical antipsychotic that is used to treat schizophrenia, bipolar disorder, delirium, and agitation. Haloperidol does have several known side effects, adverse events, and contraindications. Given the former, there is concern that it may impede recovery post ABI.

Discussion

In a retrospective chart review, agitation was managed during inpatient rehabilitation 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, although none of the treated patients obtained independence in intellectual skills (Rao et al., 1985).

Conclusions

There is level 4 evidence that haloperidol may not be effective in treating behavioral disorders post TBI. 

12.5.5 Droperidol (Inapsine)

Key Points

Droperidol may be effective in reducing agitation following TBI, although additional research is required.

Droperidol is a butyrophenone antipsychotic agent that acts as a potent dopamine receptor antagonist. It is a typical antipsychotic that has been used for the treatment of psychosis in Europe (Stanislav & Childs, 2000). There is limited research regarding its use as an intervention for post-ABI agitation.

Discussion

One study found that a single dose of droperidol effectively calmed patients displaying agitated behaviour (Stanislav & Childs, 2000). The study also found that droperidol calmed individuals more quickly than haloperidol, lorazepam, and diphenhydramine, without heavily sedating the patients like the comparative medications. It is worth noting that a standardized outcome measure was not utilized, and that a large proportion of the sample had psychiatric co-morbidities.

12.5.6 Methotrimeprazine

Key Points

Methotrimeprazine may be safe and effective for controlling agitation following an ABI, although, additional research is required.

Methotrimeprazine is a psychotropic medication that has antipsychotic properties, as mediated by dopamine blocking. It also has tranquilizing and analgesic properties, and appears to have an effect on opiate (pain) receptors (Maryniak et al., 2001). Its effect on challenging behaviours post ABI has received limited investigation.

Discussion

The oral administration of methotrimeprazine for agitation was evaluated in a retrospective review of 56 patients during inpatient rehabilitation (Maryniak et al., 2001). The authors found that methotrimeprazine was both safe and effective for controlling agitation in nearly all cases. However, the study did not utilize standardized outcome measures, include a control group, or perform statistical analysis. Therefore, a more rigorous study examining the safety and efficacy of methotrimeprazine within an ABI population is necessary before a firm conclusion can be determined.

Conclusions

There is level 4 evidence that methotrimeprazine may be effective for controlling agitation post ABI.

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).

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

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.

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.

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.

12.6.4 Intrathecal Baclofen

Key Points

Bolus injections of intrathecal baclofen likely produce short-term reductions in upper and lower extremity spasticity and improvements in walking performance post ABI.

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

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

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 evidence for the use of intrathecal baclofen 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 (Meythaler et al., 1999b). 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. It should be noted, however, that 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, with infections at the operative site being the most common (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) 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 compared to placebo 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 conflicting level 4 evidence to suggest that intrathecal baclofen may result in short-term improvement of walking performance in ambulatory patients, particularly gait velocity, stride length, and step width, in individuals post ABI.

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.

12.6.4.2 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 whether pentobarbital is superior to conventional management at improving intracranial pressure. The strongest evidence suggests there is no difference.

 Thiopental may decrease intracranial pressure, cerebral perfusion pressure, and mean arterial pressure post ABI.

 Thiopental may be more effective than pentobarbital at controlled refractory intracranial pressure, and less likely to develop adrenal insufficiency. However, thiopental may still be associated with leuko- and granulocytopenias. When used, combination with hypothermia may result in greater long-term outcomes.

 Barbiturate therapy should be avoided until all other measures for controlling elevated intracranial pressure are exhausted; special attention should be paid to monitoring immunological function, adrenal function, and blood pressure status if used.

 Pentobarbital might decrease energy expenditure and nitrogen metabolism in individuals with an ABI refractory to standard therapy.

Barbiturates have long been proposed as a useful intervention in the control of ICP. They are thought to reduce ICP by suppressing cerebral metabolism, reducing metabolic demands and decreasing cerebral blood volume (Roberts, 2000). Early reports indicated that barbiturates reduced ICP in patients 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).

A review found no evidence that barbiturates decreased blood pressure or reduced mortality in 25% of patients (Roberts & Sydenham, 2012). Therefore, it was recommended that barbiturate coma be avoided until all other measures for controlling elevated ICP are exhausted.

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 earlier EBIC guidelines recommended barbiturate use to increase sedation only after previous sedation, analgesia, hyperventilation, osmotic therapy, and CSF drainage have failed to  control ICP (Maas et al., 1997).

Discussion

Barbiturate administration is used in patients’ refractory to conventional treatment to decrease elevated ICP, and the increased cellular metabolism and protein catabolism caused by an ABI. As a result, an early PCT studied the effects of pentobarbital on surrogate markers of metabolism (Fried et al., 1989). The researchers noted lower energy expenditure, lower total urinary nitrogen excretion, and improved nitrogen balance in patients’ refractory to conventional therapy when compared to controls. The results brought forth suggest that pentobarbital effectively reduces cellular metabolism and protein catabolism post ABI, and as a result potentially improves patient survival. In order to fully elucidate the effects of pentobarbital on patients post ABI, follow up studies are required.

The findings of a 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; a finding which was corroborated by Schwartz et al. (1984) in a RCT and 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. 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 with 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). In another study, Schalen et al. infused thiopental intravenously for at least 12 hours, and noted a decrease ICP, CPP, and MAP in 82%, 84%, and 58% of patients, respectively. The conclusions drawn from this study should be interpreted with caution, as the small sample size and lack of controls warrant larger studies to further investigate the effects of thiopental.

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 et al. (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.

Conclusions

There is level 2 evidence that thiopental is more effective than pentobarbital for controlling elevated intracranial pressure refractory to conventional treatment, and less likely to induce adrenal insufficiency post ABI. 

 There is level 2 evidence that thiopental in combination with mild hypothermia has better one-year clinical outcomes compared to conventional management post ABI.

 There is level 3 evidence that thiopental induces leukopenia and granulocytopenia in patients post ABI.

 There is level 4 evidence that thiopental decreases intracranial pressure, cerebral perfusion pressure, and mean arterial pressure post ABI.

 There is conflicting (level 1b and level 2) evidence regarding whether or not pentobarbital improves intracranial pressure compared to conventional management measures post ABI. Level 1b evidence suggests there is no difference.

 There is level 2 evidence that barbiturate use is associated with development of hypotension in patients post ABI.

 There is level 2 evidence that pentobarbital decreases energy expenditure, total urinary nitrogen excretion, improves nitrogen balance, but has no effect on 3-methylhistidine excretion compared to controls in individuals with an ABI refractory to standard therapy.

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

Etidronate Disodium may prevent the development of heterotopic ossification in individuals with ABI.

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

It is unclear whether Dexanabinol in cremophor-ethanol solution is effective in controlling intracranial pressure and improving cerebral perfusion pressure, and clinical outcomes post TBI. The strongest evidence suggests no beneficial effects.

 KN38-7271, a dual cannabinold agonist, is likely effective at improving intracranial pressure, cerebral perfusion pressure and survival post TBI at high doses.

Discussion

In an early RCT, Knoller et al. (2002) found that dexanabinol (50 mg) showed significant improvements in ICP and CPP over placebo in patients with TBI.  Despite showing significant improvements on the GOS and Disability Rating Scale at 1-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.  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.

Firsching et al. (2012) utilized KN38-7271, a dual cannabinoid agonist, as means of reducing ICP. After administration of high-dose KN38-7271 (1000 µ), the authors reported significant increases in CPP and greater survival at one month, but non-significant decreases in ICP when compared to low-dose KN38-7271 (500 µ). These results suggest that the dual cannabinoid agonist may an overall positive effect on patients post TBI, especially at high doses, 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 high-dose KN38-7271 (a dual cannabinoid agonist) may improve intracranial pressure and cerebral perfusion pressure and improves survival post TBI compared to low-dose KN38-7271.

