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16. Acute Interventions for Acquired Brain Injury

Matthew J Meyer PhD, Nicolas Vanin Moreno MD(c), Pavlina Faltynek MSc, Scott Janssen MSc, Joshua Wiener BSc, Robert Teasell MD FRCPC

Abbreviations

AANS                    American Association of Neurological Surgeons

ABI                         Acquired Brain Injury

CPP                        Cerebral Perfusion Pressure

CSF                         Cerebrospinal Fluid

DC                          Decompressive Craniectomy

DMSO                   Dimethyl Sulfoxide

DOC                       Disorders of Consciousness

EBIC                       European Brain Injury Consortium

EVD                        External Ventricular Drain

GCS                        Glasgow Coma Scale

GOS                       Glasgow Outcome Scale

HTS                        Hypertonic Saline

ICH                         Intracranial Hemorrhage

ICP                         Intracranial Pressure

IPM                        Intraparenchymal Fiberoptic Monitor

MAP                      Mean Arterial Pressure

mmHg                   mm of mercury

PaCO2                             Partial Pressure of Carbon Dioxide in Arterial Blood

PaO2                                 Partial Pressure of Oxygen in Arterial Blood

PCT                        Prospective Controlled Trial

PEDro                    Physiotherapy Evidence Database rating scale

RCP                        Royal College of Physicians

RCT                        Randomized Controlled Trial

RLAS                      Rancho Los Amigos Scale

SAH                        Subarachnoid Hemorrhage

TBI                          Traumatic Brain Injury

WNSSP                 Western Neuro Sensory Stimulation Profile

Key Points


Head elevation of 30o likely lowers intracranial pressure post ABI; however, its effect on cerebral perfusion pressure are less clear.

Head elevation of 60o may lower intracranial pressure post-ABI.

Therapeutic hypothermia (32-35°C) may be an effective intervention for lowering elevated intracranial pressure post ABI but may not improve long-term outcomes.

Therapeutic hypothermia may increase the risk of complications such as pneumonia.

Hyperventilation may effectively lower elevated intracranial pressure post TBI.

Continuous rotational therapy does not improve intracranial pressure in individuals with severe TBI.

Prone positioning may increase intracranial pressure but improve cerebral oxygenation post ABI.

Intracranial pressure monitoring may improve mortality, but not neurological function in patients post ABI.

Hypertonic saline effectively lowers elevated intracranial pressure and potentially increases cerebral perfusion pressure in severe ABI.

Hypertonic saline increases serum sodium in ABI patients, however it may have no association with increased mortality.

Mannitol may effectively lower elevated intracranial pressure and cerebral perfusion pressure post ABI; however potentially only in hypertensive (intracranial pressure>20 mmHg) patients.

Enteral urea may lower elevated intracranial pressure in ABI patients with syndrome of in-appropriate antidiuretic hormone secretion.

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

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

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.

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

Dexanabinol in cremophor-ethanol solution may be effective in controlling intracranial pressure and improving cerebral perfusion pressure, and clinical outcomes post TBI.

Progesterone may not have an effect on intracranial pressure, but does reduce mortality, and improve functional and neurological outcomes post ABI.

Bradycor can prevent acute elevations in intracranial pressure and reduce therapeutic intensity levels post ABI; however, its effect on Glasgow Coma Scale scores 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 over the long-term.

Elevated intracranial pressure may be effectively reduced by paracetamol.

Cerebrospinal fluid drainage can effectively lower elevated intracranial pressure post ABI, using either a ventricular or lumbar device. In addition, ventricular devices may potentially increase cerebral perfusion pressure and cerebral blood flow.

External lumbar devices may effectively lower intracranial pressure in patients refractory to first line treatments.

It is undertermined whether decompressive craniectomy is an effective intervention for lowering elevated intracranial pressure post ABI; however, it may not improve cerebral perfusion pressure.

It is unclear wether a decompressive craniectomy is associated with improved long-term outcomes and mortality; however young age, early decompressive craniectomy, large decompressive craniectomy, and higher Glasgow Coma Score scores may all be predictors for favourable outcomes.

Head elevations of 15o and 30o can effectively lower elevated intracranial pressure post ABI; meanwhile, elevations of 45o and 60o might be able to lower elevated intracranial pressure post ABI.

It is unclear whether head elevation causes an improvement in cerebral perfusion pressure post ABI.

Head elevations ranging from 0o-60o may decrease mean arterial pressure post ABI.

Therapeutic hypothermia, either intracranial pressure or oxygenation managed, may improve intracranial pressure, morbidity and mortality in individuals with an ABI.

Selective, long-term hypothermia can be more effective than systemic, short-term hypothermia in improve intracranial pressure and long-term outcomes in ABI patients.

Hypothermia combined with standard therapy may be more effective than hypothermia alone at improving intracranial pressure, cerebral perfusion pressure and oxygenation in ABI patients.

Manipulation of body positions may increase intracranial pressure more than the supine position.

Hypertonic saline may or may not lower intracranial pressure, and reduce hospital length of stay, but 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 treament.

Hypertonic saline has similar effects on intracranial pressure and clinical out comes when compared to Ringer’s lactate solution.

Hypertonic saline may have similar effects on intracranial pressure when compared to sodium bicarbonate.

Mannitol effectively decreases intracranial pressure post ABI, but can increase urine output and plasma sodium and chloride; furthermore, high doses may yield improved intracranial pressure control, lower mortality rates and better clinical outcomes compared to lower doses.

Mannitol may be equally effective as hypertonic saline at reducing intracranial pressure and cerebral perfusion pressure, and less effective than Ringer’s (sodium) lactate at reducing intracranial pressure.

Propofol, especially at higher doses, can improve intracranial pressure and cerebral perfusion pressure more effectively than morphine. When used in conjunction with morphine, propofol may reduce the need for other intracranial pressure interventions.

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

Midazolam may not be different from propofol in its effect on intracranial pressure, cerebral perfusion pressure, or long term outcomes, but may cause longer wake-up times.

Different opioids may have different intracranial pressure and cerebral perfusion pressure effects post ABI; where fentanyl, morphine, sufentanil, and alfentanil might increase intracranial pressure and decrease cerebral perfusion pressure, remifentanil may not affect intracranial pressure compared to controls.

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

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

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

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

Conivaptan may be similar to standard therapy at lowering intracranial pressure post ABI.

Vasopressin and catecholamine treatments may be similar for improving intracranial pressure.

Ventricular cerebrospinal fluid drainage, regardless of amount drained, can effectively lower elevated intracranial pressure post ABI.

Continuous cerebrospinal fluid drainage may be more effective than intermittent drainage at acutely lowering elevated intracranial pressure post ABI, with no differences existing in long-term outcomes.

Intraparenchymal fiber optic monitors may be superior to external ventrical drains in monitoring intracranial pressure, preventing complications, and reducing the need for further treatment; however, there may be no differences in long term between devices.

Decompressive craniectomy is more effective than standard treatment at reducing intracranial pressure; however, it is unclear which treatment best improves morbidity and mortality post ABI.

Initial Glasgow Outcome Scale score, but not intracranial pressure monitoring post decompressive craniectomy, may be a predictor for improved outcomes in patients post ABI.

Decompressive craniectomy may be similar to controlled decompression in reducing elevated intracranial pressure and improving Glasgow Outcome Scale scores.

Standard craniectomy with a larger bone flap is likely more effective than limited craniectomy with a smaller bone flap in terms of intracranial pressure reduction and favourable outcome.

Decompressive craniectomies and craniotomies may be similar at reducing ICP post ABI, but DC could be superior at improving good outcomes. It is unclear which procedure improves mortality the most.

Auditory sensory stimulation may change sensory stimulation assessment meaure and Disability Rating Scale, but not Glasgow Outcome Scale scores.

Multi-sensory stimulation may not cause physicological or biochemical arousal, although the effect on heart rate is unclear.

Multi-sensory stimulation may not improve emergence or recovery from coma post ABI.

Music therapy may improve consciousness in individuals in a coma post ABI.

Median nerve stimulation may increase cerebral perfusion pressure and dopamine levels in individuals in a coma post ABI.

The effects of median nerve electrical stimulation on consciousness and arousal from coma in individuals in a coma psot ABI is unclear

Amantadine improves consciousness, cognitive function, disability, but not emergence from coma post ABI.

Citicoline and antiepileptics may not be effective interventions for restoring consciousness post ABI. However, further research is required.

Multimodal stimulation may be more effective than unimodal stimulation at improving mental and physical arousal post ABI.

Multimodal stimulation is more effective than standard care at improving consciousness and cognitive function post ABI.

Sensory stimulation may be most effective when it is early, frequent, and sustained as well as specific, directed, and regulated.

Sensory stimulation may be most effective when stimuli are familiar or delivered by a familiar individual.

Amantadine may be more effective than standard care at improving consciousness and decreasing mortality in patients in a coma post ABI.

Hypothermia may improve outcomes and reduce mortality post ABI.

Very mild hypothermia (35-36°C) may be more effective than mild hypothermia (32-34°C) at improving outcomes with fewer complications individuals with an ABI.

Conventional physiotherapy alone, or in combination with verticalization may improves long term outcomes, disability, cognitive functioning and recovery from coma.

Verticalization in combination with conventional physiotherapy may be superior to conventional physiotherapy alone at improving recovery from coma.

Verticalization using the Erigo robot may be superior to the MOTOmed machine, and conventional therapy at reducing sympathetic stress.

Thawed plasma may be superior to packed red blood cells at improving neurological function and disability in patients with multiple injuries post TBI.

Hypertonic saline may increase hospital length of stay and rates of infections, especially in patients with severe TBIs.

Mannitol may increase urine output, lower serum sodium, transiently decrease systolic blood pressure, but has the same mortality compared to hypertonic solution.

Albumin may increase mortality, specially in severe TBI patients, compared to hypertonic solution; however, there may be no difference in neurological outcomes between treatments.

Propofol and vasopressor treatment might increase the risk of developing propofol infusion syndrome post ABI.

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.

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

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 complications, such as acute respiratory distress syndrome, arise.

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

The effect of progesterone on long-term outcomes is unclear.

Recombinant erythropoietin administration may improve mortality and neurological outcomes, and acutely lower brain cell destruction markers in patients post ABI.

Anatibant, regardless of dose, may not cause serious adverse events, affect morbity, mortality or disability in patients post ABI.

Tranexamic acid in combination with standard care is likely superior to standard care alone at reducing intracranial hemorrhage growth in patients post TBI.

Selenium in addition to standard care is likely not different than standard care at improving morbidity and neurological outcomes in patients post TBI.

Prophylactic statin use may not improve mortality or neurological outcomes in patients post TBI.

Early propranolol intervention may decrease mortality, but increase time spent on a ventilator in patients post TBI.

Dexemedetomidine might improve sedation and neurological outcomes while decreasing blood pressure, heart rate, and the need for opioid administration in patients post TBI.

Diclofenac Sodium might decrease core body temperature, cerebral blood flow, heart rate and blood pressure in patients post TBI.

Tracheostomies might improve mortality in individuals post ABI; however, individualss undergoing the procedure are generally older, more injured, and require more treatment.

Decompressive craniectomies may worsen mortality, recovery and complications in patients post ABI; however young age, early decompressive craniectomy, large decompressive craniectomy, and higher Glasgow Coma Scale scores may all be predictors for favourable outcomes.

It is unclear whether decompressive craniectomy is superior to a craniotomy at improving mortality and long-term outcomes post ABI.

An intracranial hemorrhage evacuation with a decompressive craniectomy may be inferior to an intracranial hemorrhage evacuation, or the same as an intracranial hemorrhage evacuation with a craniotomy at improving mortality and long-term outcomes in patients post ABI.

Trepination after a thick subdural intracranial hemorrhage might increase patient mortality.

It is unclear wether decompressive craniectomy is superior to standard care at improving Glasgow Outcome Scale scores and mortality in patients post ABI.

The type of decompressive craniectomy (with dural slits or expansile duraplasty) post acute subdural hematoma may not affect mortality and neurological outcomes.

Introduction

This module reviews the available evidence pertaining to interventions for acute care following ABI. The majority of interventions focus on the management of intracranial pressure, with additional interventions for prompting emergence from coma, and miscellaneous outcomes. For the purposes of ERABI, acute interventions were considered any treatment or intervention that was initiated within 14 days of ABI or ABI diagnosis.

16.5 Conclusions

This acute interventions chapter focuses on interventions which were initiated within 14 days of ABI incident or diagnosis. The majority of interventions focus on the management of ICP, this secondary insult post ABI can be catastrophic if not addressed and managed properly. Other focuses include prompting emergence from coma and surgical interventions.

16.2 Management of Intracranial Pressure

During the initial stages of an acquired brain injury (ABI) irreversible damage to the central nervous system occurs, commonly known as the primary injury. Subsequently, a chain of events leads to ongoing brain injury caused by edema, hypoxia, and ischemia as a result of increased intracranial pressure (ICP), the release of toxic amounts of excitatory neurotransmitters, and impaired ionic homeostasis (Werner & Engelhard, 2007). Considering the primary injury occurs immediately upon insult and is irreversible, acute brain injury treatment therefore focuses on preventing or minimizing the extent of secondary injury. To date, interventions have focused on targeting intracranial hypertension, oxygenation, and ion homeostasis in order to reduce cellular injury.

High intracranial pressure (ICP) is one of the most frequent causes of death and disability following severe ABI. High ICP is defined as ICP ≥ 20mmHg within any intracranial space including the subdural, intraventricular, extradural, or intraparenchymal compartments (Sahuquillo & Arikan, 2006). Following ABI, the brain is extremely vulnerable to secondary ischemia due to systemic hypotension and/or diminished cerebral perfusion resulting from elevations in ICP (Doyle et al., 2001). For these reasons, the acute care of patients with ABI includes the maintenance of adequate blood pressure and management of rises in ICP. 

Elevated ICP after an ABI is generally due to edema or inflammation within the cranial cavity (Rabinstein, 2006). There are various types of edema classified by their different pathophysiologies, the most common of which are: vasogenic, cytotoxic, and interstitial edema (Rabinstein, 2006). Vasogenic edema results from disruption, and subsequent increase in permeability, in the blood brain barrier, resulting in the movement of fluid into the extravascular space. Cytotoxic edema develops from the inability of cellular ionic pumps to maintain a normal concentration gradient across the cell membrane, causing increases in intracellular water content and cell swelling. Finally, interstitial edema is the forced flow of fluid from intraventricular compartments to the parenchyma; most commonly due to an obstruction in drainage.

The Monro-Kellie hypothesis states that the intracranial compartment has fixed volumes of the following components: cerebral tissue, cerebral blood, and cerebrospinal fluid (CSF). As one compartment increases in volume or a mass lesion is added to the compartment, compensation must occur to maintain a normal ICP. This compensation initially involves displacementof CSF and venous blood into the spinal canal; but once a critical volume is reached in the intracranial compartment, cerebral compliance decreases and elastance increases, resulting in larger changes in ICP with smaller changes in volume. Therefore, small reductions in CSF can have a large impact on ICP control at this stage (Vella et al., 2017). Multiple therapies are used to maintain normal ICPs in patients with a traumatic brain injury (TBI). In order for treatments to be effective, however, interventions need to target the specific form of edema that is responsible for the increase in ICP. The degree and timing of ICP elevation are also important determinants of clinical outcome, adding a sense of urgency to intiate ICP interventions as soon as possible (Vella et al., 2017).

Currently there are two broad categories of therapies used to alleviate increased ICP in TBI patients; surgical and non-surgical (medical) interventions (Lazaridis et al., 2018; Vella et al., 2017). Non-surgical therapy focuses on reducing cerebral edema, reducing metabolic demand, and increasing cerebral blood flow, and includes the use of both pharmacological agents (diuretics, corticostroids, barbituaries, etc.) and non-pharmacological interventions (hypothermia, hyperventillation, head posture, body rotation). Conversely, surgical therapies employ physical interventions to reduce ICP by either decreasing the volume of fluid (blood, CSF) or increasing the size of the cranial compartment (Davanzo et al., 2017). Some of the most commonly performed procedures include ventriculostomy with therapeutic drainage, evacuation of mass lesions, as well as decompressive craniectomy.

Recently, the understanding of the negative effects associated with cellular level post-traumatic stress has generated interest in exploring compounds that serve as neuroprotective agents. These compounds have been used in conjunction with standard therapy to optimally reduce cellullar damage caused by increases in ICP. Traditional therapies have included sedatives such as barbiturates and opiates in an attempt to down regulate cellular metabolism. Newer initiatives have begun to target free radical production and oxidative stresses, which affect membrane viability.