 

12.10 Cardiovascular Medication

12.10.1 Beta-Blockers

Beta-blockers are a class of medications that act as competitive antagonists of the catecholamine receptors. It has been suggested that these medications may reduce restlessness, anxiety, agitation, and aggression following brain injury. Given that dosage is often high, patients may be vulnerable to adverse effects such as lethargy, sedation, and depression; although, motor recovery post injury does not seem to be negatively affected (Levy et al., 2005).

12.10.1.1 Pindolol

Key Points

Pindolol may be effective in reducing aggression following an ABI.

Pindolol is an atypical beta-blocker in that it exerts a partial agonist effect on the serotonin 1A receptor which provides a slight stimulation of the blocked receptor and helps maintain a better resting sympathetic tone. The use of pindolol in individuals with aggressive behaviour following ABI was investigated in a clinical trial.

Discussion

Greendyke and Kantor (1986) investigated the effectiveness of pindolol in improving behavioural disturbances post ABI. A significant reduction in behaviours that lead to assaults was demonstrated during treatment with pindolol, as well as improved communication and cooperation. The authors noted that the optimal dose, in terms of maximizing therapeutic efficacy and minimizing adverse events, ranged between 40-60 mg per day. The frequency of supplemented psychotropic medications was reduced with pindolol treatment, although these medications were still administered and may have contributed to the reduction in assaultive episodes.

Conclusions

There is level 1b evidence that pindolol may reduce aggression compared to placebo post ABI.

12.10.1.2 Propranolol

Key Points

Propranolol may be effective in reducing the intensity of agitation and aggression following brain injury.

Propranolol is a non-selective beta-blocker that has been used for the reduction of aggressive behaviours associated with compromised brain function. It appears to lack the serious cognitive and affective side effects associated with other medications used to treat agitation post injury (Levy et al., 2005). The use of propranolol in individuals with post-TBI aggression was investigated in two clinical trials.

Discussion

Greendyke et al. (1986) investigated the effectiveness of propranolol for the improvement of behavioural issues associated with brain disease. Significantly fewer assaults and attempted assaults occurred during the 11-week propranolol treatment as compared to placebo. Of the nine patients in the trial, five showed marked improvement, two showed moderate improvement, and two showed little or no improvement. It should be noted that the patients also had severe dementia, and so this study cannot be used to draw conclusions for the ABI population as a whole. A later study by Brooke et al. (1992) found that propranolol was effective in reducing the intensity of the agitation and use of restraints when compared to placebo. However, propranolol was not more effective than placebo in reducing the frequency of agitation episodes or the number of adjunctive medications for agitation and sedation.

Conclusions

There is level 1b evidence that propranolol compared to placebo reduces the intensity of agitated symptoms post ABI.

There is conflicting evidence (level 1b) that propranolol compared to placebo reduces the frequency of aggressive behaviour post ABI.

12.10.2 Anti-Coagulants

Key Points

Administration of pharmacological thromboembolic prophylaxis within the first 72 hours post ABI may be effective for reducing the risk of developing venous thromboembolism.

Enoxaparin is effective for the prevention of venous thromboembolism development 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).  However, these results are in conflict with Hachem et al. (2018), which found no increased risk of ICH worsening, but found no benefit regarding VTE incidence.

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 3 evidence that prophylactic anticoagulation is more effective than placebo in reducing the risk of developing deep vein thrombosis in patients post ABI.

There is level 2 evidence that the administration of enoxaparin within the first 72 hours post ABI reduces the risk of developing deep vein thrombosis and pulmonary embolism post injury compared to unfractionated heparin.

There is level 4 evidence that administering enoxaparin or heparin post ABI does not increase the risk of intracranial bleeding compared to no treatment.

12.11 Diuretics

12.11.1 Mannitol

Key Points

Mannitol may effectively improve intracranial pressure and cerebral perfusion pressure post ABI; however, this benefit may only be seen in hypertensive (intracranial pressure>20 mmHg) patients.

It is unclear whether hypertonic saline is more effective than mannitol at lowering intracranial pressure or reducing hospital length of stay.

Hypertonic saline can improve cerebral perfusion pressure, cerebral blood flow, and brain tissue oxygenation more effectively than mannitol. However, hypertonic solution is not different than mannitol in terms of morbidity and mortality associated with treatment.

Hypertonic saline is superior to barbiturates, propofol, and fentanyl at lowering intracranial pressure post TBI.

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, the 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 (Diringer et al., 2012; Scalfani et al., 2012; Tang et al., 2015), and improving CPP (Hartl et al., 1997; Tang et al., 2015) following TBI. In addition, Tang et al. reported an increase in cerebrovascular pressure reactivity, a measure of cerebrovascular autoregulation, in patients with a low baseline CPP.

The Brain Trauma Foundation recommends that mannitol only be used if a patient has signs of elevated ICP or deteriorating neurological status; this is primarily due to the significant side effects associated with mannitol treatment. While side effects were not reported, one study indicated that mannitol was only effective in diminishing ICP and improving CPP when the initial ICP was hypertensive (>20mmHg(Hartl et al., 1997)).

Several studies have compared HTS to mannitol in terms of efficacy in lowering elevated ICP and improving long-term outcomes. While one case-control study found no significant difference between the treatments in the level or duration of ICP reduction (Sakellaridis et al., 2011), another found that HTS had a longer lasting effect (Ware et al., 2005). Two cohort studies reported significantly greater reductions in ICP from HTS than mannitol (Kerwin et al., 2009; Oddo et al., 2009), with one noting that these ICP reductions were associated with greater increases in CPP (Oddo et al., 2009). The benefits of HTS were also reported in 2 retrospective studies where HTS was compared to mannitol (Mangat et al., 2015), and mannitol, propofol, fentanyl and barbiturates (Colton et al., 2014a). Both studies described improvements in either acute (Colton et al., 2014a) or sustained (Mangat et al., 2015) ICP management, with the latter also reporting a decrease in length of hospitalization compared to mannitol.   In a RCT, Vialet et al. (2003) found that patients receiving HTS had fewer episodes of ICP hypertension and fewer clinical failures than those receiving mannitol, although clinical outcomes at three months did not differ between groups. Another small RCT demonstrated that HTS yielded a significantly greater decrease in ICP over a longer period of time when compared to mannitol (Battison et al., 2005). However, three other RCTs were identified that found no benefit of HTS over mannitol in controlling elevated ICP, despite improvements in CPP (Harutjunyan et al., 2005), Cerebral Blood Flow (Cottenceau et al., 2011), and blood glucose control (Jagannatha et al., 2016). A secondary analysis of the Jagannatha et al. (2006) study attempted to explain the lack of efficacy of HTS over mannitol, and found that urinary sodium concentrations were greater in patients receiving HTS (Jagannatha et al., 2018). The authors suggested that unless sodium excretion could be reduced, the efficacy of HTS would continue to be equivalent to that of mannitol in reducing ICP.

The comparison of HTS and mannitol was not just limited to the treatment’s ICP-lowering potential, but also the morbidity and mortality associated with each. Hypertonic Saline was associated with a decrease in hospital length of stay (Mangat et al., 2015); however, no differences were observed in mortality or GOS/GOSE scores when compared to mannitol(Baker et al., 2009; Cooper et al., 2004; Mangat et al., 2015; Vialet et al., 2003).

Conclusions

There is level 1a evidence that hypertonic saline is similar to mannitol in terms of mortality or Glasgow outcome scale (extended) scores in patients post TBI.

There is conflicting (level 1b) evidence as to whether hypertonic solution lowers elevated intracranial pressure more effectively than mannitol post ABI.

There is conflicting (level 2 and level 3) evidence that hypertonic saline lowers intracranial pressure for longer compared to mannitol post ABI. The level 2 evidence suggest that it does.