Guideline Recommendations

In an attempt to standardize acute management of ABI, several consensus guidelines have been developed. The two most prominent sets of guidelines are those developed by the American Association of Neurological Surgeons (AANS) in 2016 (Carney & Ghajar, 2007), and by the European Brain Injury Consortium (EBIC) in 1997 (Maas et al., 1997). (Maas et al., 1997)These guidelines have gained credibility worldwide and are widely recognized as influencing clinical practice. As such, we have chosen to add recommendations made by either organization into our evaluation of each intervention. However, the conclusions presented in levels of evidence statements and conclusion boxes in this module are based on our methodology and have not been influenced by guideline recommendations.

16.2.1 Non-Pharmacological Interventions

16.2.1.1 Head Posture

Key Points

Head elevation of 30o likely lowers intracranial pressure post ABI; however, its effect on cerebral perfusion pressure are less clear.

Head elevation of 60o may lower intracranial pressure post-ABI.

The standard practice in most intensive care units when managing an ABI is to elevate the head above the level of the heart in an effort to reduce ICP. Head elevation is thought to reduce ICP by facilitating intracranial venous outflow, all the while maintaining, and perhaps even improving,  CPP and cardiac output (Ng et al., 2004). (Schulz-Stubner & Thiex, 2006). In addition, placing patients in an elevated head posture facilitates early provision of enteral nutrition while reducing the risk of gastric reflux and pulmonary aspiration when compared with patients kept in the supine position (Ng et al., 2004).

In a systematic review, Fan (2004) found 11 studies with a pooled sample of 178 participants. The authors noted that all studies found significant reductions in ICP associated with head elevation, while only six studies found significant improvements in CPP. A meta-analysis by Jiang et al. (2015) examined a total of 10 studies with a pooled sample of 237 participants. The authors found that a head elevation of 30° yielded a large effect in ICP reduction when compared to 0°. To summarize multiple studies, authors found a moderate effect at 10° and large effects at 15° and 45° when compared to 0°. Large effects were also observed at 30° and 45° when compared to 15°. As well, the authors found no difference in ICP reduction between 30° and 45.

Although head elevation during the management of ABI is well accepted, there is evidence suggesting that keeping patients in a flat position may be beneficial. Ng et al. (2004) note that maintaining individuals with a TBI in a flat position reduces the risk of systemic hypotension inherent in a semi-recumbent posture. Furthermore, some authors argue that a horizontal body position increases CPP, which improves cerebral blood flow (Winkelman, 2000).

The EBIC stated that no consensus existed regarding the benefits of head elevation to 30 degrees when compared to the recumbent position (Maas et al., 1997). There are currently no AANS recommendations for head posture. Studies examining the evidence on head elevation in ABI are presented in Table 16.1.

Discussion

Head elevation was found to significantly reduce ICP when compared to a flat position in numerous studies. Reductions in ICP were observed at 30o  (Feldman et al., 1992)(Feldman et al. 1992; Meixensberger at al. 1997; Ng et al. 2004; Park & Ha 1992; Parsons & Wilson 1984; Winkelmann 2000), and 60o elevation (Ropper et al. 1982). Several studies reported that reductions in ICP following head elevation were correlated with significant improvements in CPP (Meixensberger et al. 1997; Winkelman 2000) although other studies did not report similar findings (Feldman et. al 1992; Ng et al. 2004; Park & Ha 1992; Parsons & Wilson 1984). Despite fear that head elevation will precipitate systemic hypotension, ultimately worsening the patient’s condition, only one study reported a decrease in MAP (30o elevation; Feldman et al. 1992). Due to the retrospective nature of the study and lack of controls, further studies are required to ellucidate the risk of systemic hypotension brought on by head elevation.

Conclusions

There is level 2 evidence that head elevation of 30o from a flat position may effectively reduces elevated intracranial pressure compared to head elevation of 0 o in individuals post ABI.

There is level 4 evidence that head elevation of 60o from a flat position may effectively reduceelevated ICP post ABI.

There is conflicting (level 2 and level 4) evidence regarding whether or not head elevation of 30o effectively improves cerebral perfusion pressure post ABI. With level 2 evidence supporting the use of head elevation to reduce cerebral perfusion pressure.

16.2.1.2 Hypothermia

Key Points

Therapeutic hypothermia (32-35°C) may be an effective intervention for lowering elevated intracranial pressure post ABI but may not improve long-term outcomes.

Therapeutic hypothermia may increase the risk of complications such as pneumonia.

As early as half a century ago, hypothermia was explored as a neuroprotective treatment to reduce secondary brain injury in ABI (Fay 1945).  It is believed that hypothermia can control elevated ICP by a variety of mechanisms including  reducing cerebral metabolism, decreasing the inflammatory response, and decreasing the release of excitotoxic levels of glutamate and free radicals post ABI (Alderson et al., 2004; Chen et al., 2001; Clifton, 2004; Globus et al., 1995; Marion, 1997; Yan et al., 2010).

It is important to note that prolonged hypothermia is believed to be associated with various adverse effects including arrhythmias, coagulopathies, sepsis and pneumonia, which could ultimately lead to a poorer clinical outcome (Alderson et al., 2004; Schubert, 1995). It has also been suggested that there may be a threshold during rewarming, above which, pressure reactivity may reach damaging levels (Lavinio et al., 2007) and that there is a critical window beyond which hypothermia may be ineffective (Clifton et al., 2009).

The AANS noted that prophylactic hypothermia showed no significant association with improved outcomes relative to normothermic controls (Carney et al., 2017). However, they reported that increased risk of mortality may be seen when target temperatures are achieved within 2.5 hours of injury and maintained for more than 48 hours. There are currently no EBIC recommendations for hypothermia. Studies evaluating the effects of hypothermia in ABI populations are presented in Table 16.2.

Discussion

A number of studies found significant reductions in ICP following hypothermia when compared to baseline values (Flynn et al., 2015; Metz et al., 1996; Sahuquillo et al., 2009; Tateishi et al., 1998; Tokutomi et al., 2003) or a normothermia control group (Gal et al., 2002; Jiang et al., 2000; Lee et al., 2010; Liu et al., 2006; Marion et al., 1993; Qiu et al., 2006; Qiu et al., 2007; Shiozaki et al., 1993; Smrcka et al., 2005; Zhao et al., 2011; Zhi et al., 2003). A portion of these studies also reported significant increases in CPP accompanying the reduction in ICP (Gal et al., 2002; Marion et al., 1993; Marion et al., 1997; Shiozaki et al., 1993; Smrcka et al., 2005; Tokutomi et al., 2003). While most studies utilized systemic hypothermia, achieved with cooling blankets and/or gastric lavage, two studies delivered hypothermia selectively only to the head (Qiu et al. 2006; Harris et al. 2009). Despite of the difference in protocol, similar reductions in ICP were reported regardless of hypothermia administration.

On the contrary, two high-quality RCTs did not find any significant improvements in ICP or CPP following therapeutic hypothermia (Andrews et al., 2015; Clifton et al., 2001; Maekawa et al., 2015). Of note, the Clifton et al. (2001) study did report that the amount of patients with ICP>30mmHg was significantly lower in the hypothermia group compared to the control group.

In the reviewed studies, therapeutic hypothermia involved cooling patients to 32-36°C for at least 12 hours. The results of two studies suggested that very mild hypothermia (35-36°C) may be just as effective as mild hypothermia (32-34°C) at improving outcomes with fewer complications (Hayashi et al. 2005; Tokutomi et al. 2009). One aspect of study methodology which varied greatly between studies was the length of time of hypothermia treatment, which was patient-dependent, and ranged from 1 to 14 days. One trial reported that hypothermia delivered over five days, using cooling blankets, showed a greater ICP reduction and more favourable long-term outcomes than a two-day treatment (J. Y. Jiang et al. 2006). Furthermore, most studies utilized systemic hypothermia, which was achieved with cooling blankets and/or gastric lavage. Only a few studies delivered selective hypothermia to the cranium (Harris et al. 2009;; Qiu et al. 2006), which may yield greater improvements in ICP and other outcomes when compared to systemic treatment (Liu et al., 2006). There were no studies comparing specific hypothermia ranges (ie. 34-35oC vs 32-33oC) and their efficacy on ICP reduction. As a result, it is unclear what hypothermic protocol is optimal to treat ABI patients.

While hypothermia treatment is used to acutely reduce ICP in ABI patients, the intervention also has an effect on long term patient outcomes. At three to six months post-ABI, some studies reported that patients treated with hypothermia had more favourable outcomes on the GOS/GOSEand lower rates of mortality than those treated with normothermia (Hayashi et al., 2005; Jiang et al., 2000; Jiang et al., 2006; Lee et al., 2010; Liu et al., 2006; Marion et al., 1993; Marion et al., 1997; Polderman et al., 2002; Qiu et al., 2006; Qiu et al., 2007; Shiozaki et al., 1993; Smrcka et al., 2005; Yamamoto et al., 2002; Zhi et al., 2003). However, these findings were not replicated in similar studies (Gal et al., 2002; Harris et al., 2009; Shiozaki et al., 2001; Zhao et al., 2011) or in multicentre trials such as the North American Brain Injury Study (Clifton et al., 2001; Clifton et al., 2011). Furthermore, some studies reported that therapeutic hypothermia was associated with increased risk of serious complications (Clifton et al., 2001; Clifton et al., 2011; Qiu et al., 2006; Qiu et al., 2007; Sahuquillo et al., 2009). Pulmonary infections such as pneumonia were noted during cooling, and cardiovascular issues such as arrhythmia and hypotension were noted during rewarming.

Conclusions

There is conflicting level 1a evidence regarding whether or not therapeutic hypothermia effectively reduces elevated intracranial pressure post ABI compared to normothermia.

16.2.1.3 Hyperventilation

Key Points

Hyperventilation may effectively lower elevated intracranial pressure post TBI.

Controlled hyperventilation to achieve a Partial Pressure of Carbon Dioxide in Arterial Blood (PaCO2) of 30-35 mmHg during the first days post ABI has been reported to improve ICP outcomes.  Hyperventilation causes cerebral vasoconstriction, which leads to decreases in cerebral blood flow and volume, thus leading to a decrease in ICP (Muizelaar et al., 1991). While reducing blood floow to the brain seems paradoxical, the brain is able to maintainnormal cellular metabolism by increasing the amount of oxygen it extracts from the blood that is there. (Diringer et al., 2000).

One concern that arises with intensive or prolonged hyperventilation is the exacerbation of metabolic acidosis; A condition commonly caused by ABIs. Depletion of oxygen shifts the injured brain from an aerobic to an anaerobic metabolism, resulting in the build up of lactic acid — a compound that acidifies CSF andhas been correlated with poor outcomes (De Salles et al., 1987; DeSalles et al., 1986). However, since hyperventilation decreases cerebral CO2, the respiratory alkalosis generated by expelling CO2 helps diminish the detrimental impact of the developing metabolic acidosis. It is important to note that this process of acid neutralization depends on the availability of bicarbonate in the CSF, and thus prolonged hyperventilation may not be an appropriate therapeutic measure as it may deplete bicarbonate levels favoring ischemia and leading to poorer outcomes. Several studies have also discussed concerns related to pre-hospital intubation leading to inappropriate hyperventilation (Lal et al., 2003; Warner et al., 2007). Targeted hyperventilation to within 30-45 mmHg have been associated with decreased mortality rates, but both precise regulation and proper training are recommended.

The AANS has made Level II recommendations against the use of intensive prophylactic hyperventilation (PaCO2<25mmHg) (Carney et al., 2017). The EBIC recommended mild to moderate hyperventilation (PaCO2=30-35mmHg) to manage high ICP and CPP in association with sedation and analgesia (Maas et al., 1997). If ICP remains uncontrolled, even with osmolar therapy and cerebrospinal fluid (CSF) drainage, then intensive hyperventilation (PaCO2<30mmHg) was recommended (Maas et al., 1997). Studies examining the effects of hyperventilation on ICP and blood flow are presented in Table 16.3.

Discussion

The findings of two studies demonstrated that prolonged, moderate hyperventilation can effectively lower elevated ICP in individuals following ABI (Coles et al., 2002; Oertel et al., 2002). In comparing intensive (PaCO2<30mmHg) hyperventilation to moderate (PaCO2>30mmHg) hyperventilation, a higher mortality was found in the former group, but the results were not statistically significant (Mohammed F, 2013). In another study, it was found that early, brief, moderate hyperventilation did not impair global cerebral metabolism in patients with severe TBI, and thus it is unlikely to cause further neurological injury (Diringer et al., 2000).

Potential detrimental effects following hyperventilation are particularly concerning in ABI, and the issue has been addressed in two earlier studies; these can be found in section 16.2.4.1 which discusses studies that have compared the effect of non-pharmacological interventions.

Conclusions

There is level 4 evidence that hyperventilation may lower elevated intracranial pressure post TBI.

16.2.1.4 Rotational Therapy and Prone Positioning

Key Points

Continuous rotational therapy does not improve intracranial pressure in individuals with severe TBI.

Prone positioning may increase intracranial pressure but improve cerebral oxygenation post ABI.

The concept of continuous lateral rotational therapy has been used for the prevention of secondary complications resulting from immobilization. These complications include pressure ulcers, pneumonia from atelectasis, deep vein thrombosis, pulmonary emboli, muscle atrophy, and contractures (Dittmer & Teasell, 1993). Additionally, there are some indications that continuous rotational therapy may be useful in managing elevations in ICP.

Use of the prone position has been shown to be an effective treatment for patients with acute respiratory insufficiency in the ICU (Pelosi et al., 2002). However, many studies have excluded patients with ABI due to fears of increasing ICP during the rotation process and in the prone position (Johannigman et al., 2000).

The EBIC and the AANS guidelines have made no recommendations regarding continuous rotational therapy or prone positioning in acute ABI for the prevention of secondary injury.

Discussion

A single study has been identified which examined the effects of continuous rotational therapy on ICP (Tillett et al., 1993). The study failed to find any direct benefit of the therapy for managing elevated ICP, but did suggested that patients with unilateral brain injuries should not be rotated towards the side of the lesion in order to avoid further increments in ICP.

Three case series investigated the effects of prone positioning on various physiological measures. Two studies reported significant increases in ICP during prone positioning (Lee, 1989; Nekludov et al., 2006; Roth et al., 2014). Two studies demonstrated increased cerebral oxygenation in patients when they were prone (Nekludov et al., 2006; Thelandersson et al., 2006), which was maintained upon return to the supine position (Thelandersson et al., 2006). One study found increases in CPP and MAP when patients were prone (Nekludov et al., 2006), while other studies reported that these values decreased (Roth et al., 2014) or did not change (Thelandersson et al., 2006). Due to the small sample sizes and retrospective nature of these studies, further prospective research is required to determine the efficacy of prone positioning.

Conclusions

There is level 4 evidence that continuous rotational therapy may not improve intracranial pressure following severe TBI.

There is level 4 evidence that the prone position may increase intracranial pressure but improve cerebral oxygenation post ABI.

16.2.1.5 Intracranial Pressure Monitors

The Brain Trauma Foundation has stated that all comatose TBI patients should be monitored with an ICP monitor. Despite their recommendations, studies have reported a lack of compliance with the proposed guidelines in part due to a perceived lack of evidence behind implementing the practice (Hesdorffer et al., 2002). More recently studies were conducted to investigate the efficacy of ICP monitors in TBI patients, with several concluding that overall, patients with ICP monitors had lower in-hospital mortality compared to those with no monitoring (Gerber et al., 2013; Talving et al., 2013).

There are different types of ICP monitors available which can be broadly classified into invasive (Parenchymal Monitors, External Ventricular Drains [EVDs], fibreoptic monitors, etc), and non-invasive (Transcranial Doppler Ultrasonongraphy, Tympanic Membrane Displacement, Optic Nerve Sheath Diameter, MRI, CT, etc) (Raboel et al., 2012). Invasive moinitors are the more accurate tool, however they come at the expense of higher risk of complications such as infections (Davanzo et al., 2017). Parenchymal monitors as their name suggest insert directly into the parenchyma to calculate ICP. Due to the pressure gradient created during a TBI, parenchymal monitors may not be the most accurate for measuing CSF pressure (Davanzo et al., 2017). On the other hand, EVDs are placed in the lateral ventricle with the primary function of draining CSF. In addition to allowing CSF drainage however, EVDs can be used as an ICP monitor and as a result they are currently the preferred ICP monitor (Le Roux, 2016; Raboel et al., 2012). Recently, the development of Fibre Optic monitors, which attach to the end of the EVD catherer and provides a constant ICP reading regardless of the current EVD setting or function, have gained traction as a more accurate measurement of ICP (Le Roux, 2016).

Regardless of ICP monitor, their use has been touted by agencies such as The Brain Trauma Foundation as necessary for optimal patient care post TBI. This section will examine the existing literature to ellucidate the benefit of ICP monitoring in patients post ABI.