There is level 2 evidence that hypertonic saline is superior to mannitol at improving cerebral perfusion pressure, cerebral blood flow, and blood-glucose control in patients post ABI.

There is level 2 evidence that urinary sodium excretion is higher in hypertonic saline patients compared to those receiving mannitol post ABI.

There is level 4 evidence that hypertonic saline is superior to barbiturates, propofol, and fentanyl at lowering intracranial pressure post ABI.

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

There is level 4 evidence that mannitol may be effective in increasing cerebral perfusion pressure post ABI.

There is level 4 evidence that mannitol may only improve intracranial pressure and cerebral perfusion pressure post ABI in hypertensive patients (Intracranial pressure>20mmHg).

12.12 Dopaminergic Medications

Although it is a very small and simple molecule, dopamine fulfills many functions in the brain. It acts as a neurotransmitter activating dopamine receptors and when released by the hypothalamus it inhibits the release of prolactin from the anterior lobe of the pituitary gland. Dopaminergic medications are often used by individuals with Parkinson’s disease and those who have sustained an ABI.

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

Key Points

Amantadine may improve consciousness, cognitive function, and disability post ABI; however, it might not affect emergence from coma post ABI. It is important to note that these benefits are only seen during amantadine administration, and so treatment must be continued to sustain the improvements made.

Amantadine is a dopamine agonist that acts both pre- and post-synaptically to upregulate 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 has been used in the treatment of Parkinson’s disease.  Its properties as a potential neuroactive agent were quickly recognized (Zafonte et al., 2001), and there is interest in its use as a potential treatment in the management of ABI (Schneider et al., 1999b). Researchers believe that amantadine could significantly improve arousal in patients who are comatose. Potential side effects include over-stimulation, peripheral edema, livedo reticularis, and lowering of the seizure threshold, however, these are easily reversible (Schneider et al., 1999b). The favorable risk-benefit profile of amantadine suggests that it may be an attractive treatment option for inducing arousal from coma (Hughes et al., 2005).

The RCP reported that the preliminary research on amantadine was positive, but suggested that its longer-term effects required further exploration (Prolonged disorders of consciousness: National clinical guidelines, 2013). The authors concluded that there was insufficient evidence to make formal recommendations regarding its use in enhancing recovery of consciousness. However, if medication is prescribed for patients with DOC, it was recommended that it be done in the setting of a clinical trial with formal monitoring and blinded assessors

Discussion

One retrospective study that assessed amantadine was identified. The results of the study found that there was no difference in emergence from coma after amantadine administration (Hughes et al., 2005). Upon further analysis, it was found that the only predictors for emergence from coma were age, GCS score, and somatosensory evoked potential.

Two RCTs identified 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 significantly improved 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 administration. While patients made some natural recovery on placebo, the authors noted that patients made more pronounced improvements on amantadine. In addition, the authors went on to suggest that amantadine aids in recovery regardless of the time of administration. Similarly, a trial by Giacino et al. (2012) found a significant reduction in the disability of 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 should be continued until recovery goals are reached, although it should be approached with caution.

In a chart review, patients who were treated with amantadine showed significant improvements in consciousness at discharge and decreased mortality rates when compared to those who received standard therapy (Saniova et al., 2004). While the retrospective nature of this study makes it difficult to draw conclusions, the author recommends amantadine as a safe intervention with promising potential but suggested that further research was warranted.

Conclusions

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

There is level 3 evidence that amantadine treatment does not improve emergence from coma compared to control in patients post ABI.

There is level 3 evidence that amantadine is superior to standard care at improving consciousness in patients in a coma post ABI.

 

12.12.1.2 Amantadine and Cognitive Rehabilitation

Key Points

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

Amantadine is not effective at improving generalized cognition. Its impact on executive functioning should be studied further.

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., 1999b). It is also thought to work pre- and post-synaptically by increasing the amount of dopamine (Napolitano et al., 2005).

Discussion

Presently, only one study has examined the effects of amantadine on attention and processing speed and found no significant effects on attention or processing speed following treatment, any results which were found to be significant on other cognitive measures were not maintained at 60 day follow-up (Hammond et al., 2018). Further studies are needed to examine whether or not amantadine may be a viable treatment for attention and processing speed deficits following an ABI.

In a small sample RCT by Schneider et al. (1999b) 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. A RCT reinforces these findings after finding no significant differences on measures of cognition following 6-weeks of amantadine treatment (Ghalaenovi et al, 2018). 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 studies, future studies exploring the efficacy of amantadine for learning and memory are warranted.

Conclusions

There is level 1b evidence that amantadine is not effective for improving attention compared to placebo following an ABI.

There is level 1b evidence that Amantadine may not help to improve general functioning deficits in patients with TBI compared to placebo.

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

12.12.1.3 Amantadine and Aggression

Key Points

Amantadine requires further research before conclusions can be drawn regarding its effects on aggression and irritability following a TBI.

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

Two RCTs compared the effects of amantadine and placebo on irritability and aggression post TBI. Hammond and colleagues (2014) found that the frequency and severity of irritability were reduced when individuals received amantadine for 28 days compared to placebo. However, amantadine only significantly reduced aggression in individuals who had moderate to severe aggression at baseline (Hammond et al., 2014). A subsequent trial by Hammond and colleagues (2015) found that 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 level 1b evidence that amantadine compared to placebo may reduce aggression post TBI in individuals with moderate to severe aggression.

There is conflicting (level 1b) evidence as to whether amantadine reduces irritability compared to placebo post TBI.

12.12.3 (-)-OSU6162

Key Points

(-)-OSU6162 treatment may not be effective for reducing fatigue post TBI.

(-)-OSU6162 is a monoaminergic stabilizer that has been investigated for the treatment of Huntington’s disease, alcohol dependence, and fatigue (Berginstrom et al., 2017; Khemiri et al., 2015; Kloberg et al., 2014; Nilsson et al., 2017). (-)-OSU6162 works on both the dopamine and serotonin systems, but is classified as a dopaminergic stabilizer due to its affinity for D2 and D3 receptors, meaning it can both inhibit and stimulate dopamine behavior (Berginstrom et al., 2017). In this section, we specifically examine the effect of (-)-OSU6162 on fatigue.

Discussion

In a RCT by Berginstrom et al. (2017) (-)-OSU6162 was compared to placebo in patients with TBI (GCS>5). On both the Fatigue Severity Scale and the Mental Fatigue Scale, both groups showed significant reductions in fatigue; however, no between-group differences were observed. It is worth noting that participants received a dose of 15mg twice per day, and at the end of the trial the mean plasma concentration was lower than expected (0.14μM). However, signficantly larger changes in folic acid, prolactin, and heart rate were recorded for the experimental group, suggesting that these plasma levels may still have been high enough to elicit a physiological effect. Based on this study, (-)-OSU6162 may not be effective in reducing fatigue in patients with TBI.

Conclusions

There is level 1b evidence that (-)-OSU6162 may not be effective for treating fatigue compared to placebo in patients with TBI.

12.12.2 Bromocriptine

Key Points

Bromocriptine does not appear to improve attention in those with an ABI.

Bromocriptine is a dopaminergic agonist which exerts its effects primarily through the binding of 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. Two 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). 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, the Stroop test, the Wisconsin Card Sorting Test and the controlled oral word association test (McDowell et al., 1998). However, bromocriptine did not significantly influence working memory tasks. However, a later study by Whyte et al. (2008) found that bromocriptine had little effect on attention and 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 (2.5 mg 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.

Conclusions

There is conflicting evidence as to whether bromocriptine improves performance on attention tasks compared to placebo in patients post TBI.

12.13 Hormone Therapy

12.13.1 Medroxyprogesterone

Key Points

Medroxyprogesterone intramuscularly may reduce sexual aggression.

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). One study revealed inappropriate sexual talk to be the most common inappropriate sexual behaviour in a sample of patients with TBI (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.

12.13.2 Progesterone

Key Points

Progesterone does not improve functional outcomes post TBI, with the potential exception of patients who are not severely ill upon admission (Glasgow coma scale score>5)

 

Progesterone is likely associated with the development of phlebitis and thrombophlebitis.

 

Progesterone has no effect on intracranial pressure, but does reduce mortality, and improves functional and neurological outcomes post ABI.

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 a RCT, progesterone treatment did not appear to improve functionality short-term (<3 mo), however at 6mo follow-up patients had significantly higher Glasgow Outcome Scale Extended and Functional Independence Measure scores (Soltani et al., 2017) . Furthermore, the control group experienced significantly higher mortality than the progesterone group. In contrast to these results, a systematic review of 5 studies concluded that there are no sure benefits to progesterone administration compared to placebo (Ma et al., 2016).  Authors consistently found no difference between disability or mortality between groups.

In a RCT, Wright et al. (2007) evaluated patients receiving progesterone 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 additionally 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. The researchers reported a lack of improvement in ICP over placebo, but significantly greater morbidity (GOS) and independence (FIM) scores at three months and six months. In addition, there was significantly lower incidence of mortality at six months associated with the progesterone group. Notably, there were no reported complications associated with progesterone administration.  In contrast, other studies have reported no significant differences in favourable outcomes between those receiving progesterone or placebo after three months (Shakeri et al., 2013) or six months (Shakeri et al., 2013; Skolnick et al., 2014b; 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 associated with increased rate of serious adverse event such as phlebitis and thrombophlebitis  (Wright et al., 2014). Given the conflicting findings between studies, further studies investigating the use of progesterone in ABI are suggested.

Conclusions

There is level 1a evidence that progesterone treatment is no better than placebo at improving Glasgow outcome scale scores at 3 and 6 mo post TBI.

 

There is level 1b evidence that progesterone is superior to placebo at improving Glasgow outcome scale scores in patients with an initial Glasgow coma scale score >5 post TBI.

 

There is level 1b evidence that progesterone treatment may be associated with adverse events such as phlebitis and thrombophlebitis.

 

There is level 1a evidence that progesterone does not improve intracranial pressure compared to placebo post ABI.

 

There is level 1a evidence that progesterone improves mortality and Glasgow outcome scale scores compared to placebo in patients post ABI.

12.13.3 Growth Hormone Replacement Therapy

Key Points

Growth hormone deficiency may be effectively treated with hormone replacement therapy and insulin growth like factor-1 therapy.

The administration of human growth hormones appears to have positive (although sometimes limited effects) on general and executive functioning in those with an ABI.

Following an ABI, it is not uncommon for individuals to be diagnosed with hypopituitarism. It is estimated that as many as 25 to 40% of individuals with a moderate to severe ABI demonstrate chronic hypopituitarism (Bondanelli et al., 2007; Kelly et al., 2006; Schneiderman et al., 2008). Despite this, few patients are screened for Growth Hormone (GH) deficiencies; thus, the link between cognitive impairment and growth hormone deficiencies has not yet been definitively established (High et al., 2010). The benefits of GH replacement therapy on patient’s executive and general cognitive function post TBI is investigated below.

Discussion

Research has found that growth hormone replacement therapy effectively elevates serum IGF-I levels in individuals with GHD post ABI (Devesa et al., 2013; Dubiel et al., 2018), as well as improves their quality of life (Gardner et al., 2015; Moreau et al., 2013a). In a randomized controlled trial (RCT) of individuals with TBI, patients received IGF-I (5mg) via continuous intravenous infusion within 72 hours after injury and continued for 14 days, or placebo (Hatton et al., 1997). The authors found that patients receiving IGF-I treatment showed better outcomes in terms of glucose concentration, nitrogen balance, body weight, and recovery (Hatton et al., 1997). Mossberg et al. (2017) found that although recombinant human growth hormone did not improve respiratory capacity or symptoms, fatigue and depression scores significantly improved with treatment. Similarly, another RCT (Dubiel et al., 2018) found that more than just IGF-1 concentrations improved with recombinant growth hormone (rhGH) treatment. Cogntive and Motor Functional Independence Measure scores were seen to significantly increase in those receiving rhGH treatment at 6-month follow-up (Dubiel et al., 2018).

A 2010 RCT compared the long term (6 mo and 1 yr) effects of rhGH administration to placebo in a TBI population (High Jr et al. 2010). Significant improvements were noted in processing speed, executive functioning (Wisconsin Card Sorting Test), and learning (California Verbal learning test II) for both he rhGH and placebo groups. It is important to note while processing speed also improved in both groups at 6 mo, the improvement was only sustained in the treatment group at 1 year. Further positive results were reported in a PCT by Moreau et al. (2013). Patient quality of life, instrumental activities of daily living, attention, memory and visuospatial ability improved over the treatment period in both the treatment and control group. However, the treatment group improved significantly more in the functional and personal subscales of quality of life assessments. Reimunde et al. (2011) also examined the use of recombinant human growth hormone in a cohort study. Results of the study indicate that those receiving the rhGH improved significantly on the various cognitive subtests such as: understanding, digits, numbers and incomplete figures (p<0.05), verbal IQ, Manipulative IQ, and Total IQ (p<0.01). The control group also showed significant improvement but only in digits and manipulative intelligence quotient (p<0.05).  Of note IGF-I levels were similar between both groups at the end of the study. These findings support the consensus that neuroendocrine dysfunction is a heterogeneous topic and treatment intervention may need to be tailored over time to an individual’s specific needs.

Conclusions

There is level 1b evidence that growth hormone replacement therapy may improve clinical outcomes compared to placebo in patients with GHD post ABI.

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is superior to placebo at improving processing speed (6 mo), executive function and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is effective for improving quality of life, instrumental activities of daily living (iADL), attention, memory, and visuospatial ability in patients post TBI.

There is level 2 evidence that recombinant human Growth Hormone (rhGH) administration improves intelligence and other cognitive subtests in TBI patients with growth hormone deficiency compared to TBI patients without; however, insulin-like growth factor-1 (IGF-1) levels may be the same between groups.

There is level 4 evidence that growth hormone replacement therapy may be effective in treating GHD, fatigue, and depression post ABI.

12.13.4 Melatonin

Key Points

Melatonin treatment may improve sleep quality, sleep efficiency, and reduce fatigue in patients post TBI.

Melatonin treatment may not effect sleep onset latency or daytime sleepiness.

Melatonin is an endogenous hormone that plays a role in the regulation of sleep-wake cycles (Driver & Stork, 2018). Individuals with TBI show lower levels of melatonin production in the evening, which may cause disruptions to the sleep-wake cycle (Shekleton et al., 2010). In an observational overnight study, Grima et al. (2016) compared melatonin production of individuals with TBI to healthy controls. Patients with TBI showed 42% less melatonin production, and was delayed by 1.5 hours on average (Grima et al., 2016). Melatonin offers very minimal side effects, enhancing the drugs usefulness in aiding treatment of sleep disorders (Grima et al., 2018). One article met the inclusion criteria investigating a melatonin intervention in individuals with severe TBI.

Conclusions

There is level 1b evidence that melatonin treatment may be effective in improving sleep quality, sleep efficiency, and fatigue compared to a placebo group in patients post TBI.

 

There is level 1b evidence that melatonin treatment may not effect sleep onset latency or daytime sleepiness in patients post TBI.