Discussion

One study was reviewed in which patients receiving ICP monitoring post-ABI were compared to controls. The researchers reported that mortality in the hospital, and 6 months after discharge, was significantly lower in the group of patients who received ICP monitoring compared to those who did not (Agrawal et al., 2017). Despite the improvement in mortality, there was no significant difference between the groups in terms of GOS scores at 6 months post-discharge. The results of this study suggest that ICP monitoring can help improve mortality in patients post ABI, however more studies need to be analyzed to reach a defnitive conclusion. In addition, no reports were made on the side effects and complications associated with ICP monitoring. Further studies will have to be analyzed to weigh the benefits of ICP monitoring against the complications observed.

Conclusions

There is level 2 evidence that intracranial pressure monitoring may improve mortality in-hospital, and 6 months post-discharge in patients post ABI compared to control.

There is level 2 evidence that intracranial pressure monitoring may not improve Glasgow Outcome Scale scores in patients post ABI compared to control.

16.2.2 Pharmacological Interventions

16.2.2.1 Osmolar Therapies

Osmolar therapy is a major treatment approach in controlling intracranial hypertension and edema following ABI. Although mannitol is the drug most widely used in this regard, saline has gained popularity and some studies have called for examination of it as a primary measure for ICP control (Horn et al., 1999; Ware et al., 2005). Recently, although no longer used as a first-line treatmennt, studies have begun to investigate the use of urea in specific ABI cases where the common therapies- mannitol, HTS- are not appropriate.

16.2.2.1.1 Hypertonic Saline

Key Points

Hypertonic saline effectively lowers elevated intracranial pressure and potentially increases cerebral perfusion pressure in severe ABI.

Hypertonic saline increases serum sodium in ABI patients, however it may have no association with increased mortality.

Hypertonic saline (HTS) exerts its effect mainly by increasing serum sodium concentrations and plasma osmolarity, thereby increasing the osmotic gradient between the intracellular and extracelullar compartments. The increased osmotic gradient allows water to passively diffuse from the cerebral intracellular and interstitial space into blood capillaries, causing a reduction in water content and ICP (Khanna et al., 2000). While mannitol works in a similar manner, HTS has a better reflection coefficient (1.0) than mannitol (0.9) making HTS less likely to cross the Blood Brain Barrier (BBB) and allowing it to act as a more effective osmotic agent  (Suarez, 2004). In addition,It has also been proposed that HTS normalizes resting membrane potential and cell volume by restoring normal intracellular electrolyte balance in injured cells (Khanna et al., 2000).

Despite increasing use of HTS in individuals with ABI, the AANS concluded that there was insufficient evidence available to support a formal recommendation (Carney et al., 2017). The EBIC made no recommendations for the use of HTS.

Discussion

An abundance of retrospective studies have found that HTS treatment following ABI yields a significant decrease in ICP (Colton et al., 2014a; Colton et al., 2016; Colton et al., 2014c; Horn et al., 1999; Lewandowski-Belfer et al., 2014; Li et al., 2015; Major et al., 2015; Paredes-Andrade et al., 2012; Qureshi et al., 1998; Roquilly et al., 2011; Schatzmann et al., 1998). Prospective studies have supported these findings as well, demonstrating that HTS was responsible for significant reductions in ICP and increases in CPP (Dias et al., 2014; Eskandari et al., 2013; Lescot et al., 2006; Pascual et al., 2008; Rockswold et al., 2009). While most of these studies reported on short-term outcomes, one found that the effects lasted up to 12 hours (Eskandari et al., 2013).

Hypertonic saline administration was found to have improved cerebral blood flow in one studies (Dias et al., 2014) with subsequent increases in cerebral oxygenation in two other studies (Oddo et al., 2009; Pascual et al., 2008). Thus, HTS may be a valuable component in resuscitation of patients with ABI, although further research into this matter is required. Using CT technology, Lescot et al. (2006) assessed the effectiveness of HTS on volume, weight, and specific gravity of contused and non-contused brain tissue. Three days after TBI, contused tissue was shown to increase in volume after administration of HTS. The authors recommended further research assessing the effects of HTS on different tissue types, so that contusion site and size might be appropriately factored into clinical decisions.

While complications were largely not reported, a number of studies noted significant increases in serum sodium (Lescot et al., 2006; Lewandowski-Belfer et al., 2014; Qureshi et al., 1998; Rockswold et al., 2009; Roquilly et al., 2011; G. Tan et al., 2016), and days spent in the ICU (G. Tan et al., 2016) after HTS treatment. While technically considered a complication of HTS treatment, Tan et al. (2016) reported that the hypernatremia was not associated with an increase in mortality.

Conclusions

There is level 3 evidence that hypertonic saline compared to control treatment may be effective in lowering elevated intracranial pressure post ABI.

There is level 4 evidence that hypertonic saline may be effective in increasing cerebral perfusion pressure.

16.2.2.1.2 Mannitol

Key Points

Mannitol may effectively lower elevated intracranial pressure and cerebral perfusion pressure post ABI; however potentially only in hypertensive (intracranial pressure>20 mmHg) patients.

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

Despite the fact 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; 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)).

Conclusions

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 only may improve intracranial pressure and cerebral perfusion pressure post ABI in hypertensive patients (Intracranial pressure>20mmHg).

16.2.2.1.3 Urea

Key Points

Enteral urea may lower elevated intracranial pressure in ABI patients with syndrome of in-appropriate antidiuretic hormone secretion.

Urea is a nitrogenous waste product of protein metabolism that is excreted by the kidneys. An osmotically active agent, Urea gained popularity in the 1950’s as a compound that could rapidly reduce ICP. Although an effective agent, intravenous urea use was associated with comlications such as rebound hypertension (due to its filtration into the brain), local skin necrosis and sloughing, platelet dysfunction, and renal dysfunction (Rocque, 2012) . In the decades that followed urea was replaced as the mainstay in treatment for compounds with equal efficacy but much safer profiles, such as mannitol and recently HTS . Today urea is rarely used to treat ICP in ABI, save for very specific cases were the mainstay therapies are not appropriate.

Discussion

Annoni et al. (2017) studied the effect of enteral urea administration on ABI patients who presented with elevated ICP and syndrome of in-appropriate antidiuretic hormone secretion (SIADH). The researches concluded that urea administration effectively lowered ICP, and was able to increase serum sodium in the process. In addition to the primary outcomes, no notable side-effects or complications were reported. Although a small trial, these findings point to the suggestion that enterally-administered urea has a safer profile than the previously common intravenous route.

Conclusions

There is level 4 evidence that enteral urea may lower elevated intracranial pressure in ABI patients with syndrome of in-appropriate antidiuretic hormone secretion.

16.2.2.10 Other Medications

Key Points

Elevated intracranial pressure may be effectively reduced by paracetamol.

In addition to the aforementioned medications, other pharmacological interventions have been evaluated for effectiveness in reducing elevated ICP post ABI, including analgesics, hormones, and selective inhibitors.

Discussion

In a retrospective study, paracetamol (acetaminophen) was found to significantly reduce ICP, CPP, MAP, and core body temperature post TBI (Picetti et al., 2014). Despite the improvement in ICP, the decrease in CPP and MAP caused by paracetamol could further exacerbate the injury and thus nullify any potential improvements made by reducing ICP. Given the limited research of paracetamol use in ICP management, additional clinical trials are required to make firm conclusions.

Conclusions

There is level 4 evidence that paracetamol may lower elevated intracranial pressure post ABI.

16.2.2.2 Propofol

Key Points

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

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 has been 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 EBIC recommended sedation as part of the treatment course for ABI but make 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). 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 ABI patients will be further discussed later in the “comparative section” as its efficacy is directly contrasted to other sedatives.

Conclusions

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

16.2.2.3 Midazolam

Key Points

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

Midazolam is a fast-acting benzodiazepine with a short half-life and inactive metabolites (McCollam et al., 1999). Midazolam is anxiolytic and displays anti-epileptic, sedative, and amnestic properties. It is a protein-bound, highly lipid-soluble drug that crosses the blood brain barrier and has a rapid onset of action — one to five minutes in most patients (McClelland et al., 1995). However, delayed elimination of midazolam resulting in prolonged sedation has been demonstrated in some critically ill patients.

Studies conducted in the operating room or intensive care unit have demonstrated midazolam to be relatively safe in euvolemic patients or in the presence of continuous hemodynamic monitoring for early detection of hypotension (Davis et al., 2001). Midazolam has been found to reduce CSF pressure in patients without intracranial mass lesions as well as decrease cerebral blood flow and cerebral oxygen consumption (McClelland et al., 1995).

The AANS made no recommendations regarding the efficacy of midazolam but, if used, suggested a 2.0 mg test dose followed by a 2.0-4.0 mg/hr infusion (Carney et al., 2017). The EBIC recommended sedation but made no specific reference to midazolam (Maas et al., 1997).

Discussion

An early retrospective study by Papazian et al. (1993) reported that midazolam did not yield -significant reductions in ICP, but was associated witha decrease in both CPP and MAP. Furthermore, subgroup analysis revealed that patients with low intitial ICP (<18mmHg) exeperienced greater decreases in MAP compared to those with high initial ICP (≥18mmHg) The results of this study call into question the utility of midazolam in ABI treatment, as there was no reduction in ICP, and blood flow to the brain was further compromised.

Conclusions

There is level 4 evidence that midazolam may have no effect on intracranial pressure, and may decrease mean arterial pressure and cerebral perfusion pressure, in TBI patients.

16.2.2.4 Opioids

Key Points

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.

Opiods are substances with analgesic and nervous system depressant properties that primarily act on the CNS and gastrointestinal tract by binding to opiod receptors. The pharmacodynamic response each opiod elicits is determined by both the type of opiod receptor it binds, and its affinity for that receptor. Morphine has been the most commonly used opioid following ABI, while fentanyl and its derivatives have gained popularity due to their more rapid onset and shorter duration of effect (Metz et al., 2000). However, controversy persists regarding the effect of opioids on ICP and CPP.  It has been reported that opioids can increase cerebral blood flow (CBF), 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 AANS and the EBIC made no recommendations regarding opioids in acute ABI.

Discussion

As discussed in the introduction a large number of opiod derivatives exist, each with their own physiological and pharmacologial properties. It follows that a variety of studies have individually analyzed said derivatives to help ellucidate their effects on ABI patients.

One study was reviewed where the researchers studied the effects of IV remifentanil on ABI patients. 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 ABI patients 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) (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.

Conclusions

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.

16.2.2.5 Barbiturates

Key Points

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

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

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

Discussion

Studies examining the use of thiopental post-ABI were reviewed. Of those studies, only one fulfilled the criteria of exclusively using thiopental to treat ABI (Schalen et al., 1992) . The rest of the studies used a combination of treatments and will thus be discussed in the “comparative/ combinational” section.

Schalen et al. infused thiopental intravenuosly 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.

Conclusions

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

16.2.2.6 Cannabinoids

Key Points

Dexanabinol in cremophor-ethanol solution may be effective in controlling intracranial pressure and improving cerebral perfusion pressure, and clinical outcomes post TBI.

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

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

Discussion

In an early RCT, Knoller et al. (2002) found that dexanabinol (50mg) 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 one month post treatment, these benefits progressively lost significance over the 6-month follow-up.  Maas et al. (2006) conducted a large-scale multicenter RCT to better establish the efficacy of dexanabinol in the treatment of TBI.  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.

Conclusions

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

16.2.2.7 Progesterone

Key Points

Progesterone may not have an effect on intracranial pressure, but does reduce mortality, and improve 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 an 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 additionaly 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.

Conclusions

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

16.2.2.8 Bradykinin Antagonists

Key Points

Bradycor can prevent acute elevations in intracranial pressure and reduce therapeutic intensity levels post ABI; however, its effect on Glasgow Coma Scale scores 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). Recent 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

We identified two trials that 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 1a evidence that Bradycor may be effective at preventing acute elevations intracranial pressure and reducing therapeutic intensity levels post ABI when compared to placebo.

16.2.2.9 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 over the long-term.

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 increas 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

Two retrospective 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.

Conclusions

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

16.2.3 Surgical Interventions

16.2.3.1 Cerebrospinal Fluid Drainage

Key Points

Cerebrospinal fluid drainage can effectively lower elevated intracranial pressure post ABI, using either a ventricular or lumbar device. In addition, ventricular devices may potentially increase cerebral perfusion pressure and cerebral blood flow.

External lumbar devices may effectively lower intracranial pressure in patients refractory to first line treatments.

In an attempt to control ICP, ventricular CSF drainage is a frequently used neurosurgical technique. Catheters are generally inserted in to the anterior horn of a lateral ventricle and attached to an external strain gauged transducer  allowing for concurrent pressure monitoring and fluid drainage (Bracke et al., 1978; March, 2005). Generally, a few milliliters of fluid are drained from the ventricle at a time, resulting in an immediate decrease in ICP (Kerr et al., 2000).  However, ventricular space is often compressed due to associated brain swelling, which limits the potential for drainage as a stand-alone therapy for ICP (James, 1979). Criticisms of external ventricular drainage generally surround the intrusiveness of the procedure and the complication of potential infections (Hoefnagel et al., 2008; Zabramski et al., 2003).

When ventricular drainage is not possible, lumbar drainage has been proposed as an alternative method for reducing elevated ICP. Standard practice has been to avoid lumbar drainage for fear of transtentorial or tonsillar herniation. However, technological improvements have renewed interest in its potential for reducing ICP in patients refractory to other treatments (Tuettenberg et al., 2009).

The AANS guidelines made a Level III recommendation for the use of CSF drainage to lower ICP in patients with GCS<6 during the first 12 hours post injury (Carney et al., 2017). As well, the authors noted that an external ventricular system at the midbrain may be more effective with continuous drainage than with intermittent use. According to the EBIC, CSF drainage is an acceptable treatment for ICP reduction post ABI (Maas et al., 1997).

Discussion

Ventricular drainage of CSF has shown to be an effective intervention for lowering elevated ICP post ABI in small-scale studies (Fortune et al., 1995; Kerr et al., 2000; Timofeev et al., 2008b). While the retrospective studies noted steady increases in ICP after treatment cessation (Fortune et al., 1995; Kerr et al., 2000), the prospective studies found that ICP reductions were maintained for up to 24 hours in select participants (Lescot et al., 2012; Timofeev et al., 2008b).  Two of the studies reported significant improvements in CPP associated with ICP reductions (Kerr et al., 2000; Lescot et al., 2012), and only one reported short-term improvements in cerebral blood flow (Fortune et al., 1995). Lumbar drainage of CSF has shown similar effectiveness in lowering elevated ICP post ABI. The results of two small retrospective studies showed significant reductions in ICP after lumbar drainage (Llompart-Pou et al., 2011; Murad et al., 2008), which were supported by two prospective studies (Murad et al., 2012; Tuettenberg et al., 2009). The rate of favourable long-term outcomes in these studies ranged from 36% (Tuettenberg et al., 2009) to 62% (Llompart-Pou et al., 2011), and one study reported a 70% decrease in therapeutic intensity levels following treatment. Following the increasing body of evidence for the benefit of lumbar drainage, Manet et al. (2017) sutdied the efficacy of an External Lumbar Device (ELD) in patients refractory to standard ICP treatment. The ELD allowed for continuous CSF extraction, draining an average of 199mL/d, which resulted in a 3.6 fold reduction in ICP. Based on these findings, lumbar drainage appears to be a viable alternative when ventricular drainage is not possible.

Conclusions

There is level 4 evidence that ventricular cerebrospinal fluid drainage may effectively lower elevated intracranial pressure post ABI.

There is level 4 evidence that ventricular cerebrospinal fluid drainage may increase cerebral perfusion pressure and cerebreal blood flow.

There is level 4 evidence that lumbar cerebrospinal fluid drainage may effectively lower elevated intracranial pressure post ABI.

There is level 4 evidence that continuous cerebrospinal fluid extractions through an external lumbar device may effectively lower intracranial pressure in patients refractory to standard intracranial pressure treatment.

16.2.3.2 Decompressive Craniectomy

Key Points

It is undetermined whether decompressive craniectomy is an effective intervention for lowering elevated intracranial pressure post ABI; however, it may not improve cerebral perfusion pressure.

It is unclear whether a decompressive craniectomy is associated with improved long-term outcomes and mortality; however young age, early decompressive craniectomy, large decompressive craniectomy, and higher Glasgow Coma Score scores may all be predictors for favourable outcomes.

Surgical decompression is the removal of skull sections in ABI patients to reduce the rising ICPcaused by secondary injury (i.e., delayed brain damage).  Sahuquillo and Arikan (2006) identified two types of surgical decompression: prophylactic/primary decompression and therapeutic/secondary decompressive craniectomy (DC). The former involves performing the surgical procedure as a preventive measure against expected increases in ICP while the latter is performed to control high ICP “refractory to maximal medical therapy” (Sahuquillo & Arikan, 2006).

However, debate regarding if and when to perform these surgeries continues. Factors such as age and initial GCS score have been proposed as potential prognostic factors (Guerra et al., 1999).  Currently, the majority of decompressive techniques are precipitated by evacuation of a mass lesion (Compagnone et al., 2005). On the other hand, therapeutic DC is typically performed after other therapeutic measures to control ICP have been exhausted (Morgalla et al., 2008) Once decompression is decided upon, resection of a larger bone fragment is generally recommended to allow for greater dural expansion with less risk of herniation (Compagnone et al., 2005; Csókay et al., 2001).. Two meta-analyses evaluated the effectiveness of DC in ICP were analysed. The earlier study found that postoperative ICP was significantly lower than preoperative values and remained stable for up to 48 hours (Bor-Seng-Shu et al., 2012), while the later study reported that DC resulted in reduced ICP and shorter hospital stay when compared to standard care (Wang et al., 2015). However, both studies were limited by a small sample size, lack of high-quality studies, significant heterogeneity between studies, and absence of a bias assessment. In a 2006 Cochrane review, the authors found no evidence to recommend routine use of DC to reduce unfavorable outcomes in adults with uncontrolled ICP (Sahuquillo & Arikan, 2006). A recent systematic review reported improved GOS scores and reduced mortality rates associated with DC, particularly in younger individuals with less severe (GCS>5) and more acute (<5hr) injuries (Barthelemy et al., 2016). However, the authors refrained from providing clinical recommendations given a lack of prospective data and significant results

The AANS reported that there was insufficient evidence to support Level I recommendations regarding DC, although Level II recommendations were provided (Carney et al., 2017). A bifrontal DC was not recommended for improving long-term outcomes in individuals with severe TBI and prolonged, elevated ICP. The authors noted, however, that bifrontal DC demonstrated significant reductions in ICP and ICU stay. As well, a larger frontotempoparietal DC was recommended over a smaller procedure for reduced mortality and improved neurological outcomes. The EBIC suggested that DC should only be considered in “exceptional situations” (Maas et al., 1997).

Discussion

The effectiveness of DC following ABI has been examined in numerous retrospective studies. The majority of these studies reported significant decreases in ICP immediately following the procedure (Aarabi et al., 2006; Bao et al., 2010; Daboussi et al., 2009; De Bonis et al., 2011; Eberle et al., 2010; Goksu et al., 2012; Grindlinger et al., 2016; Ho et al., 2008; Howard et al., 2008; Nambiar et al., 2015; Olivecrona et al., 2007; Polin et al., 1997; Schneider et al., 2002; Skoglund et al., 2006; Soustiel et al., 2010; Stiefel et al., 2004; Timofeev et al., 2008a; Tuettenberg et al., 2009; Ucar et al., 2005; Whitfield et al., 2001; Williams et al., 2009), while only one did not (Munch et al., 2000). Given that the overwhelming number of studies accredit DC with a decrease in ICP, this last study stands as an outlier and its results should be interpreted in the context of the existing data.

In addition to the effects on ICP, several studies reported a change in the CPP of patients after a DC. Of those studies the majority reported an increase in CPP (Bao et al., 2010; Daboussi et al., 2009; Heppner et al., 2006; Ho et al., 2008; Schneider et al., 2002; Soustiel et al., 2010; Stiefel et al., 2004), while a few reported no change (Munch et al., 2000; Olivecrona et al., 2007; Whitfield et al., 2001), or a decrease (Eberle et al., 2010; Nambiar et al., 2015) after receiving a DC post ABI. Given the heterogeneity of results, further research is necessary to ellucidate the effect of DC on CCP.

Considering the intensiveness of DC and its potential complications, evaluating its long-term outcomes is of particular importance. Few studies have reported an association between decreased ICP and improved long-term outcomes (Chibbaro et al., 2008; Galal, 2013; Kim et al., 2009; Nambiar et al., 2015; Skoglund et al., 2006; Williams et al., 2009). Several factors were found to correlate with positive long-term outcomes, including younger age (Chibbaro et al., 2011; Chibbaro et al., 2008; Huang et al., 2013; Limpastan et al., 2013; Meier et al., 2008; Nambiar et al., 2015; Ucar et al., 2005; Williams et al., 2009; Yang et al., 2008; Yuan et al., 2013), higher GCS score (De Bonis et al., 2011; Goksu et al., 2012; Gong J, 2014; Ho et al., 2011; Howard et al., 2008; Huang et al., 2013; Limpastan et al., 2013; Meier et al., 2008; Ucar et al., 2005; Williams et al., 2009; Yang et al., 2008; Yuan et al., 2013), earlier DC (Chibbaro et al., 2011; Chibbaro et al., 2008; Girotto et al., 2011; Polin et al., 1997), and larger DC (Li et al., 2008; Skoglund et al., 2006). Furthermore, certain studies found that DC was associated with improved GOS scores and reduced mortality (Bao et al., 2010; Grindlinger et al., 2016; Kim et al., 2009; Skoglund et al., 2006)() while others reported poor outcomes in the majority of their patients (Aarabi et al., 2006; De Bonis et al., 2011; Eberle et al., 2010; Goksu et al., 2012; Munch et al., 2000; Nambiar et al., 2015; Schneider et al., 2002)(). When interpreting these results, it is important to consider that DC is used to control high ICP refractory to standard treatment, and the poor outcomes reported could be a result of the fragile state that patients were in before the procedure. At this moment however, given the conflicting results, it is unclear if DCs impact long term outcomes and mortality positively or negatively.

Conclusions

There is conflicting level 3 and level 4 evidence regarding whether or not a decompressive craniectomy compared to no treatment effectively reduces elevated intracranial pressure post ABI.

There is conflicting level 4 evidence regarding whether or not a decompressive craniectomy effectively improves cerebral perfusion pressure post ABI.

16.2.4 Multimodal/Combination Therapy

16.2.4.1 Non-Pharmacological Interventions

16.2.4.1.1 Comaprison of Head Elevation

Key Points

Head elevations of 15o and 30o can effectively lower elevated intracranial pressure post ABI; meanwhile, elevations of 45o and 60o might be able to lower elevated intracranial pressure post ABI.

It is unclear whether head elevation causes an improvement in cerebral perfusion pressure post ABI.

Head elevations ranging from 0o-60o may decrease mean arterial pressure post ABI.

For more information on head posture therapies, refer to section 16.2.1.1.

This section speficically focuses on various head elevations and postures as an ICP therapy.

Discussion

Head elevation was found to significantly reduce ICP when compared to a flat position in numerous studies. Reductions in ICP were observed at 15° elevation (Durward et al., 1983; Ledwith et al., 2010; Moraine et al., 2000; Schneider et al., 1993), 30° elevation (Durward et al., 1983; Feldman et al., 1992; Ledwith et al., 2010; Meixensberger et al., 1997; Moraine et al., 2000; Ng et al., 2004; Park & Ha, 1992; Parsons & Wilson, 1984; Rosner & Coley, 1986; Schneider et al., 1993; Schulz-Stubner & Thiex, 2006; Winkelman, 2000), 45° elevation (Kenning et al., 1981; Mahfoud et al., 2010; Moraine et al., 2000; Schneider et al., 1993), and 60° elevation (Mahfoud et al., 2010; Ropper et al., 1982). Several studies reported that reductions in ICP following head elevation were correlated with significant improvements in CPP (Ledwith et al., 2010; Mahfoud et al., 2010; Meixensberger et al., 1997; Moraine et al., 2000; Schulz-Stubner & Thiex, 2006; Winkelman, 2000), although other studies did not find changes in CPP (Durward et al., 1983; Feldman et al., 1992; Ng et al., 2004; Park & Ha, 1992; Parsons & Wilson, 1984; Rosner & Coley, 1986; Schneider et al., 1993).  Only one study reported that head elevation did not improve ICP or CPP (March et al., 1990); due to the small sample size, these results should be taken with caution.

In most studies, a greater degree of elevation was associated with a greater reduction in ICP. For example, Rosner and Coley (1986) found that ICP decreased by 1 mmHg with every 10° of elevation. In an earlier study, however, Durward et al. (1983) found no significant difference in ICP reduction between different degrees of elevation. More recently, Ledwith et al. (2010) suggested that no single position is optimal for improving neurodynamic parameters in those who sustain an ABI. Participants were placed into different positions with three levels of head elevation (15°, 30°, and 45°) in a randomized order. The authors reported significant reductions in ICP with head elevations of 30° and 45° in the supine position and 15° in the right and left lateral positions; all of the reductions were similar in magnitude.

The main concerns associated with head elevation are the development of systemic hypotension, followed by a subsequent decrease in CPP. After reviewing the studies gathered, there does not seem to be a concensus as to the effect of head elevation on CPP. However, 3 studies noted a decrease in mean arterial pressure associated with various head elevations; (15o, 30o, 45o) (Schneider et al., 1993), (30o, 60o)(Mahfoud et al., 2010), and 10o, 20o, 30o, 40o, 50o)(Rosner & Coley, 1986). These findings coupled by the ambiguous results on the effects of CPP suggest that care should be taken to monitor for the development of hypotension during head elevation when treating patients with ABI.

Conclusions

There is level 2 evidence that head elevations of 15° and 30° compared to 0° may, effectively reduce elevated intracranial pressure post ABI when compared to a flat position.

There is level 4 evidence that head elevation of 45o and 60o may effectively reduce elevated intracranial pressure post ABI when compared to a flat position.

There is conflicting (level 2 and level 4) evidence regarding whether or not head elevation can improve cerebral perfusion pressure post ABI.

There is level 4 evidence that head elevation of 10o-60o may decrease mean arterial pressure post ABI.

16.2.4.1.2 Compartative or combined hypothermia with miscellaneous interventions

Key Points

Therapeutic hypothermia, either intracranial pressure or oxygenation managed, may improve intracranial pressure, morbidity and mortality in individuals with an ABI.

Selective, long-term hypothermia can be more effective than systemic, short-term hypothermia in improve intracranial pressure and long-term outcomes in ABI patients.

Hypothermia combined with standard therapy may be more effective than hypothermia alone at improving intracranial pressure, cerebral perfusion pressure and oxygenation in ABI patients.

Hypothermia can be explored further in section 16.2.1.2. This section focuses on the various techniques to control temperature at which ABI patients were treated to investigate effect on ICP.

Discussion

In the reviewed studies, therapeutic hypothermia involved cooling patients to 32-36°C for at least 12 hours. The results of two studies suggested that very mild hypothermia (35-36°C (Tokutomi et al., 2009); 35-37oC (Maekawa et al., 2015), may be just as effective as mild hypothermia (32-34°C) at improving ICP.  However, while Tokutomi et al. reported fewer complications and mortality, Maekawa et al. found no differences in rates of good outcome and mortality between conditions. A post-hoc analysis of Maekawa et al. fruther stratified patients by diffuseness of injury and noted a decrease in ICP in ABI patients with diffuse II injury, and an increased rate of mortality in diffuse III injury after mild hypothermia treatment (Suehiro et al., 2015). The findings of this post-hoxc analysis suggest that even even though mild hypothermia may be just as effective in reducing ICP and potentially improving morbity and mortability, cooler temperatures may be necessary for specific type of ABIs

Similarly, the length of time in hypothermia varied greatly between studies, ranging from one to 14 days. One trial reported that hypothermia delivered over five days, using cooling blankets, showed a greater ICP reduction and more favourable long-term outcomes than a two-day treatment (Jiang et al., 2006). Furthermore, most studies utilized systemic hypothermia, which was achieved with cooling blankets and/or gastric lavage. Only a few studies delivered selective hypothermia which may yield greater improvements in ICP and other outcomes when compared to systemic treatment (Liu et al., 2006).

Four studies compared either therapeutic hypothermia to conventional treatment, or hypothermia and standard care to controls (Andrews et al., 2015; Flynn et al., 2015; Polderman et al., 2002). Two of the studies found a significant decreased in ICP in the hypothermia group compared to the conventional treatment group (Andrews et al., 2015; Flynn et al., 2015; Polderman et al., 2002). However, the largest study, a high quality RCT, reported no difference between the groups in ICP, MAP, CPP (Andrews et al., 2015; Flynn et al., 2015; Polderman et al., 2002) . Conflicting results were also reported in regards to mortality and morbidity outcomes with mortality and GOS scores inproving in one (Andrews et al., 2015; Flynn et al., 2015; Polderman et al., 2002), and negative outcomes (GOSE) and mortality increasing in another (Andrews et al., 2015; Flynn et al., 2015; Polderman et al., 2002).In the combinational study, ICP, CPP, and oxygenation improved significantly more in the hypothermia + 25 g manntiol group compared to hypothermia alone (Sun et al., 2016). A rebound of all measured parameters occured after 90 min, however it was found that this could be avoided by increased the dose of mannitol to 50 g.

One study stands alone in the protocol it employed. Lee at al. (2010)compared controls to both ICP/CPP-managed, and brain tissue oxygen managed hypothermia. Irrespective of the treatment, both treatment groups had significantly lower ICP and displayed a trend towards lower mortality compared to controls. However, no significant differences were found between treatment groups in any parameter reported.

Conclusions

There is conflicting (level 1b and level 2) evidence that therapeutic hypothermia may improve intracranial pressure compared to controls in ABI patients.

There is level 1b evidence that hypothermia interventions may be more effective at decreasing intracranial pressure and improving long-term outcomes when administered for long-term (120 h) compared to short term (48 h)

There is level 1b evidence that intracranial pressure/cerebral perfusion pressure and brain tissue oxygen managed hypothermia are similar at reducing intracranial pressure in individuals with an ABI when compared to controls.

There is level 2 evidence that selective hypothermia may be superior to systemic hypothermia in improving intracranial pressure post ABI when compared to controls.

There is level 4 evidence that hypothermia treatment combined with mannitol may be more effective at sustaining improved intracranial pressure, cerebral perfusion pressure, and oxygenations compared to hypothermia alone post ABI.

16.2.4.1.3 Combination or comparative hyperventilation treatment modalities

Please refer to section 16.2.1.3 for additional hyperventaliation therapies. This section focused on combined treatments for ICP.

Discussion

Potential detrimental effects following hyperventilation are particularly concerning in ABI, and the issue has been addressed in two earlier studies. In a small retrospective study, Thiagarajan et al. (1998) noted that hyperoxia (PaO2=200-250 mmHg) was able to counteract the reduced cerebral oxygenation following hyperventilation. In a large clinical trial, Muizelaar et al. (1991) evaluated the effects of prolonged hyperventilation in combination with intravenous tromethamine. Long-term outcomes were significantly better in individuals who received the combination therapy than those who received hyperventilation alone and similar to those who received normal ventilation. The authors suggested that the presence of a buffer system, such as tromethamine, can help neutralize cerebral bicarbonate depletion due to hyperventilation.

16.2.4.1.4 Comparative Rotational Therapy and Prone Positioning

Key Points

Manipulation of body positions may increase intracranial pressure more than the supine position.

Rotational therapy versus other therapies can be explored further in section 16.2.1.4. This section focuses on various head elevations in relation to their effects on ICP.

Discussion

A single case study was identified investigating the effects of different body positions on ICP (Lee, 1989). Compared to the supine positioin, all other positions, supine with head down 30º; 75% supine; and 75% prone significantly increased ICP. The results of this early study suggest that manipulating body position during the acute stages post ABI should not be considered, as changes may increase ICP and have detrimental squelae.

Conclusions

There is level 4 evidence that the positions supine with head down 30º; 75% supine; and 75% prone may increase intracranial pressure more than the supine position in patients post ABI.

16.2.4.2 Pharmacological Interventions

16.2.4.2.1 Osmolar Therapies

16.2.4.2.1.1 Comparative or combination Hypertonic Saline therapies

Key Points

Hypertonic saline may or may not lower intracranial pressure, and reduce hospital length of stay, but 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 has similar effects on intracranial pressure and clinical out comes when compared to Ringer’s lactate solution.

Hypertonic saline may have similar effects on intracranial pressure when compared to sodium bicarbonate.

Hypertonic saline (HTS) exerts its effect mainly by increasing serum sodium concentrations and plasma osmolarity, thereby increasing the osmotic gradient between the intracellular and extracelullar compartments. This section reviews varying dosages or concentrations of HTS, please refer to section 16.2.2.1.1 for additional information.

Discussion

In a trial by Baker et al. (2009), HTS-dextran solution showed greater reductions in ICP compared to those receiving normal saline solution, as well as better control of inflammation that may lead to secondary brain injury.

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), and one noted 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 barbituaries (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 lenght of hospitalization compared to manntiol.   In an 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 different 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).

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 lenght 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)

Hypertonic saline has also been compared to Ringer’s lactate solution for acute management of ABI. In an early RCT, Shackford et al. (1998) reported that both treatments lead to reductions in ICP and improvements in GOS, without any significant differences between them. The authors also found that those treated with HTS required a significantly greater number of additional medical interventions to lower ICP. However, it should be noted that they had a significantly greater number of patients with severe ABI. In a later RCT, Cooper et al. (2004) found that patients receiving either treatment were similar in terms of survival, favourable outcome, cognitive functioning, functional independence, and return to work at three to six months.