12.14 Psychostimulants

12.14.1 Methylphenidate

12.14.1.1 Methylphenidate and Cognitive Functioning

Key Points

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

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

Response to methylphenidate may depend on the presence of the Met 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

The majority of studies evaluating the efficacy of methylphenidate have been RCTs. In a 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) and Pavlovskaysa (2007) found that methylphenidate significantly improved attention and concentration, and visuo-spatial attention, respectively. 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. A variety of studies with different dosing regimens and durations have found positive effects of methylphenidate (Gualtieri & Evans, 1988; Whyte et al., 1997; Zhang et al., 2004).

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. Conflicting results continue to be reported, as two high-quality RCTs reached different conclusions regarding methylphenidate use. While Dymowski et al. (2017) noted no improvements in any measures of attention and mental processing, Zhang et al. (2017) noted improvements in reaction time, arithmetic tests, and even mental health outcomes after intervention by methylphenidate.

A potential explanation for these conflicting results is proposed 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 level 1a evidence regarding the effectiveness of methylphenidate following brain injury for the improvement of attention and concentration in individuals post ABI.

There is level 1a evidence that methylphenidate improves reaction time of working memory compared to placebo in individuals post ABI.

There is level 1b evidence that individuals carrying the Met allele may be more responsive to methylphenidate than those without the Met allele when it comes to the ABI population.

12.14.1.2 Methylphenidate and Fatigue

Key Points

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.

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.

12.15 Stimulants

12.15.1 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.

12.15.2 Dextroamphetamine

Key Points

Dextroamphetamine is moderate evidence to suggest that dextroamphetamine is not effective for the remediation of general functioning.

Dextroamphetamine is another central nervous stimulant, and similar to methylphenidate it is used to treat narcolepsy and ADHD. Dextroamphetamine is a non-catecholamine and sympathomimetic amine that acts as a stimulant, unfortunately more direct mechanisms of action are not known.

Discussion

One RCT evaluated the effects of dextroamphetamine on general and executive functioning using a variety of outcomes (Hart et al., 2018). Although dextroamphetamine was seen to significantly reduce agitation compared to the placebo group, no significant effects were seen on measures of cognition. Given the use of dextroamphetamine in other attentional disorders such as ADHD, the lack of results on any cognitive measures between these two studies is unexpected.

Conclusions

There is level 1b evidence that dextroamphetamine is not effective for the remediation of general cognitive functioning following an ABI.

12.15.3 Pramiracetam

Key Points

Pramiracetam might improve memory in males post TBI, however, additional studies are required.

Pramiracetam is a nootropic (cognitive) activator that is used to facilitate learning, memory deficiencies, and other cognitive problems. Pramiracetam produces an increased turnover of acetylcholine in hippocampal cholinergic nerve terminals and it is at least 100 times more potent than its original compound piracetam (McLean et al., 1991).

Discussion

McLean Jr. et al. (1991) conducted a study evaluating Pramiracetam in four males post brain injury. Improvements were found for memory and these improvements remained at one month following discontinuation of the drug. Given the small sample size and the lack of data reported to support the findings, future studies should be conducted.

Conclusions

There is level 2 evidence that pramiracetam may improve males’ memory compared to placebo post TBI. 

12.16 Sedative Anaesthetic

12.16.1 Propofol

Key Points

Propofol may improve intracranial pressure and cerebral perfusion pressure post ABI, without producing adverse outcomes.

 Propofol and vasopressor treatment in combination, but not as monotherapy, might increase the risk of developing propofol infusion syndrome post ABI.

 Propofol, especially at higher doses, likely improves favourable outcomes, intracranial pressure and cerebral perfusion pressure more effectively than morphine.

 Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on morbidity outcomes, or intracranial, cerebral perfusion, and mean arterial pressure.

 The combination of morphine and midazolam may confound the comparison between propofol and morphine, however, it is prudent to conclude propofol is at least as safe and effective as morphine

Propofol is a fast-acting sedative that is absorbed and metabolized quickly, leading to pronounced effects of short duration (Adembri et al., 2007). Propofol decreases 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 is characterized by severe metabolic acidosis, rhabdomyolosis, cardiac dysrhythmias, and potential cardiovascular collapse (Corbett et al., 2006).

The AANS reported 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 earlier EBIC recommended sedation as part of the treatment course for ABI but made no specific mention of propofol (Maas et al., 1997).

Discussion

Propofol was investigated for its beneficial role as an intervention post-ABI. Farling et al. (1989) in a case series of 10 subjects, reported that propofol administration reduced ICP, increased CPP, and was not associated with any adverse outcomes. Overall, this study suggests that propofol is an effective agent at providing safe and effective sedation. Given the retrospective nature and small sample size, results and conclusions drawn from this study should be taken with caution. The effects of propofol in patients with ABI will be further discussed later in the “comparative section” as its efficacy is directly contrasted to other sedatives.

In a retrospective review, Smith et al. (2009) identified three patients with propofol infusion syndrome. The authors noted that each of these patients were receiving both propofol and vasopressors, and that no patient on either propofol or vasopressors alone developed propofol infusion syndrome. Due to lack of a control group and the retrospective nature of the study, care should be taken when interpreting the conclusions reached. However, the evidence suggests that patients receiving both propofol and vasopressors are at the highest risk of developing propofol infusion syndrome, and thus careful monitoring is needed in this patient population.

Three studies comparing the effects of propofol to other sedatives were reviewed. In a crossover RCT, treated patients with ABI with either propofol or dexmedetomidine initially, followed by a crossover halfway through the treatment 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”.

The remaining 2 studies compared propofol to morphine, or a combination of morphine and midazolam. While 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, Kelly et al. (1999) noted propofol was significantly more effective than morphine at reducing ICP – especially at higher doses. With respect to morbidity outcomes, one study reported no difference (Stewart et al., 1994) and the other an increase (Kelly et al., 1999) in favourable outcomes compared to the other treatment. Despite the disagreement in relationship directionality between studies, it can be concluded that propofol is at least as safe to use as morphine alone, or morphine with midazolam.

Conclusions

There is level 4 evidence that propofol may improve intracranial pressure and cerebral perfusion pressure, with no associated adverse outcomes post ABI.

There is level 4 evidence that propofol and vasopressor treatment may increase the risk of developing propofol infusion syndrome post ABI.

There is level 1b evidence that propofol is more effective than morphine at improving favourable outcomes and reducing intracranial pressure post TBI- specially at higher doses.

There is level 2 evidence that propofol is similar to midazolam and morphine with regards to sedation, morbidity, changes in intracranial pressure, cerebral perfusion, and mean arterial pressure post ABI.

There is level 2 evidence that propofol may not differ from dexmedetomidine in its effect on intracranial pressure and cerebral perfusion pressure post ABI.

12.16.2 Midazolam

Key Points

Midazolam is likely not different than propofol at improving mortality, disability, or neurological outcomes.

 

High doses of midazolam might be associated with hypotension, specially following intubation.

 Midazolam may have no effect on intracranial pressure but may reduce mean arterial pressure and cerebral perfusion pressure in patients, post-ABI.

 Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on morbidity outcomes, or intracranial, cerebral perfusion, and mean arterial pressure.

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).

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 1b evidence that midazolam is no different than propofol at improving Glasgow Outcome Scale scores, mortality, or disability in patients post ABI.

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

 There is level 4 evidence that high doses of midazolam are associated with decreases in systolic blood pressure and hypotension following intubation in patients post ABI.

 There is level 2 evidence that propofol is similar to midazolam and morphine with regards to sedation, morbidity, changes in intracranial pressure, cerebral perfusion, and mean arterial pressure post ABI.

 There is level 4 evidence that midazolam has no effect on intracranial pressure but decreases mean arterial pressure and cerebral perfusion pressure post TBI.

12.17 Anti-Inflammatory Medications

12.17.1 Corticosteroids

Key Points

Corticosteriods such as methylprednisolone, dexamethasone, and other glucocorticoids may worsen outcomes, and should not be used. However, methylprednisolone may be effective at improving mortality when specific complications, such as acute respiratory distress syndrome secondary to sepsis, arise.