Furthermore, sodium bicarbonate solutions have been compared to HTS for managing acute ABI. In a small trial, Bourdeaux et al. (2011) reported that sodium bicarbonate yielded similar ICP reductions to HTS, but that these reductions were longer lasting. Additional studies are required to determine the efficacy of albumin and sodium bicarbonate in controlling elevated ICP and improving long-term outcomes post ABI.

Conclusions

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

There is level 1b evidence that the use of hypertonic solution results in similar ICP clinical outcomes when compared to Ringer’s lactate solution post ABI.

There is level 1b evidence that the use of hypertonic solution may be more effective than mannitol in increasing cerebral perfusion pressure, cerebral blood flow, and brain tissue oxygen tension.

There is level 2 evidence that the use of hypertonic soluion may be similar to Ringer’s lactate solution and sodium bicarbonate in lowering elevated intracranial pressure.

16.2.4.2.1.2 Comparative or combination Mannitol therapies

Key Points

Mannitol effectively decreases intracranial pressure post ABI, but can increase urine output and plasma sodium and chloride; furthermore, high doses may yield improved intracranial pressure control, lower mortality rates and better clinical outcomes compared to lower doses.

Mannitol may be equally effective as hypertonic saline at reducing intracranial pressure and cerebral perfusion pressure, and less effective than Ringer’s (sodium) lactate at reducing intracranial pressure.

Rapid administration of mannitol is among the first-line treatments recommended for the management of increased ICP.  This section reviews varying dosages or combination therapies involving mannitol, please refer to section 16.2.2.1.2 for additional information.

Discussion

Overall, a large proportion of studies reported that mannitol is effective in significantly reducing ICP (Cruz et al., 2001, 2002; Cruz et al., 2004; Francony et al., 2008; Ichai et al., 2009; Scalfani et al., 2012; Sorani et al., 2008). Consequently, some studies went on to further contrats the therapeutic difference between high and low doses of mannitol in treating ABI patients. Cruz and colleagues conducted three separate trials to investigate the effects of high dose mannitol on clinical outcomes in patients with ABI at six months post injury (Cruz et al., 2001, 2002; Cruz et al., 2004). All three trials reported that high dose mannitol (1.4 g/kg) was superior to conventional mannitol (0.7 g/kg) in lowering elevated ICP and improving clinical outcomes. Further supporting the benefits of high-dose over low-dose mannitol, Sorani et al. (2008) found that for every 0.1 g/kg increase in mannitol dosage there was a 1.0 mmHg drop in ICP.

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

Three studies analyzed compared mannitol to either HTS or Ringer’s (sodium) lactate as therapy for ABI.

Francony et al. (2008) found that equimolar doses of mannitol and HTS were comparable in reducing ICP in stable patients with intact autoregulation post ABI. Mannitol was shown to improve brain circulation through possible improvements in blood rheology, however treatment also significantly increased urine output. The authors suggested that both treatments may be effective, but patient pre-treatment factors should be considered before selection. A second study reported that while mannitol significantly decreased ICP, increased CPP, and stabalized mean arterial pressure, saline treatment yielded the same results with no inter-group differences reported (Scalfani et al., 2012). The results from these studies suggest mannitol and HTS may have similar abilities to improve ICP and CPP, and given the favored safety profile of saline, HTS may become the preferred osmolar treatment for ABI.

In another trial, Ichai et al. (2009) reported that an equimolar dose of Ringer’s (sodium lactate) had a significantly greater effect on lowering elevated ICP that lasted longer than treatment with mannitol. Sodium lactate was also successful in reducing elevated ICP more frequently. Based on these results, further research into the effectiveness of sodium lactate in reducing ICP is warranted.

Conclusions

There is level 1b evidence that mannitol is no more effective than hypertonic saline in improving intracranial pressure or cerebral perfusion pressure in individuals with an ABI.

There is level 1b evidence that mannitol is less effective than Ringer’s (sodium) lactate in controlling elevated intracranial pressure post ABI.

There is level 2 evidence that early versus late administration of mannitol may not effectively lower elevated intracranial pressure in individuals with an ABI, but does not adversely affect blood pressure.

16.2.4.2.10 Other Medications

Key Points

Conivaptan may be similar to standard therapy at lowering intracranial pressure post ABI.

Vasopressin and catecholamine treatments may be similar for improving intracranial pressure.

In addition to the aforementioned medications, other pharmacological interventions have been evaluated for effectiveness in reducing elevated ICP post ABI, including analgesics, hormones, and selective inhibitors.

Discussion

In a small clinical trial, conivaptan demonstrated decreased ICP and increased serum sodium post ABI when compared to standard acute care, which included osmolar therapy, sedation, analgesia, and/or head/body positioning (Galton et al., 2011). In a later trial, it was reported that vasopressin and catecholamine treatment yielded similar improvements to ICP and CPP post TBI (Van Haren et al., 2013). In addition, there was no significant differences in morbidity and mortality between treatments as demonstrated by similar hospital LOS, and mortality between groups. Given the limited research on each of these medications, additional clinical trials are required to make firm conclusions.

Conclusions

There is level 1b evidence that conivaptan may be similar to standard care (e.g. osmolar therapy, sedation, analgesia) in lowering elevated intracranial pressure post ABI.

There is level 1b evidence that vasopressin and catecholamine may be similarly effective in lowering elevated intracranial pressure post ABI.

16.2.4.2.2 Multimodal Propofol Interventions

Key Points

Propofol, especially at higher doses, can improve intracranial pressure and cerebral perfusion pressure more effectively than morphine. When used in conjunction with morphine, propofol may reduce the need for other intracranial pressure interventions.

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

Propofol is a fast-acting sedative that is absorbed and metabolized quickly, leading to pronounced effects of short duration. This section reviews varying dosages or combination therapies involving propofol, please refer to section 16.2.2.2 for additional information.

Discussion

Three studies comparing the effects of propofol to other sedatives. The most recent study,  a crossover RCT, treated ABI patients with either propfol or dexmedetomidine intially, 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 profolol 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- specially 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 1b evidence that propofol may reduce intracranial pressure and the need for other intracranial pressure-decreasing interventions when used in conjunction with morphine compared to when used alone post ABI.

There is level 1b evidence that propofol may be more effective at reducing intracranial pressure compared to morphine, especially at high propofol doses, 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.

16.2.4.2.3 Multimodal Midazolam Interventions

Key Points

Midazolam may not be different from propofol in its effect on intracranial pressure, cerebral perfusion pressure, or long term outcomes, but may cause longer wake-up times.

Midazolam is a fast-acting benzodiazepine with a short half-life and inactive metabolites (McCollam et al., 1999). This section compares the use of midazolam alone, or in comgination with other pharmacological agents to improve ICP outcomes. Please refer to section 16.2.2.3 for further interventions.

Discussion

One study was reviewed comparing midazolam and propofol interventions in ABI patients. 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). Furthermore, all 3 treatments had similar incidences of adverse effects, with the exception of the high levels of triglycerides found in patients receiving propofol.

Conclusions

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

16.2.4.2.4 Comparative or combined Opioid Interventions

Key Points

Different opioids may have different intracranial pressure and cerebral perfusion pressure effects post ABI; where fentanyl, morphine, sufentanil, and alfentanil might increase intracranial pressure and decrease cerebral perfusion pressure, remifentanil may not affect intracranial pressure compared to controls.

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

This section reviews varying dosages or concentrations of opioids for ICP management, please refer to section 16.2.2.4 for additional information.

Discussion

Analgesic sedation with opioids is commonly used in conjunction with hypnotic agents (i.e., midazolam, propofol) to reduce nociceptive stimulation, which makes it difficult to evaluate the effects of opioids in isolation. However, it has been reported that using an opiod such as sufentanil with midazolam significantly improves ICP for a prolonged period of time (2 d), albeit at the expense of decreasing mean arterial pressure (MAP)(Scholz et al., 1994).

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 opiod administration (Albanese et al., 1999; de Nadal et al., 2000; Sperry et al., 1992). To note, 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 opiod treatment.

The remaning three 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).

Conclusions

There is conflicting level 1a and level 1b evidence as to whether morphine, fentanyl, and sufentanil increase intracranial pressure, and decrease cerebral perfusion pressure, compared to controls post ABI.

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 4 evidence that sufentanil with midazolam decreases intracranial pressure and mean arterial pressure post ABI.

16.2.4.2.5 Comparative or combined barbiturate interventions

Key Points

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

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

Barbiturates have long been proposed as a useful intervention in the control of ICP. They are thought to reduce ICP by suppressing cerebral metabolism,  reducing metabolic demands and decreasing cerebral blood volume (Roberts, 2000). This section reviews varying dosages or concentrations of barbituates for ICP management, please refer to section 16.2.2.5 for additional information.

Discussion

The findings of an RCT by Eisenberg et al. (1988) suggested that pentobarbital was an effective adjunctive therapy for the management of elevated ICP refractory to conventional therapeutic measures. However, this study only supported the use of the high dose barbiturate for a small subgroup of patients with severe ABI (GCS≤7). In contrast, the findings of an RCT by Ward et al. (1985) suggested that pentobarbital was no better than conventional ICP management measures; a finding which was corroborated by Schwartz et al. (1984) in an 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. More recently, Majdan et al. (2013) found that barbiturate administration was associated with a significant increase in the amount of time spent with low MAP, despite a decrease in the amount of time with elevated ICP. Furthermore, the authors reported that high doses of barbiturate were associated increased intubation days, days in the ICU, and did not improve clinical outcomes.

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

Llompart-Pou et al. (2007) found thiopental less likely to induce adrenal insufficiency when compared to pentobarbital, further supporting its use when barbiturate coma is indicated. It should be noted that in an earlier study, Stover 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 conflicting (level 1b and level 2) evidence regarding whether or not pentobarbital improves intracranial pressure compared to conventional management measures post ABI.

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

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

16.2.4.2.6 Dual Cannabinoid Dosage Interventions

Key Points

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

This section examines dual cannadinoid dosage interventions for ICP management. Please refer to sections 16.2.2.6 for additional interventions.

Discussion

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 level 1b evidence that high-dose KN38-7271 (a dual cannabinoid agonist) may increase intracranial pressure and cerebral perfusion pressure, and improves survival post TBI compared to low-dose KN38-7271.

16.2.4.2.7 Comparative Dosage for Corticosteroid Treatment

This section examines the use of low dose versus high dose dexamethasone for ICP management.

Discussion

Cooper et al. (1979) studied the effects different doses of dexamethasone had on lowering ICP, and neurological outcomes (GOS) compared to placebo. It was reported that irrelevant of the dose of dexamethasone received (low or high), there were no significant differences between groups in terms of ICP of neurological outcomes at 6 months.

Although caution should be taken when drawing conclusions from a single study, this early RCT calls into question the efficacy of corticosteroids in ICP reduction post ABI. Numerous studies were conducted after the release of this one to study the morbidity and mortality associated with steroid use post ICP, and these findings will be discussed in later sections. Given the result of this study, and the lack of other studies evaluating the ICP-lowering effects of corticosteroids, it can be assumed that corticosteroids are not effective agents in lower ICP post ABI.

16.2.4.2.8 Multimodal Bradykinin Antagonist Interventions

This section examines the use of varying dosages of bradykinin antagonist agents for ICP management. Please refer to section 16.2.2.8 for additional information.

Discussion

Anatibant is believed to be a more potent bradykinin antagonist than Bradycor, and was evaluated by Marmarou et al. (2005). Due to 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.

16.2.4.2.9 Comparative Dimethyl Sulfoxide Dosage Interventions

This section examines varying doses of dimethyl sulfoxide for ICP management. Please refer to section 16.2.2.9 for additional interventions.

Discussion

Marshall et al. (1984) observed the effects of using DMSO on ABI patients. 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.

16.2.4.3 Comparative Surgical Interventions

16.2.4.3.1 Cerebrospinal Fluid Drainage

Key Points

Ventricular cerebrospinal fluid drainage, regardless of amount drained, can effectively lower elevated intracranial pressure post ABI.

Continuous cerebrospinal fluid drainage may be more effective than intermittent drainage at acutely lowering elevated intracranial pressure post ABI, with no differences existing in long-term outcomes.

Intraparenchymal fiber optic monitors may be superior to external ventrical drains in monitoring intracranial pressure, preventing complications, and reducing the need for further treatment; however, there may be no differences in long term between devices.

This section examines the use of varying drainage protocols with respect to ICP management. Please refer to section 16.2.3.1 for additional information on CSF drainage.

Discussion

In previous sections the efficacy of CSF drainage was discussed and the conclusion was reached that both ventricular and lumbar drainage are effective ICP-lowering mechanisms post ABI. However, how much CSF to drain, and in which manner, to produce optimal results was not clear from the studies analyzed.

 

A case-control study examining drainage frequency showed that continuous treatment demonstrated significantly greater reductions in ICP than intermittent treatment (Nwachuku et al., 2014). However, both treatments yielded comparable long-term outcomes and required similar therapeutic intensity levels. In a prospective trial evaluating drainage intensity, Kerr et al. (2001) randomized patients to have different amounts of CSF drained. The authors found that all patients experienced significant decreases in ICP and increases in CPP in the short term, regardless of the fluid amount drained. As such, ventricular CSF drainage, regardless of amount, is a feasible treatment when elevated ICP remains refractory to other interventions.

The effectiveness of an external ventricular drain (EVD) in managing elevated ICP when compared to an intraparenchymal fiberoptic monitor (IPM) is currently unclear. The results from a large retrospective study found the EVD to be inferior to the IPM (Kasotakis et al., 2012). While there were no significant differences between treatments in terms of mortality and long-term outcomes, the EVD had significantly higher rates of surgical decompression and device-related complications. In addition, the authors also found that the EVD required longer ICP monitoring and ICU stay than the IPM.

Conclusions

There is level 1b evidence that ventricular cerebrospinal fluid drainage, regardless of amount drained, may effectively lower elevated intracranial pressure, and may increase cerebral perfusion pressure post ABI.

There is level 3 evidence that continuous cerebrospinal fluid drainage is superior to intermittent cerebrospinal fluid drainage at lowering intracranial pressure post ABI compared to intermittent drainage.

There is level 3 evidence that an intraparenchymal fiberoptic monitor may yield lower intensive care unit length of stay, device complications, need for surgical decompressions, and need for intracranial pressure monitoring compared to an external ventrical drainage post ABI.

16.2.4.3.2 Decompressive Craniectomy

Key Points

Decompressive craniectomy is more effective than standard treatment at reducing intracranial pressure; however, it is unclear which treatment best improves morbidity and mortality post ABI.
Initial Glasgow Outcome Scale score, but not intracranial pressure monitoring post decompressive craniectomy, may be a predictor for improved outcomes in patients post ABI.

Decompressive craniectomy may be similar to controlled decompression in reducing elevated intracranial pressure and improving Glasgow Outcome Scale scores.

Standard craniectomy with a larger bone flap is likely more effective than limited craniectomy with a smaller bone flap in terms of intracranial pressure reduction and favourable outcome.

Decompressive craniectomies and craniotomies may be similar at reducing ICP post ABI, but DC could be superior at improving good outcomes. It is unclear which procedure improves mortality the most.

This section examines the use of combination or comparision surgical protocols with respect to ICP management. Please refer to section 16.2.3.2 for additional information on decompressive crainectomy.

Discussion

The effectiveness of DC following an ABI has been previously discussed, with evidence pointing to DC being an effective treatment for lowering ICP. A couple of studies delved further and compared patients who received DC to those treated with standard therapy and found that DC more effectively lowers ICP, and the time spent with cranial hypertension (ICP>20 mmHg; (Cooper et al., 2011; Hutchinson et al., 2016a). Furthermore, one study noted a decrease in hospital LOS (Hutchinson et al., 2016b) while both associated DC with an increase in poor outcomes (GOSE<4) compared to standard care. It is worth noting however that in Cooper et al., after controlling for age and intial GCS scores, there was no longer a significant difference in poor outcomes between treatments. There was less agreement however as to which treatment was superior at improving mortality, with one study reporting a decrease in mortality up to a year after DC (Hutchinson et al., 2016a) and the other finding no difference in mortality between treatments (Cooper et al., 2011). There were a number of concerns regarding the methodological quality of the Cooper et al. trial, including time to randomization, length of accrual, initial group differences, timing of DC, and DC technique (Cooper et al., 2011). As well, the ICP threshold was deemed too low (>20 mmHg for >15 min) such that standard medical management was not fully exhausted. As a result, conclusions from this study should be drawn with caution.

Decompressive craniectomies are performed after standard treatment has been exhausted and ICP control has not yet been achieved. However, craniotomies, or the prophylactic removal of skull sections, have recently been compared to DCs to explore their viability in treating ABIs. Girotto et al. (2011) compared patients receiving either a DC or craniotomy to those receiving standard therapy alone, and found that patients who underwent surgery spent significantly less time in cranial hypertension (ICP>25 mmHg). Furthermore, a second study went on to directly compare DC (>24 h, refractory to first line treatments) to a craniotomy (<24 h) and concluded that treatments were not different in their ability to decreased ICP post ABI (Al-Jishi et al., 2011). While the procedures similarly lowered ICP, they differed in their morbidity and morality outcomes. Decompressive craniectomies were associated with better GOS scores and good outcomes, however conflicting results exist regarding their benefit on patient mortality. Given the available data, and considering the intrusiveness and potential complications of removing bone fragments from the skull, it is suggested that DCs remain a last line intervention to ICP refractory to first line treatment.

More recently, researchers have published the results of clinical trials evaluating long-term outcomes following DC. A retrospective study analyzed patients who has undergone a DC, and found that only the patient’s initial GCS score was associated with favourable outcomes post DC (Howard et al., 2008). When compared to controlled decompression, one trial found that DC was just as effective in reducing elevated ICP and improving GOS score (Wang et al., 2014). The impact of bone flap size was investigated in two other trials (Jiang et al., 2005; Qiu et al., 2009). Participants received either standard trauma craniectomy with a unilateral frontotemporoparietal bone flap (12x15cm) or limited craniectomy with a routine temporoparietal bone flap (6x8cm). Both studies reported that significantly more patients in the former group showed favourable outcomes on the GOS than those in the latter group at six months (Jiang et al., 2005) and one year (Qiu et al., 2009). As well, ICP fell more rapidly and to a lower level following standard craniectomy than limited craniectomy (Jiang et al., 2005; Qiu et al., 2009). Finally, researchers investigated the need to provide ICP monitoring post DC to optimize patient outcomes (Aarabi et al., 2009). No differences were observed between DC + ICP monitoring and DC monitoring alone in terms of survival or outcomes.

Conclusions

There is level 1a evidence that decompressive craniectomy may be more effective than standard care at reducing elevated intracranial pressure post ABI.

There is level 1b evidence that a decompressive craniectomy may be similar to controlled decompression in reducing elevated intracranial pressure and improving Glasgow Outcome Scale scores post ABI.

There is level 1b evidence that a decompressive craniectomy with a unilateral frontotemporoparietal bone flap (12x15 cm) may be superior to a limited decompressive craniectomy with a temporoparietal bone flap (6x8 cm) in lowering intracranial pressure and improving Glasgow Outcome Scale scores post ABI.

There is level 3 evidence that decompressive craniectomy and craniotomy interventions may be similar at decreasing intracranial pressure post ABI.

There is conflicting (level 3) evidence as to whether decompressive craniectomies have better mortality outcomes compared to a craniotomy post ABI.

16.3 Prompting Emeregence from Coma

Consciousness is composed of two distinct dimensions: arousal (i.e., wakefulness or vigilance) and awareness (i.e., knowledge of self and environment) (Zeman, 2006). Disorders of consciousness (DOC) are a spectrum of medical conditions that inhibit elements of consciousness (Schiff & Plum, 2000), and include the following:

  • Coma: a state of complete unconsciousness, lacking both arousal and awareness (Posner & Plum, 2007).
  • Vegetative state: a state of arousal without awareness, considered “persistent” when lasting longer than one month (Jennett, 2002).
  • Minimally conscious state: a state of arousal with limited but discernable awareness (Giacino et al., 2002).

DOC present clinical challenges in both the diagnosis and treatment of patients following brain injury, and thus significantly impact outcomes in acute care (Nakase-Richardson et al., 2012).

 

Guideline Recommendations

The Royal College of Physicians (RCP) in the UK developed a set of guidelines for the diagnosis and management of DOC, in order to update and replace a previous report from 2003 (Prolonged disorders of consciousness: National clinical guidelines, 2013). We have added these recommendations into our evaluation of each intervention, but our conclusions are based on our methodology and have not been influenced by the guidelines. The RCP provided descriptive guidelines but did not incorporate levels of evidence.

16.3.1 Non-Pharmacological Interventions

16.3.1.1 Sensory Stimulation

Key Points

Auditory sensory stimulation may change sensory stimulation assessment meaure and Disability Rating Scale, but not Glasgow Outcome Scale scores.

Multi-sensory stimulation may not cause physicological or biochemical arousal, although the effect on heart rate is unclear.

Multi-sensory stimulation may not improve emergence or recovery from coma post ABI.

It has been reported that one in eight patients with severe closed head injury suffer from prolonged coma and vegetative state following their injury (Levin et al., 1991). It has also been estimated that 50% of survivors from severe brain injuries who are in a vegetative state regain consciousness within one year of their injury, with up to 40% subsequently improving to a higher level on the Glasgow Outcome Scale (Multi-Society Task Force on PVS, 1994). The theory that sensory stimulation could enhance the speed and degree of recovery from coma has gained traction as a viable treatment post ABI. Early studies employed a single stimuli to a single sense (unimodal stimulation), whereas more current studies have focused on stimulation to all the senses using various stimuli (multimodal stimulation). These studies have evaluated stimulation of several modalities: visual, auditory, tactile, olfactory, gustatory, kinesthetic, proprioceptive, and vestibular.

We identified two systematic reviews evaluating the effectiveness of sensory stimulation in improving consciousness of individuals in a coma or vegetative state following ABI. In a Cochrane review, Lombardi et al. (2002) identified three clinical trials with a total of 68 patients. The studies were found to be of poor quality and there was considerable diversity between them in terms of experimental design and conduct. Due to the lack of consistent outcome measures in these studies, a quantitative meta-analysis could not be conducted. The authors concluded that there was no reliable evidence supporting the efficacy of intensive multisensory stimulation programs. They recommended that larger multicenter RCTs be conducted with rigorous methodology and specific outcomes for impairment and disability. However, in a more recent review, Padilla and Domina (2016) found strong evidence for multisensory stimulation improving arousal and enhancing clinical outcomes. The authors recommended early, frequent, and sustained stimulation that is tailored to patient tolerance and preferences.

The RCP reported a lack of high-quality research regarding sensory stimulation programs for patients with DOC (Prolonged disorders of consciousness: National clinical guidelines, 2013). However, the authors noted that such programs may provide the best opportunities to observe recovery in patients. It was recommended that stimulation focus on pleasurable and familiar sensations that are presented discretely, in order to detect individual effects and minimize overstimulation.

Discussion

One of the major challenges for evaluating the efficacy of sensory stimulation in promoting recovery of consciousness is that outcome assessment measures are often qualitative and difficult to assess. In addition, stimulation protocols vary greatly between studies making comparisons and conclusions difficult and conditional.

A single study was reviewed that investigated the effects of a structured auditory sensory stimulation program (5-8x/d for 5-15min each up to 7d days) on patients post ABI (Davis & Gimenez, 2003). The researches reported no significant difference between groups in GCS scores, however they did note that both DRS scores and SSAM scores had a significant greater change in the treatment group compared to the control group.

Recently, focus has shifted from stimulation of a single sense to multi-sensory stimulation as a means of arousing patients from a coma post ABI. Of the 3 studies analyzed, 2 groups quantified the response to the multimodal stimulation by measuring either physiological (Gruner & Terhaag, 2000; Johnson et al., 1993), or biochemical (Johnson et al., 1993) parameters. After multimodal stimulation Johnson et al. only reported a change in the plasma concentration of MHPG, a metabolite of norepinephrine and an indicator of recent sympathetic nervous sytem arousal, but found no differences in heart rate, skin conductance, or concentration of molecules associated with sympathetic nervous system activation (serotonin, catecholamines, AChase). Interestingly, Gruner & Terhaag did note that multimodal stimulation caused a change in heart and respiratory rate frequencies, however no statistical tests were performed. The difference in results could be attributed to the lack of appropriate statistical tests in Gruner & Terhaag, as the observed change could be non-significant. In addition, the protocols employed by the different studies were different; while both interventions stimulated the 5 senses (olfactory, visual, auditory, gustatory, and tactile) the treatment in Johnson et al. involved stimulation for 20 min/d during ICU stay, compared to 1 hr, 2 x/d for 10 d (1-30 d) in Gruner & Terhaag. The last study that looked at multi-sensory stimulation discussed the efficacy of the intervention (multimodal stimulation by close family for up to 8 hr/d and 7 d/wk, continuing until conventional rehabilitation) in the context of morbidity outcomes (Pierce et al., 1990). The study found no difference in emergence from coma, GOS scores, or recovery rate in patients receiving treatment when compared to those who did not (Pierce et al., 1990).

Based on the currently reviewed studies, it is difficult to support any uni or multimodal stimulation protocols as effective interventions in the arousal of patients from a coma post ABI.

Conclusions

There is level 2 evidence that structured auditory sensory stimulation may improve Sensory Stimulation Assessment Measure and Disability Rating Scale, but not Glasgow Outcome Scale scores compared to controls in individuals in a coma post ABI.

There is level 3 evidence that multi-sensory stimulation has no effect on emergence from coma, Glasgow Outcome Scale scores, or recovery post ABI compared to controls.

There is conflicting (level 3 and level 4) evidence that multi-sensory stimulation may reduce heart rate in patients in a coma post ABI.

There is level 4 evidence that multi-sensory stimulation may reduce respiratory frequency in patients in a coma post ABI.

16.3.1.2 Music Therapy

Key Points

Music therapy may improve consciousness in individuals in a coma post ABI.

Musical sounds stimulate the auditory pathway and activate an emotional response in the brain (Sun & Chen, 2015).  If the music is familiar to the patient, then the stimuli can become meaningful for them.  Anecdotally, it has been noted that music encourages arousal from coma post ABI. We identified two studies which used music therapy as a specific treatment for this purpose, these are presented in Table 16.38.

The RCP made no specific recommendations regarding the use of music therapy for the recovery of consciousness post ABI.

Discussion

In a prospective trial conducted by Sun and Chen (2015), participants were subjected to either musical stimuli or silence. While the authors reported that GCS scores and brain electrical activity improved in both groups, the increases were significantly greater in those that received musical stimuli. The promising results of this study suggest that music therapy may improve outcomes and warrants future research. In addition, the study proposes the use of the QEEG as a means of objectively quantifying brain activity and has the potential to be an effective tool in monitoring recovery from coma in patients post ABI.

Conclusions

There is level 2 evidence that musical therapy may improve consciousness and brain activity compared to silence in individuals in a coma post ABI.

16.3.1.3 Electrical Stimulation

Key Points

Median nerve stimulation may increase cerebral perfusion pressure and dopamine levels in individuals in a coma post ABI.

The effects of median nerve electrical stimulation on consciousness and arousal from coma in individuals in a coma post ABI is unclear.

Electrical stimulation is a common therapeutic approach used in the rehabilitation of a variety of neurological diseases. Some reports have proposed that electrical stimulation may be beneficial in patients with severe ABI. It is believed that electrical stimulation applied peripherally may stimulate the reticular activating centre and cortical areas responsible for consciousness and arousal (Peri et al., 2001). Furthermore, stimulation of the median nerve has been shown to cause significant increments in blood flow and improved electroencephalogram activity (Cooper et al., 1999).

The RCP reported that the research regarding neurostimulation, including electrical stimulation, only showed modest results in recovery of consciousness (Prolonged disorders of consciousness: National clinical guidelines, 2013). The authors cautioned against the use of invasive techniques, such as those that involve electrode implantation, due to significant ethical concerns. As such, it was recommended that neurostimulation only be used as part of an approved and registered clinical trial.

Discussion

Three studies investigating the efficacy of median nerve electrical stimulation in promoting emergence from coma were identified. In the first of these studies, the authors reported that patients treated with stimulation showed better improvements on the GCS and GOS as well as shorter lengths of stay in the intensive care unit when compared to sham-stimulated controls (Cooper et al., 1999). However, the lack of statistical group comparisons weakens any conclusions that could be drawn from these findings. In a high quality RCT, Peri et al. (2001) found that median nerve electrical stimulation did not significantly improve the duration of coma, GOS scores, or functional independence/assessment measure scores over sham stimulation. The differences in results between the studies could be attributed to either the lack of statistical analysis of the Cooper et al. study, and/or the difference in protocols employed by the groups.  Further RCTs with greater sample sizes are required to appropriately draw conclusions regarding median nerve electrical stimulation and consciousness/ arousal outcomes.

Liu et al. (2003) employed a single group design and reported that median nerve electrical stimulation caused considerable increments in CPP. They also found elevations in dopamine levels, which may been involved in the regulation of consciousness (Krimchansky et al., 2004). However, the authors failed to demonstrate a direct correlation between dopamine levels and increased levels of consciousness.

Conclusions

There is conflicting level 1b and level 2 evidence that median nerve electrical stimulation may not improve consciousness and arousal from coma compared to sham post ABI.

There is level 4 evidence that median nerve electrical stimulation may increase cerebral perfusion pressure and dopamine levels in individuals in a coma post ABI.

16.3.1.4 Physiotherapy

The physical rehabilitation of patients has been found to be vital in the recovery of movement, balance, coordination and cognitive function post ABI (Aboulafia-Brakha & Ptak, 2016; Lendraitiene et al., 2016). In addition, physical therapy has the benefit of serving as a preventative measure against comlications such as pneumonia and thromboembolisms (Lendraitiene et al., 2016). We identified one study which observed the effects of physiotherapy on patient outcomes in both the acute and post-acute phase of ABI.

Discussion

Physical rehabilitation has been credited with improiving both motor and cognitive outcomes post ABI. An RCT by Lendraitiene et al. found that patients who spent 1 or 2 weeks in a coma, significantly improved their motor (MAS) and cognitive (MMSE) scores after physiotherapy. Interestingly, MAS scores were improved significantly more in the group of patients who had been in a coma for up to one week, compared to those who had been in a coma for 2 weeks or more.

16.3.2 Pharmacological Interventions

16.3.2.1 Amantadine

Key Points

Amantadine improves consciousness, cognitive function, disability, but not emergence from coma post ABI.

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 is now commonly 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., 1999). Researchers believe that amantadine could significantly improve arousal in patients who are comatose. Potential side effects include over-stimulation, peripheral edema, livido reticularis, and lowering of the seizure threshold; however these are easily reversible (Schneider et al., 1999). 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 studies that assessed amantadine were 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 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 significantly inmproved 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 when 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.

Conclusions

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

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

16.3.2.2 Other Medications

Key Points

Citicoline and antiepileptics may not be effective interventions for restoring consciousness post ABI. However, further research is required.

In addition to amantadine, other pharmacological interventions have been evaluated for effectiveness in restoring consciousness post ABI.

Discussion

Two clinical trials have evaluated other pharmacological interventions for restoring consciousness post ABI: citicoline (Shokouhi et al., 2014) and antiepileptics (Bagnato et al., 2013). In both trials, consciousness improved similarly in both the treated and untreated control groups over time, and thus the medications provided no discernable benefit. Given the limited research on each of these medications, additional clinical trials are required prior to making firm conclusions.

Conclusions

There is level 2 evidence that citicoline or antiepileptics may not be effective at restoring consciousness post ABI compared to controls.

16.3.3 Multimodal/ Combination Therapies after Coma

16.3.3.1 Non-Pharmacological Interventions

16.3.3.1.1 Sensory Stimulation

Key Points

Multimodal stimulation may be more effective than unimodal stimulation at improving mental and physical arousal post ABI.

Multimodal stimulation is more effective than standard care at improving consciousness and cognitive function post ABI.

Sensory stimulation may be most effective when it is early, frequent, and sustained as well as specific, directed, and regulated.

Sensory stimulation may be most effective when stimuli are familiar or delivered by a familiar individual.

This section refers to combination or comparative sensory stimulation therapies post coma, please refer to section 16.3.1.1 for additional information.

Discussion

One of the major challenges for evaluating the efficacy of sensory stimulation in promoting recovery of consciousness is that outcome assessment measures are often qualitative and difficult to assess.  Several studies have reported improvements in parameters such as coma duration (M. A. H. Gorji et al., 2014; Mitchell et al., 1990; Pierce et al., 1990)and behaviour (Wilson et al., 1996). Clinical assessment tools for measuring level of consciousness are preferred, including the GCS, Coma Recovery Scale, Coma/Near Coma Scale, and DOC Scale. These measures can be used in conjunction with the RLAS or Wessex Head Injury Matrix for the assessment of cognitive functioning. As well, tools such as WNSSP, Sensory Stimulation Assessment Measure, and Sensory Modality Assessment & Rehabilitation Technique were developed in order to better quantify the efficacy of sensory stimulation programs (Ansell & Keenan, 1989; Gill-Thwaites, 1997; Rader & Ellis, 1994).

Two prospective trials using multisensory stimulation programs described marked improvements in terms of coma duration, recovery rate, or long term outcomes when compared to standard care. One study reported that patients receiving treatment had significantly shorter coma duration than those who received standard care (Mitchell et al., 1990). The other study noted that treated patients showed significantly greater improvement on the RLAS (Kater, 1989). It also found that patients with moderate or severe coma (GCS≤10) showed greater benefit from the multisensory treatment. More recently, trials have examined intensive and frequent multisensory stimulation delivered over a period of one to two weeks. These studies reported significant improvements on the GCS (Abbasi et al., 2009; Megha et al., 2013; Moattari et al., 2016; Urbenjaphol et al., 2009), RLAS (Urbenjaphol et al., 2009), WNSSP (Megha et al., 2013; Moattari et al., 2016), and Sensory Modality Assessment & Rehabilitation Technique (Moattari et al., 2016; Urbenjaphol et al., 2009) when compared to standard care.