Triamcinolone may improve outcomes in individuals post ABI with a Glasgow Coma Scale score less than 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

Two studies assessed methylprednisolone in ABI management. The studies reported either no difference in morbidity (Giannotta et al., 1984; Saul et al., 1981), or a decrease in mortality (Giannotta et al., 1984) when compared to controls. It is important to note that the decrease in mortality in the study by Giannotta et al. was only observed in patients under 40 years of age receiving high dose methylprednisolone, and not any other group. In light of a series of inconclusive studies concerning 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). The study never reached its conclusion and was stopped early due to increased mortality in the methylprednisolone group. A relative mortality risk of 1.8 (P=0.0001) was reported in the treatment group and as a result the authors suggest that corticosteroids should not be used for the treatment of ABI regardless of injury severity, or refractoriness to first line treatments.   Despite the recommendations put forth by this study, a group analyzed the effects of Solu-Medrol (methylprednisolone) in patients with ARDS secondary to sepsis post ABI (Oliynyk et al., 2016). It was found that both the type of mechanical ventilation received (BiPAP) and methylprednisolone reduced mortality rates in the patient population. The findings of this study suggest that while methylprednisolone is contraindicated as a first line ABI treatment, it might be effective in improving specific complications that develop post-ABI. In light of the overwhelming evidence warning against methylprednisolone use however, extreme caution should be applied when trying to interpret this finding outside of the specific setting in which it was studied.

Four RCTs were found that assessed dexamethasone in ABI. While one study reported no difference in morbidity or mortality (Braakman et al., 1983), other studies reported non-significant decreases in morbidity (Dearden et al., 1986)  and an increase in dose-specific complications such a CSF infections, SIADH, and hyperglycemia (Kaktis & Pitts, 1980) when compared to placebo. Lastly, Cooper et al. (1979) compared doses of dexamethasone and their effects on lowering ICP and neurological outcomes (GOS). They found that regardless of the dose of dexamethasone received (low or high), there were no significant differences in ICP or neurological outcomes at 6 months between groups. Given the results of this study, and the guideline reccomendations against the use of corticosteroids for ICP management, corticosteroids may not be effective agents in lowering ICP post ABI.

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 to patients treated without corticosteroids for the risk of development of post-traumatic seizures (PTS). The researchers 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 treatment. There was no increased risk of PTS in patients receiving treatment after the first day. The authors suggest that this adds further strength to the argument against routine corticosteroid use in TBI (Watson et al., 2004).

Grumme et al. (1995) conducted a RCT in which GOS scores were assessed one year after injury in patients treated with the synthetic corticosteroid triamcinolone. While no overall effect was found between groups, 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 conflicting (level 1b) evidence that methylprednisolone increases mortality rates compared to placebo in individuals post ABI. The largest trial strongly recommends against its use due to increased mortality.

There is level 1b evidence that high (60 mg loading dose, 24 mg every 6 hr) and low (10 mg loading dose, 4 mg every 6 hr) dose dexamethasone are the same as placebo at improving intracranial pressure, and neurological outcomes (6 mo) post TBI.

There is conflicting (level 2) evidence that dexamethasone increases mortality and the rate of complications (hyperglycemia, cerebral spinal fluid infections) when compared to placebo post ABI.

There is level 1b evidence that triamcinolone may improve outcomes compared to placebo in individuals post ABI with a Glasgow Coma Scale score less than 8 and a focal lesion.

There is level 2 evidence that glucocorticoid administration on the first day post-injury may increase the risk of developing first late seizures compared to placebo.

There is level 4 evidence that methylprednisolone improves mortality rates in patients with acute respiratory distress syndrome secondary to sepsis post ABI.

12.17.2 Bradykinin Antagonists

Key Points

Anatibant, regardless of dose, likely does not cause serious adverse events, affect morbidity, mortality or disability in patients post ABI.

It is unclear if a higher dose of anatibant is superior to a lower dose at improving intracranial pressure, however it may improve functional outcomes up to 6 months post injury.

Bradycor can prevent acute elevations in intracranial pressure and reduce therapeutic intensity levels post ABI; however, its effect on morbidity and mortality outcomes is not clear.

Any type of tissue injury or cell death following brain injury acts as a strong stimulus for initiation of an inflammatory response. An important player in the acute inflammatory cascade is the kinin-kallikrein pathway; a pathway which generates the compound bradykinin. (Marmarou et al., 1999; Narotam et al., 1998). The binding of bradykinin to its BK2 receptor leads to a  cascade of events, ultimately yielding altered vascular permeability and tissue edema (Francel, 1992). Upregulation of kinins following blunt trauma has been reported, emphasizing their importance in the pathophysiology of brain injury (Hellal et al., 2003). Animal research using BK2 receptor knockout mice has demonstrated direct involvement of this receptor in the development of the inflammatory-induced secondary damage and subsequent neurological deficits resulting from diffuse TBI (Hellal et al., 2003).  These findings strongly suggest that specific inhibition of the BK2 receptor could prove to be an effective therapeutic strategy following brain injury.

Bradycor is a bradykinin antagonist that acts primarily at the BK2 receptor (Marmarou et al., 1999; Narotam et al., 1998), making it attractive for the management of post-ABI inflammation.  Anatibant is another BK2 receptor antagonist that is believed to more strongly bind the BK2 receptor compared to Bradycor (Marmarou et al., 2005).  Animal research has suggested that Anatibant dampens acute inflammation, reduces brain edema, and improves long-term neurological function (Hellal et al., 2003; Kaplanski et al., 2002; Pruneau et al., 1999; Stover et al., 2000).

The AANS and EBIC made no recommendations regarding bradykinin antagonists in acute ABI.

Discussion

Shakur et al. (2009) conducted a large-scale multicenter trial of Anatibant. The authors reported a non-significant elevated risk of serious adverse events among patients receiving the medication, without improvements in morbidity (DRS, GCS) or mortality. As such, the trial was terminated early on by the investigators, leading to a legal dispute with its sponsors.

Anatibant is believed to be a more potent bradykinin antagonist than Bradycor, and was evaluated by Marmarou et al. (2005) to study its effects on ICP and morbidity outcomes. Due to a small sample size and lack of baseline comparability between groups, the authors were unable to draw any significant conclusions regarding the efficacy of Anatibant in preventing brain edema or deteriorations in ICP and CPP. However, patients who received a higher dose of the medication had more favourable outcomes on the GOS at three months and six months when compared to a lower dose and placebo.

Two trials evaluated the efficacy of Bradycor in the acute treatment of ABI.  Both trials reported that treatment with Bradycor resulted in a significant reduction in ICP elevations when compared to placebo – as indicated by the time spent under intracranial hypertension (Narotam et al., 1998). In the smaller of the two trials, Narotam et al. (1998) found that patients in the placebo group experienced a greater deterioration in GCS scores over the course of the study. These findings were not replicated in Marmarou et al., as the researchers reported no significant differences between groups in mortality rates, improvements in GOS scores at three months and six months, or the intensity of additional therapeutic interventions needed to control ICP.

Conclusions

There is level 1b evidence that Anatibant, regardless of dose, has no effect on serious adverse events, mortality, Glasgow Coma Scale, Modified Oxford Handicap Scale, or Disability Rating Scale scores in individuals post ABI.

There is level 2 evidence that high-dose anatibant is superior to low-dose anatibant and placebo at improving Glasgow outcome scale scores at 3 and 6 mos post TBI.

There is level 1a evidence that Bradycor is effective at preventing acute elevations intracranial pressure and reducing therapeutic intensity levels post ABI when compared to placebo. 

There is conflicting (level 1b) evidence that Bradycor improves mortality and Glasgow outcome scale scores in patients post ABI.