The type of stimulation and form of delivery may have an impact on its effectiveness.Inan early trial, it was demonstrated that specific, directed, and regulated stimulation yielded greater improvements on the GCS and RLAS (Wood et al., 1992)SSAM when compared to indiscriminate stimulation. In the same year, Hall et al. (1992) found that while both specific directed stimulation (SDS; multisensory input), and non-directed stimulation (no multisensory input) increased GCS, RLAS and WNSSP, only the SDS was able to increase SSAM scores. Further lending support to the engagement of multiple senses, a study found that multimodal stimulation was superior than unimodal stimulation at increasing behaviours corresponding with arousal (Wilson et al., 1996). For example, in the multimodal stimulation group but not the unimodal group increases were noted in the “frequency with which eyes were open”, and the “frequency of eyes shut with no body movement” was decreased. More recently, Park et al. (2016) discovered that both direct and indirect stimulation improved GCS and SSAM scores. Notably, direct stimulation increased SSAM scores more than the indirect stimulation intervention. A later retrospective study found that patients had greater improvements on the Wessex Head Injury Matrix following enriched stimulation than basic cognitive stimulation (Di Stefano et al., 2012). In a recent trial, Megha et al. (2013) found that stimulation delivered five times a day generated greater improvements on GCS and WNSSP than when delivered twice a day. Further, Moattari et al. (2016) showed that stimulation was most effective at improving GCS, RLAS, and WNSSP when delivered by a family member compared to a nurse.

Studies evaluating auditory stimulation over standard care have also shown favourable results. Patients who listened to recordings of familiar voices or music had shorter coma duration (M. A. Gorji et al., 2014), showed improvements on GCS (Tavangar et al., 2015) compared to those receiving standard care. Similarly, patients were found to have a greater response to the sound of their name than a musical sound (Cheng et al., 2013). Patient responsiveness to both sounds was associated with higher Coma Recovery Scale scores.

Conclusions

There is level 1a evidence that multisensory stimulation may be more effective than standard care at improving consciousness and cognitive function post ABI.

There is level 1b evidence that familiar auditory stimulation may be more effective than standard care at imroving consciousness post ABI.

There is level 1b evidence that multisensory stimulation delivered five times per day may be more effective at improving consciousness and cognitive function post ABI than stimulation delivered twice a day.

There is level 1b evidence that multisensory stimulation delivered by a family member may be more effective at improving consciousness and cognitive function post ABI when compared to stimulation delivered by a nurse.

There is level 2 evidence that specific, directed, and regulated sensory stimulation may be more effective at improving consciousness and cognitive function post ABI than indiscriminate stimulation.

There is level 2 evidence that multimodal stimulation may be superior to unimodal stimulation at improving consciousness and behaviours associated with arousal from coma post ABI.

16.3.3.1.2 Electrical Stimulation

This section refers to combination or comparative electrical stimulation therapies post coma, please refer to section 16.3.1.3 for additional information.

Discussion

One study comparing the efficacy of median nerve electrical stimulation to standard care in promoting emergence from coma was identified. Lei et al. (2015) determined that patients who received median nerve electrical stimulation showed no more improvement after two weeks than patients who received standard care. However, six-month follow-up data showed that a significantly higher proportion of patients who received stimulation regained consciousness and had improved FIM scores. These results suggest median nerve electrical stimulation improves consciousness more significantly than standard care alone, however future studies are encouraged to utilize an RCT design.

16.3.3.2 Pharmacological Interventions

16.3.3.2.1 Multimodal Amantadine Interventions

Key Points

Amantadine may be more effective than standard care at improving consciousness and decreasing mortality in patients in a coma post ABI.

This sections refers to comparative amantadine interventions after coma, please refer to section 16.3.2.1 for additional information.

Discussion

The use of amantadine was reviewed in a previous section and it was concluded that there is strong evidence favouring its use to improve consciousness, cognitive function and disability in patients in a coma post ABI. By extension, this section will contrast amantadine and standard therapy to determine which treatment is superior in treating patients in a coma post ABI.

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

16.4 Miscellaneous Outcomes

16.4.1 Non-Pharmacological Interventions

16.4.1.1 Hypothermia

Key Points

Hypothermia may improve outcomes and reduce mortality post ABI.

Very mild hypothermia (35-36°C) may be more effective than mild hypothermia (32-34°C) at improving outcomes with fewer complications individuals with an ABI.

This section houses information with miscellaneous outcomes for hypothermia interventions. Please refer to section 16.2.1.2 for additional information.

Discussion

Two studies investiagting the effects of therapeutic hypothermia were reviewed. Overall, it was reported that therapeutic hypothermia improved neurological outcomes (Hayashi et al., 2005) and reduced mortality (Chen et al., 2001) when compared to normothermia or control groups. Upon further analysis, Hayashi et al. went on to suggest that very mild hypothermia (35-36°C) may be more effective than mild hypothermia (32-34°C) at improving neurological outcomes with fewer complications (Hayashi et al., 2005). Althought both studies reported positive outcomes, different cooling protocols were employed by the groups (72-84 hr, Hayashi et al.; 10 hr/d, 3-10 d, Chen et al.). As a result, further studies are required to ellucidate the optimal hypothermia protocol.

Conclusions

There is level 2 evidence that systemic hypothermia may improve favourable and reduces unfavourable outcomes compared to control in patients post ABI.

There is level 2 evidence that very mild hypothermia (35-36°C) may more effective than mild hypothermia (32-34°C) at improving neurological outcomes with fewer complications in patients post ABI.

There is level 2 evidence that hypothermia may reduce mortality compared to in patients post ABI.

16.4.1.2 Rotational therapy

Key Points

Conventional physiotherapy alone, or in combination with verticalization may improves long term outcomes, disability, cognitive functioning and recovery from coma.

Verticalization in combination with conventional physiotherapy may be superior to conventional physiotherapy alone at improving recovery from coma.

Verticalization using the Erigo robot may be superior to the MOTOmed machine, and conventional therapy at reducing sympathetic stress.

This section discusses information with miscellaneous outcomes for rotational therapies. Please refer to section 16.2.1.4 for additional information.

Discussion

Two studies investigating variations of rotational therapy were identified. The first, a multi-center RCT, reported that all outcome measures (GCS, DRS, LCF, CRSr) improved significantly over the duration of the study in both treatment groups (Frazzitta et al., 2016). However, CRSr scores were significantly greater in the treatment group (fifteen 30 min sessions of verticalization + conventional physiotherapy) compared to the control group (physiotherapy alone).

The second study compared different mobilization techniques and their effect on patient stress— as determined by plasma catecholamine levels and hypotensive incidents (Rocca et al., 2016). While all groups similarly affected blood pressure, only the MOTOmed and standard mobilization interventions significantly increased patient plasma catecholamine levels from baseline. Results of this study suggest that mobilization with the Erigo robot (tilting table with an integrated leg movement system) is superior to both the MOTOmed robot and standard mobilization, as it does not cause hypotension and results in less sympathetic stress.

Conclusions

There is level 2 evidence that conventional physiotherapy alone, or in combination with verticalization may improve Glasgow Coma Scale, Coma Recovery Scale-Revised, Level of Cognitive Functioning, and Disability Rating Scale scores compared to controls in patients post ABI.

There is level 2 evidence that verticalization plus conventional physiotherapy may be superior to conventional physiotherapy alone at improving Coma Recovery Scale-Revised scores in patients post ABI.

There is level 2 evidence that verticalization using the Erigo robot may cause less sympathetic stress in ABI patients compared to the verticalization using the MOTOmed machine, or conventional therapy.

16.4.1.3 Blood products

Key Points

Thawed plasma may be superior to packed red blood cells at improving neurological function and disability in patients with multiple injuries post TBI.

Pre-hospital resuscitation of hypotensive ABI patients focuses on maintaining appropriate blood pressure, and by extension adequate cerebral perfusion, to reduce the extent of secondary brain injury in ABI patients (Hernandez et al., 2017; Werner & Engelhard, 2007). While isotonic fluid is commonly used for resuscitation, evidence exists supporting the use of packed red blood cells (RBC) in severely injured ABI patients (Hernandez et al., 2017; Riskin et al., 2009). Recently however, studies have come out proposing that plasma, or blood products with a high plasma to RBC ratio, are superior to RBCs alone at improving mortality in severely injured ABI patients (Bhangu et al., 2013; del Junco et al., 2013). Complimentary to those findings, large animal trials with TBI models have found improvements in post-injury neurological outcomes after administration of plasma (Halaweish et al., 2016; Shakeri et al., 2013) (Shakeri et al., 2013).

Despite recent evidence supporting the use of blood products, and specifically plasma, in the resuscitation of severe TBI patients, the Brain Trauma Foundation recommends solely the use of isotonic fluid in the management of hypotensive patients (Bratton et al., 2007).

Discussion

One study was reviewed investigating the effects of different blood products on neurological and disability outcomes. In the study by Hernandez et al. (2017) TBI patients with multiple injuries who received either thawed plasma, or pRBCs were retrospectively analyzed. The study concluded that the thawed plasma group demonstrated significantly higher neurological function and DRS scores at both discharge and follow up compared the to pRBC group. While further research is required, these results show promise in the benefits of plasma products in patients with multiple injuries post TBI.

Conclusions

There is level 3 evidence that thawed plasma may be superior to packed red blood cells at improving neurological function and disability at both discharge and follow up in patients with multiple injuries post TBI.

16.4.2 Pharmacological Interventions

16.4.2.1 Osmolar Therapy

Key Points

Hypertonic saline may increase hospital length of stay and rates of infections, especially in patients with severe TBIs.

Mannitol may increase urine output, lower serum sodium, transiently decrease systolic blood pressure, but has the same mortality compared to hypertonic solution.

Albumin may increase mortality, specially in severe TBI patients, compared to hypertonic solution; however, there may be no difference in neurological outcomes between treatments.

Osmolar therapy is a major treatment approach in controlling intracranial hypertension and edema following ABI. Although mannitol is most commonly used to control ICP, results from some studies have called for the its replacement as the primary osmolar intervention with saline; a safer and more effective compound (Horn et al., 1999; Ware et al., 2005).

Discussion

Three studies were analyzed comparing HTS to either mannitol (Sayre et al., 1996), albumin (Myburgh et al., 2007), or a control group (Coritsidis et al., 2015). Although HTS has gained traction as an effective treatment of ICP post ABI, a recent case control study found increases in hospital LOS, and rates of infections after HTS use in patients post ABI (Coritsidis et al., 2015). Furthermore, the authors suggest that treatment should be administered with caution in patients with severe TBI (GCS<8), as they had significantly increased odds for developing pulmonary infections.

Sayre et al. (1996) conducted an RCT to investigate the effects of early mannitol administration in an out-of-hospital emergency care setting. The authors reported that mannitol administration was associated with increased urine output, lower serum sodium, and a transient (2 h) decrease in systolic blood pressure when compared to HTS. Despite the improved side effect profile associated with HTS administration, mortality between groups was the same.

Finally, a very high quality RCT compared HTS to albumin in patients post ABI (Myburgh et al., 2007). The study noted an increase in mortality, especially in GCS<9 patients, but no differences in GOSE scores in the albumin group compared to those receiving HTS. The results from this study suggest that HTS is safer than albumin, and should be considered first when administering an osmolar therapy to treat patients post ABI.

Conclusions

There is level 3 evidence that hypertonic solution may increase hospital length of stay and rates of infections compared to controls post ABI.

There is level 3 evidence that hypertonic solution may increase the risk of pulmonary infections in individuals with an ABI and a Glasgow Coma Scale score less than 8 compared to hypertonic solution.

There is level 1b evidence that mannitol may increase urine output, lowers serum sodium, transiently decreases systolic blood pressure, but may have the same effect on mortality compared to hypertonic solution post ABI.

There is level 1b evidence that albumin may increase mortality, specifically in individuals with an ABI and a Glasgow Coma Scale score less than 9, compared to hypertonic solution.

There is level 1b evidence that albumin may not differ from hypertonic solution for improving Glasgow Outcome Scale Extended scores in patients post ABI.

16.4.2.2 Propofol

Key Points

Propofol and vasopressor treatment might increase the risk of developing propofol infusion syndrome post ABI.

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

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

Discussion

In 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 results of this study. However, the results suggest 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.

Conclusions

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

16.4.2.3 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 is a fast-acting benzodiazepine with a short half-life and inactive metabolites (McCollam et al., 1999). Midazolam is anxiolytic and displays anti-epileptic, sedative, and amnestic properties. Furthermore, midazolam  is a protein-bound, highly lipid-soluble drug that crosses the blood brain barrier and has a rapid onset of action— one to five minutes in most patients (McClelland et al., 1995). However, delayed elimination of midazolam resulting in prolonged sedation has been demonstrated in some critically ill patients.

Studies conducted in the operating room or intensive care unit have demonstrated midazolam to be relatively safe in euvolemic patients or in the presence of continuous hemodynamic monitoring for early detection of hypotension (Davis et al., 2001). Midazolam has been found to reduce CSF pressure in patients without intracranial mass lesions as well as decrease cerebral blood flow and cerebral oxygen consumption (McClelland et al., 1995).

The AANS made no recommendations regarding the efficacy of midazolam but, if used, suggested a 2.0 mg test dose followed by a 2.0-4.0 mg/hr infusion (Carney et al., 2017). The EBIC recommended sedation but made no specific reference to midazolam (Maas et al., 1997).

Discussion

Two studies investigating the effects of midazolam in patients post ABI were reviewed. While the efficacy of midazolam in lowering ICP has been discussed in previous sections, one case series found that higher doses of midazolam were associated with hypotension following intubation, as well as decreases in systolic blood pressure (Davis et al., 2001). In addition, a separate RCT compared midazolam to propofol and found no differences in GOS scores, mortality, or disability between treatments (Ghori et al., 2008).  Based on the studies reviewed, no differences in long term outcomes exist between propofol and midazolam, however care should be taken as to avoid high doses of the latter to prevent hypotension in patients post ABI.

Conclusions

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

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

16.4.2.4 Barbiturates

Key Points

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

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

Discussion

Barbiturate administration in patient’s refractory to conventional treatment is used 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 ellucidate the effects of pentobarbital on patients post ABI, follow up studies are required.

Conclusions

There is level 2 evidence that pentobarbital my decrease 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.

16.4.2.5 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 complications, such as acute respiratory distress syndrome, arise.

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

Corticosteroids are steroid hormones produced by within the body and can be classified as either a glucocorticoid (anti-inflammatory, metabolic), or a mineralocorticoid (regulate electrolyte and water balance). 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 action of steroids in ABI treatment. 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 previously 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. For example, 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 were brought forth regarding the safety of corticosteroid administration Alderson and Roberts (1997) conducted a systematic review of the existing 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 ABI 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 authors also conducted a systematic review and meta-analysis of existing trials using corticosteroids for head injury. Before the CRASH trial, a 0.96 relative risk of death was seen in the corticosteroid group. Once the patients from the CRASH trial were added, the relative risk changed to 1.12. The authors suggest that based on this large multinational trial, corticosteroids should not be used in head injury care no matter the severity of injury.

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 reportedeither 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 40ys 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 experiment 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 recently 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 can be effective in improving complications that develop post-ABI.

Three RCTs were found that assessed dexamethasone in ABI. While one study reported no difference in morbity 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 controls.

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 risk the 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 reveiving 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 an 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 level 1b evidence that methylprednisolone may increase mortality rates compared to placebo in individuals post ABI and should not be used.

There is level 2 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 3 evidence that glucocorticoid administration 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.

16.4.2.6 Progesterone

Key Points

The effect of progesterone on long-term outcomes is unclear.

Progesterone has drawn interest as a neuroprotective agent given that animal studies have suggested progesterone use 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

Recent trials have reported no significant differences in favourable outcomes between those receiving progesterone or placebo after three months (Shakeri et al., 2013) and six months (Shakeri et al., 2013; Brett E. Skolnick et al., 2014; Wright et al., 2014). However, in a subgroup analysis of patients with initial GCS>5, Shakeri (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 1b evidence that progesterone treatment may be associated with adverse events such as phlebitis and thrombophlebitis.

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

16.4.2.7 Erythropoietin

Key Points

Recombinant erythropoietin administration may improve mortality and neurological outcomes, and acutely lower brain cell destruction markers in patients post ABI.