12.18 Dimethyl Sulfoxide

Key Points

Dimethyl sulfoxide may cause temporary improvements in intracranial pressure and cerebral perfusion pressure post ABI, however these improvements may not be sustained long-term.

DMSO might be able to transiently lower intracranial pressure; however, it is associated with the development of electrolyte imbalances. Both responses appear to be dose-dependent.

Dimethyl Sulfoxide (DMSO) is an organic sulfur-containing compound that has been shown to  stabilize cell membranes, protect cells from mechanical damage and reduce edema in tissue (Kulah et al., 1990). Furthermore, DMSO is believed to act as an antioxidant and has been credited with the ability to increase tissue perfusion, neutralize metabolic acidosis, and to decrease intracellular fluid retention (Kulah et al., 1990). As a result, DMSO has been suggested for the treatment of elevated ICP following ABI.

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

Discussion

Three studies have examined the effects of DMSO in the management of ICP post ABI.  In a study by Kulah et al. (1990), the authors reported that in the majority of cases DMSO was effective in controlling ICP elevations within minutes of injection, which was followed by a concomitant increase in CPP.  However, continuous infusions of DMSO for up to seven days failed to control elevations in ICP and values returned to baseline. In a similar study conducted by Karaca et al. (1991), patients were treated with repeated injections of DMSO for up to 10 days.  Although reductions in ICP were observed within the first 30 minutes after administration, the effect was not sustained and most patients required maintenance doses to minimize fluctuations in ICP. The results from both of these retrospective studies suggest that DMSO may acutely reduce ICP, however it is not an appropriate agent when attempting to maintain long-term ICP control.

Marshall et al. (1984) observed the effects of using DMSO on patients with ABI. Originally, patients received 10% DMSO and temporary ICP decreases were observed; however, ICP quickly returned to baseline (2-24 min) and electrolyte disbalances such as hypernatremia were observed. Subsequently, the remaining patients received 20% DMSO and while ICP reduction was maintained longer, electrolyte imbalances continued to develop despite close patient monitoring.

Conclusions

There is level 4 evidence that dimethyl sulfoxide temporarily reduces intracranial pressure elevations, and increases cerebral perfusion pressure post ABI.

There is level 4 evidence that increasing concentrations of DMSO provide longer intracranial pressure reduction, but are accompanied by an increase in electrolyte imbalances post ABI.

Summary


There is conflicting (level 1a and level 2) evidence as to whether fentanyl, morphine, or sufentanil increase intracranial pressure, and decrease cerebral perfusion pressure post ABI. The level 1a evidence suggests that it increases intracranial pressure and decreases cerebral perfusion pressure.

There is level 1b evidence that propofol is more effective than morphine at improving favourable outcomes and reducing intracranial pressure post TBI- specially at higher doses.

There is level 2 evidence that alfentanil may result in a decrease in cerebral perfusion pressure and mean arterial pressure, and a transient increase in intracranial pressure, post ABI compared to controls.

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

There is level 2 evidence that propofol is similar to midazolam and morphine with regards to sedation, morbidity, changes in intracranial pressure, cerebral perfusion, and mean arterial pressure post ABI.

There is level 4 evidence that remifentanil may not improve intracranial pressure, cerebral perfusion pressure, mean arterial pressure, or cerebral blood flow velocity post ABI.

There is level 4 evidence that sufentanil may decrease mean arterial pressure, cerebral perfusion pressure, and heart rate post ABI.

There is level 4 evidence that sufentanil may transiently increases intracranial pressure post ABI.

There is level 4 evidence that sufentanil may increase intracranial pressure in patients with low mean arterial pressure post ABI.

There is level 4 evidence that sufentanil with midazolam decreases intracranial pressure and mean arterial pressure for 2 days 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 that phenytoin is effective in reducing the rate of only early onset post-traumatic seizures in patients with TBI.

There is conflicting evidence regarding whether or not phenytoin is effective in preventing post-traumatic seizure disorder long term compared to placebo treatment in patients with TBI. 

There is level 1a evidence that valproate is not more effective as a prophylactic anti-seizure medication compared to phenytoin in ABI populations.

There is level 1b evidence that levetiracetam and phenytoin do not show significant differences between them as prophylactic anti-seizure medication for individuals with ABI.

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 lamotrigine may reduce inappropriate behaviours post TBI.

There is level 4 evidence that cerebrolysin may improve attention scores post ABI.

There is conflicting level 1b (positive) and level 2 (negative) evidence that donepezil may improve attention compared to placebo post ABI.

There is level 1b evidence that oral physostigmine may improve long-term memory compared to placebo in men with TBI, however more recent studies are required.

There is level 1b evidence that Rivastigmine compared to placebo is not effective for improving concentration or processing speed in post ABI individualsbut may increase vigilance.

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 that quetiapine may reduce aggressive behaviour.

There is level 4 evidence that ziprasidone may reduce agitation post TBI.

There is level 4 evidence that haloperidol may not be effective in treating behavioral disorders post TBI. 

There is level 4 evidence that methotrimeprazine may be effective for controlling agitation post ABI.

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 1b evidence that bolus intrathecal baclofen injections may produce short-term (up to six hours) reductions in upper and lower extremity spasticity compared to placebo 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 conflicting level 4 evidence to suggest that intrathecal baclofen may result in short-term improvement of walking performance in ambulatory patients, particularly gait velocity, stride length, and step width, in individuals post ABI.

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 level 2 evidence that thiopental is more effective than pentobarbital for controlling elevated intracranial pressure refractory to conventional treatment, and less likely to induce adrenal insufficiency post ABI. 

There is level 2 evidence that thiopental in combination with mild hypothermia has better one-year clinical outcomes compared to conventional management post ABI.

There is level 3 evidence that thiopental induces leukopenia and granulocytopenia in patients post ABI.

There is level 4 evidence that thiopental decreases intracranial pressure, cerebral perfusion pressure, and mean arterial pressure post ABI.

There is conflicting (level 1b and level 2) evidence regarding whether or not pentobarbital improves intracranial pressure compared to conventional management measures post ABI. Level 1b evidence suggests there is no difference.

There is level 2 evidence that barbiturate use is associated with development of hypotension in patients post ABI.

There is level 2 evidence that pentobarbital decreases energy expenditure, total urinary nitrogen excretion, improves nitrogen balance, but has no effect on 3-methylhistidine excretion compared to controls in individuals with an ABI refractory to standard therapy.

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 high-dose KN38-7271 (a dual cannabinoid agonist) may improve intracranial pressure and cerebral perfusion pressure, and improves survival post TBI compared to low-dose KN38-7271.

There is level 1b evidence that pindolol may reduce aggression compared to placebo post ABI.

There is level 1b evidence that propranolol compared to placebo reduces the intensity of agitated symptoms post ABI.

There is conflicting evidence (level 1b) that propranolol compared to placebo reduces the frequency of aggressive behaviour post ABI.

There is level 3 evidence that prophylactic anticoagulation is more effective than placebo in reducing the risk of developing deep vein thrombosis in patients post ABI.

There is level 2 evidence that the administration of enoxaparin within the first 72 hours post ABI reduces the risk of developing deep vein thrombosis and pulmonary embolism post injury compared to unfractionated heparin.

There is level 4 evidence that administering enoxaparin or heparin post ABI does not increase the risk of intracranial bleeding compared to no treatment.

There is level 1a evidence that hypertonic saline is similar to mannitol in terms of mortality or Glasgow outcome scale (extended) scores in patients post TBI.

There is conflicting (level 1b) evidence as to whether hypertonic solution lowers elevated intracranial pressure more effectively than mannitol post ABI.

There is conflicting (level 2 and level 3) evidence that hypertonic saline lowers intracranial pressure for longer compared to mannitol post ABI. The level 2 evidence suggest that it does.

There is level 2 evidence that hypertonic saline is superior to mannitol at improving cerebral perfusion pressure, cerebral blood flow, and blood-glucose control in patients post ABI.

There is level 2 evidence that urinary sodium excretion is higher in hypertonic saline patients compared to those receiving mannitol post ABI.

There is level 4 evidence that hypertonic saline is superior to barbiturates, propofol, and fentanyl at lowering intracranial pressure post ABI.

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

There is level 4 evidence that mannitol may be effective in increasing cerebral perfusion pressure post ABI.

There is level 4 evidence that mannitol may only improve intracranial pressure and cerebral perfusion pressure post ABI in hypertensive patients (Intracranial pressure>20mmHg).

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

There is level 3 evidence that amantadine treatment does not improve emergence from coma compared to control in patients post ABI.

There is level 3 evidence that amantadine is superior to standard care at improving consciousness in patients in a coma post ABI.

There is level 1b evidence that amantadine is not effective for improving attention compared to placebo following an ABI.

There is level 1b evidence that Amantadine may not help to improve general functioning deficits in patients with TBI compared to placebo.

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

There is level 1b evidence that amantadine compared to placebo may reduce aggression post TBI in individuals with moderate to severe aggression.      

There is conflicting (level 1b) evidence as to whether amantadine reduces irritability compared to placebo post TBI.

There is conflicting evidence as to whether bromocriptine improves performance on attention tasks compared to placebo in patients post TBI.

There is level 1b evidence that (-)-OSU6162 may not be effective for treating fatigue compared to placebo in patients with TBI.

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

There is level 1a evidence that progesterone treatment is no better than placebo at improving Glasgow outcome scale scores at 3 and 6 mo post TBI.

There is level 1b evidence that progesterone is superior to placebo at improving Glasgow outcome scale scores in patients with an initial Glasgow coma scale score >5 post TBI.

There is level 1b evidence that progesterone treatment may be associated with adverse events such as phlebitis and thrombophlebitis.

There is level 1a evidence that progesterone does not improve intracranial pressure compared to placebo post ABI.

There is level 1a evidence that progesterone improves mortality and Glasgow outcome scale scores compared to placebo in patients post ABI.

There is level 1b evidence that growth hormone replacement therapy may improve clinical outcomes compared to placebo in patients with GHD post ABI.

There is level 1b evidence that recombinant human Growth Hormone (rhGH) is superior to placebo at improving processing speed (6 mo), executive function and learning in patients post TBI.

There is level 2 evidence that growth hormone (GH) therapy is effective for improving quality of life, instrumental activities of daily living (iADL), attention, memory, and visuospatial ability in patients post TBI.

There is level 2 evidence that recombinant human Growth Hormone (rhGH) administration improves intelligence and other cognitive subtests in TBI patients with growth hormone deficiency compared to TBI patients without; however, insulin-like growth factor-1 (IGF-1) levels may be the same between groups.

There is level 4 evidence that growth hormone replacement therapy may be effective in treating GHD, fatigue, and depression post ABI.

There is level 1b evidence that melatonin treatment may be effective in improving sleep quality, sleep efficiency, and fatigue compared to a placebo group in patients post TBI.

There is level 1b evidence that melatonin treatment may not effect sleep onset latency or daytime sleepiness in patients post TBI.

There is conflicting level 1a evidence regarding the effectiveness of methylphenidate following brain injury for the improvement of attention and concentration in individuals post ABI.

There is level 1a evidence that methylphenidate improves reaction time of working memory compared to placebo in individuals post ABI.

There is level 1b evidence that individuals carrying the Met allele may be more responsive to methylphenidate than those without the Met allele when it comes to the ABI population.

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.

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 dextroamphetamine is not effective for the remediation of general cognitive functioning following an ABI.

There is level 2 evidence that pramiracetam may improve males’ memory compared to placebo post TBI. 

There is level 4 evidence that propofol may improve intracranial pressure and cerebral perfusion pressure, with no associated adverse outcomes post ABI.

There is level 4 evidence that propofol and vasopressor treatment may increase the risk of developing propofol infusion syndrome post ABI.

There is level 1b evidence that propofol is more effective than morphine at improving favourable outcomes and reducing intracranial pressure post TBI- specially at higher doses.

There is level 2 evidence that propofol is similar to midazolam and morphine with regards to sedation, morbidity, changes in intracranial pressure, cerebral perfusion, and mean arterial pressure post ABI.

There is level 2 evidence that propofol may not differ from dexmedetomidine in its effect on intracranial pressure and cerebral perfusion pressure post ABI.

There is level 1b evidence that midazolam is no different than propofol at improving Glasgow Outcome Scale scores, mortality, or disability in patients post ABI.

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

There is level 4 evidence that high doses of midazolam are associated with decreases in systolic blood pressure and hypotension following intubation in patients post ABI.

There is level 2 evidence that propofol is similar to midazolam and morphine with regards to sedation, morbidity, changes in intracranial pressure, cerebral perfusion, and mean arterial pressure post ABI.

There is level 4 evidence that midazolam has no effect on intracranial pressure but decreases mean arterial pressure and cerebral perfusion pressure post TBI.

There is conflicting (level 1b) evidence that methylprednisolone increases mortality rates compared to placebo in individuals post ABI. The largest trial strongly recommends against its use due to increased mortality.

There is level 1b evidence that high (60 mg loading dose, 24 mg every 6 hr) and low (10 mg loading dose, 4 mg every 6 hr) dose dexamethasone are the same as placebo at improving intracranial pressure, and neurological outcomes (6 mo) post TBI.

There is conflicting (level 2) evidence that dexamethasone increases mortality and the rate of complications (hyperglycemia, cerebral spinal fluid infections) when compared to placebo post ABI.

There is level 1b evidence that triamcinolone may improve outcomes compared to placebo in individuals post ABI with a Glasgow Coma Scale score less than 8 and a focal lesion.

There is level 2 evidence that glucocorticoid administration on the first day post-injury may increase the risk of developing first late seizures compared to placebo.

There is level 4 evidence that methylprednisolone improves mortality rates in patients with acute respiratory distress syndrome secondary to sepsis post ABI.

There is level 1b evidence that Anatibant, regardless of dose, has no effect on serious adverse events, mortality, Glasgow Coma Scale, Modified Oxford Handicap Scale, or Disability Rating Scale scores in individuals post ABI.

There is level 2 evidence that high-dose anatibant is superior to low-dose anatibant and placebo at improving Glasgow outcome scale scores at 3 and 6 mos post TBI.

There is level 1a evidence that Bradycor is effective at preventing acute elevations intracranial pressure and reducing therapeutic intensity levels post ABI when compared to placebo. 

There is conflicting (level 1b) evidence that Bradycor improves mortality and Glasgow outcome scale scores in patients post ABI.

There is level 4 evidence that dimethyl sulfoxide temporarily reduces intracranial pressure elevations, and increases cerebral perfusion pressure post ABI.

There is level 4 evidence that increasing concentrations of DMSO provide longer intracranial pressure reduction, but are accompanied by an increase in electrolyte imbalances post ABI.

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TABLE OF CONTENTS:


Abbreviations
Key Points
Introduction
12.1 Analgesics 12.10 Cardiovascular Medication 12.11 Diuretics 12.12 Dopaminergic Medications 12.13 Hormone Therapy 12.14 Psychostimulants 12.15 Stimulants 12.16 Sedative Anaesthetic 12.17 Anti-Inflammatory Medications 12.18 Dimethyl Sulfoxide
12.2 Anticonvulsant Medications 12.3 Anti-Cholinesterase Inhibitors 12.4 Anti-Depressants 12.5 Anti-Psychotics 12.6 Antispasticity Treatments 12.7 Barbiturates
12.8 Bisphosphonates 12.9 Cannabinoids
Summary
References

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