Eryhtropoietin (EPO) is a hormone produced by the kidneys and functions as the main stimulus for red blood cell formation, or erythropoiesis. Erythropoietin has been found to promote neurogenesis, angiogenesis, and reduce apoptotic and inflammatory responses; properties which have garnered interest for its use as a neuroprotective agent in ABI (Kumral et al., 2011; Li et al., 2016; Simon et al., 2017; Wang et al., 2015). While animal models have shown the benefit of recombinant EPO use in TBI models, the benefit in humans post ABI is unclear (Matejkova et al., 2013; Peng et al., 2016; Wang et al., 2015).

Discussion

Two studies were identified evaluating the effects of recombinant human EPO (rhEPO) in patients post ABI. Compared to a control (saline) population, patients receiving rhEPO were found to have improved neurological outcomes (GOS), as well as decreased markers of brain cell destruction (Li et al., 2016). However, it is important to note that the decreased brain destruction markers were only present on day 7 of the treatment protocol, and not again at 3 mo. In a follow up to a separate RCT, Skrifvars and colleagues (2017) discovered a decrease in mortality in patients receiving EPO, especially those who underwent a neurosurgical operation before treatment with EPO. Based on the available data, rEPO administration appears to provide an appreciable mortality and neurological benefit in patients post ABI, however further studies are required to support these findings.

Conclusions

There is level 1b evidence that recombinant erythropoietin administration may improve neurological outcomes and transiently decreases markers of brain cell destruction compared to saline post ABI.

There is level 1b evidence that recombinant erythropoietin administration may decrease mortality compared to saline, especially in patients who have undergone an operation previously, post ABI.

16.4.2.8 Bradykinin Antagonists

Key Points

Anatibant, regardless of dose, may not cause serious adverse events, affect morbity, mortality or disability in patients post ABI.

Tissue injury or cell death following brain injury acts as a strong stimulus for the 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. Recent 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 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 bind the BK2 receptor more strongly than Bradycor (Marmarou et al., 2005).  Animal research has suggested that Anatibant dampens acute inflammation, reduces brain edema, and improves long-term neurological function in ABI models (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.

Conclusions

There is level 1b evidence that Anatibant, regardless of dose, may not cause serious adverse events, affect mortality, Glasgow Coma Scale, Modified Oxford Hanicap Scale, or Disability Rating Scale in individuals post ABI.

16.4.2.9 Other Medications

Key Points

Tranexamic acid in combination with standard care is likely superior to standard care alone at reducing intracranial hemorrhage growth in patients post TBI.

Selenium in addition to standard care is likely not different than standard care at improving morbidity and neurological outcomes in patients post TBI.

Prophylactic statin use may not improve mortality or neurological outcomes in patients post TBI.

Early propranolol intervention may decrease mortality, but increase time spent on a ventilator in patients post TBI.

Dexemedetomidine might improve sedation and neurological outcomes while decreasing blood pressure, heart rate, and the need for opioid administration in patients post TBI.

Diclofenac Sodium might decrease core body temperature, cerebral blood flow, heart rate and blood pressure in patients post TBI.

In addition to the aforementioned medications, other pharmacological interventions have been evaluated for the treatment of ABI and complications resulting from ABIs. These interventions include antifibrinolytic agents, dyslipidemia drugs, nonsteroidal anti-inflammatory drugs, sedatives, beta blockers, and selenium.

Discussion

A number of pharmacological agents have recently been studied by different groups for the treatment of ABI.

Tranexamic acid, an antrifibrinolytic agent, was examined for it efficacy in treating ICH when used in combination with standard care (Jokar et al., 2017). The researchers found that patients who only received standard care had significantly larger ICH growth compared to the group who additionally received tranexamic acid. Further research is required to make definitive conclusions on the efficacy of tranexamic acid in ICH treatment, however early results show promise of its use in limiting ICH growth.

Selenium, an element in the periodic table, is a compound used today for the treatment of a vast range of conditions including cardiovascular diseases, osteoarthritis, neurological diseases, and depression. A group led by Moghaddan (2017) compared patients receiving standard care to those receiving selenium in addition to standard care on number of morbidity (SOFA, APACHE, side effects, LOS) and neurological outcomes measures (GOSE, FOUR). There were no significant differences between groups in any outcome measure, however patients in the selenium group reported nausea (n=1) as well as facial flushing (n=3). These results suggest that selenium may not be benificial in the treatment of ABI, and while not alarming, can be associated with side effects that affect quality of life.

Patient records were identified from a database and severe TBI patients taking a statin prior to injury were matched to severe TBI patients with no prior statin use (Neilson et al., 2016). After analysis, it was determined that no differences existed between the groups in terms of GOS scores, or survival (14 d and 6 mo). The results of this study suggest that statins, a class of drug used to lower the risk of cardiovascular disease and treat dyslipidemia, are not effective agents in the treatment of TBI. In a separate case control study, researchers administered propranolol in the early stages post-TBI to determine its effects on morbidity and mortality (Ko et al., 2016). The group reported that patients who received propranolol had a lower mortality, but spent more days on a ventilator compared to patients who did not receive propranolol. No difference was noted between groups in the length of time they stayed in the hospital. Further randomized studies are required to determine the effects of early propranolol intervention in TBI patients.

Diclofenac Sodium (DCFS) is a non-steroidal anti-inflammatory drug (NSAID) used to reduce fever in patients in the ICU. A group out of Italy studied the effects of intramuscular DCFS to control fever in ABI patients, and noted a decrease in core temperature, systolic blood pressure, diastolic blood pressure, MAP, heart rate and CPP (Picetti et al., 2016). While DCFS effectively reduce core body temperature, it also compromised patient blood pressure and blood flow to the brain. Further studies are required to study the full effects of DCFS in patients with TBI, however early results do not support its use as a fever control agent.

Conclusions

There is level 1b evidence that tranexamic acid in combination with standard care may be superior to standard care alone at reducing intracranial hemorrhage growth in patients post TBI.

There is level 1b evidence that selenium in addition to standard care may not be different than standard care alone at improving morbidity and neurological outcomes in patients post TBI.

There is level 3 evidence that statin use prior to injury may not improve mortality or neurological outcomes compared to no prior statin use in patients post TBI.

There is level 3 evidence that early propranolol intervention may decrease mortality and increases time spent on a ventilator compared to late intervention in patients post TBI.

There is level 4 evidence that dexmedetomidine may decrease blood pressure and heart rate, increases Glasgow Coma Scale and Richmond Agitation-Sedation Scale scores, and reduces the need for opiod administration in patients post TBI.

There is level 4 evidence that diclofenac sodium may decrease core body temperature, blood pressure, heart rate, and cerebral perfusion pressure in patients post TBI.

16.4.3 Surgical Interventions

16.4.3.1 Tracheostomy

Key Points

Tracheostomies might improve mortality in individuals post ABI; however, individuals undergoing the procedure are generally older, more injured, and require more treatment.

Patients with ABI enter the ICU in varying degress of consciousness, frequently requiring mechanical assistance from a ventilator to maintain adequate respiration. While patients often arrive to the ICU with an endotracheal tube, ventilation through a tracheostomy tube is the preferred method of ventilation in patients requiring assistance for a prolonged period of time (Cheung & Napolitano, 2014; Durbin, 2010). Currently, conflicting results exist regarding the potential benefits of a tracheostomy in patients post ABI. While some studies have reported shorter duration of ventilation  (Teoh et al., 2001) and hospital LOS (D’Amelio et al., 1994), others have associated tracheostomies with detrimental effects, such as increases in ICP (Kocaeli et al., 2008; Stocchetti et al., 2000).

Discussion

Intubated ABI patients who underwent a tracheostomy were compared to intubated patients who did not undergo a tracheostomy (Baron et al., 2016). The researchers found that compared to those who did not undergo a tracheostomy, patients who did receive the intervention had a lower mortality ratio, required more treatment, were older, and had more severe injuries. While drawing conclusions from a single study is difficult, these results suggest that a tracheostomy may provide a greater survival benefit to ABI patients who are in worse condition.

Conclusions

There is level 3 evidence that individuals with ABI receiving a tracheostomy may have improved mortality compared to individuals not receiving a tracheostomy.

16.4.3.2 Decompressive Craniectomy

Key Points

Decompressive craniectomies may worsen mortality, recovery and complications in patients post ABI; however young age, early decompressive craniectomy, large decompressive craniectomy, and higher Glasgow Coma Scale scores may all be predictors for favourable outcomes.

It is unclear whether decompressive craniectomy is superior to a craniotomy at improving mortality and long-term outcomes post ABI.

An intracranial hemorrhage evacuation with a decompressive craniectomy may be inferior to an intracranial hemorrhage evacuation, or the same as an intracranial hemorrhage evacuation with a craniotomy at improving mortality and long-term outcomes in patients post ABI.

Trepination after a thick subdural intracranial hemorrhage might increase patient mortality.

It is unclear wether decompressive craniectomy is superior to standard care at improving Glasgow Outcome Scale scores and mortality in patients post ABI.

The type of decompressive craniectomy (with dural slits or expansile duraplasty) post acute subdural hematoma may not affect mortality and neurological outcomes.

Surgical decompression is the removal of skull sections in ABI patients to reduce the rising ICP caused by secondary injury (i.e., delayed brain damage).  Sahuquillo and Arikan (2006) identified two types of surgical decompression: prophylactic/primary decompression and therapeutic/secondary decompressive craniectomy (DC). The former involves performing the surgical procedure as a preventive measure against expected increases in ICP while the latter is performed to control high ICP “refractory to maximal medical therapy” (Sahuquillo & Arikan, 2006).

Debate regarding if and when to perform these surgeries currently exists. Factors such as age and initial GCS score have been proposed as potential prognostic factors (Guerra et al., 1999).  Currently, the majority of decompressive techniques are precipitated by evacuation of a mass lesion (Compagnone et al., 2005). On the other hand, therapeutic DC is typically performed after other therapeutic measures to control ICP have been exhausted (Morgalla et al., 2008). Once decompression is decided upon, resection of a larger bone fragment is generally recommended to allow for greater dural expansion with less risk of herniation (Compagnone et al., 2005; Csókay et al., 2001).. A recent systematic review reported improved GOS scores and reduced mortality rates associated with DC, particularly in younger individuals with less severe (GCS>5) and more acute (<5hr) injuries (Barthelemy et al., 2016). However, the authors refrained from providing clinical recommendations given a lack of prospective data and significant results.

The AANS reported that there was insufficient evidence to support Level I recommendations regarding DC, although Level II recommendations were provided (Carney et al., 2017). A bifrontal DC was not recommended for improving long-term outcomes in individuals with severe TBI and prolonged, elevated ICP. The authors noted, however, that bifrontal DC demonstrated significant reductions in ICP and ICU stay. As well, a larger frontotempoparietal DC was recommended over a smaller procedure for reduced mortality and improved neurological outcomes. The EBIC suggested that DC should only be considered in “exceptional situations” (Maas et al., 1997).

Discussion

Considering the intensiveness of a DC and its potential complications, evaluating the long-term outcomes associated with the procedure is of particular importance. Several factors were found to correlate with positive long-term outcomes, including younger age (Chibbaro et al., 2011; Chibbaro et al., 2008; Huang et al., 2013; Limpastan et al., 2013; Meier et al., 2008; Nambiar et al., 2015; Ucar et al., 2005; Williams et al., 2009; Yang et al., 2008; Yuan et al., 2013), higher GCS score (De Bonis et al., 2011; Goksu et al., 2012; Gong J, 2014; Ho et al., 2011; Howard et al., 2008; Huang et al., 2013; Limpastan et al., 2013; Meier et al., 2008; Ucar et al., 2005; Williams et al., 2009; Yang et al., 2008; Yuan et al., 2013), earlier DC (Chibbaro et al., 2011; Chibbaro et al., 2008; Girotto et al., 2011; Polin et al., 1997), and larger DC (Li et al., 2008; Skoglund et al., 2006). However, a number of studies reported high mortality rates (Agrawal et al., 2012), low recovery rates (Morgalla et al., 2008), and expansion of new/ existing hemorrhagic contusions (Flint et al., 2008) after treatment with DC.

Some retrospective studies found that DC was associated improved GOS scores and reduced mortality when compared to standard care (Polin et al., 1997; Rubiano et al., 2009), while others did not (Girotto et al., 2011; Nirula et al., 2014; Quintard et al., 2015). The results are similarly mixed when DC is compared to other procedures. An earlier study found that DC yielded more favourable long-term outcomes than craniotomy (Huang et al., 2008), but later studies found that there were no significance differences between the procedures (Chen et al., 2011; Li et al., 2012). Conversely, other studies exist reporting that a DC is associate with greater mortality (Rush et al., 2016; Tapper et al., 2017), longer hospital LOS (Rush et al., 2016), and a greater chance of developing unfavourable outcomes (Tapper et al., 2017).

Decompressive craniectomy was further discussed in terms of its efficacy as an intervention for the development of ICH post ABI. A group led by Otani (REF 2010) concluded that in comparison to a hematoma evacuation alone, DC + hematoma evacuation resulted in a lower rate of favourable outcomes (78.2% versus 55.8%). Conflicting results exist comparing a DC to a craniotomy for the treatment of ICH. While one group noted that patients who underwent a DC showed an increase in mortality and hospital LOS compared to those receiving a craniotomy (Rush et al., 2016), another found that DC combined with ICH evacuation was no different from a craniotomy combined with ICH evacuation in the same parameters (Jehan et al., 2017). Notably, while the latter study did not report a difference in mortality, GOS score, GCS score, or hospital LOS, the DC group did have an increased return to the OR, number of events of hydrocephalus requiring a shunt, and number of days on a ventilator compared to the craniotomy group. Finally, Shibahashi et al. (2017) found that in thick subdural ICH’s, trepanation was associated with higher mortality compared to those who did not undergo trepanation.

Concluding the discussion on DC, Khan et al. (Khan et al., 2016) conducted an RCT conmparing DCs with expasile duraplasty to DCs with dural-slits. The study reported no differences existed between the techniques with respect to mortality or GOS scores; however, the expansile duraplasty surgery was significantly shorter than the dural-slit procedure.

Conclusions

There is level 4 evidence that decompressive craniectomy may be associated with increased mortality, low recovery rates, and expansion of hemorrhagic contusions in patients post ABI.

There is level 4 evidence that younger age, higher intital Glasgow Coma Scale score, and earlier decompressive craniectomy may be associated with positive long-term outcomes in patients post ABI.

There is level 3 evidence that a larger decompressive craniectomy may associated with positive long-term outcomes compared to routine care in patients post ABI.

There is conflicting (level 2 and level 4) evidence as to whether decpmpressive craniectomy is superior to craniotomy at improving mortality, long-term outcomes, and hospital length of stay in patients post ABI.

There is level 3 evidence that an intracranial hemorrhage evacuation with a decompressive craniectomy may cause an increase in additional treatment required, but is not different in terms of mortality and neurological outcomes, compared to an intracranial hemorrhage evacuation with a craniotomy post ABI.

There is level 3 evidence that a hematoma evacuation may be superior to a hematoma evacuation combined with decompressive craniectomy at producing favourable outcomes in patients post ABI.

There is level 4 evidence that trepination in patients with thick subdural intracranial hemorrhages may increase mortality post ABI.

There is conflicting (level 3) evidence as to whether decompressive craniectomy is associated with higher Glasgow Outcome Scale scores and lower mortality when compared to standard care post ABI.

There is level 2 evidence that a decompressive craniectomy with expansile duraplasty is not different than a decompressive craniectomy with dural-slits with respect to mortality or Glasgow Outcome Scale scores in patients post acute subdural hematoma.

Summary


There is level 2 evidence that head elevation of 30o from a flat position may effectively reduces elevated intracranial pressure compared to head elevation of 0 o in individuals post ABI.

There is level 4 evidence that head elevation of 60o from a flat position may effectively reduceelevated ICP post ABI.

There is conflicting (level 2 and level 4) evidence regarding whether or not head elevation of 30o effectively improves cerebral perfusion pressure post ABI. With level 2 evidence supporting the use of head elevation to reduce cerebral perfusion pressure.

There is conflicting level 1a evidence regarding whether or not therapeutic hypothermia effectively reduces elevated intracranial pressure post ABI compared to normothermia.

There is level 4 evidence that hyperventilation may lower elevated intracranial pressure post TBI.

There is level 4 evidence that continuous rotational therapy may not improve intracranial pressure following severe TBI.

There is level 4 evidence that the prone position may increase intracranial pressure but improve cerebral oxygenation post ABI.

There is level 2 evidence that intracranial pressure monitoring may improve mortality in-hospital, and 6 months post-discharge in patients post ABI compared to control.

There is level 2 evidence that intracranial pressure monitoring may not improve Glasgow Outcome Scale scores in patients post ABI compared to control.

There is level 3 evidence that hypertonic saline compared to control treatment may be effective in lowering elevated intracranial pressure post ABI.

There is level 4 evidence that hypertonic saline may be effective in increasing cerebral perfusion pressure.

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 only may improve intracranial pressure and cerebral perfusion pressure post ABI in hypertensive patients (Intracranial pressure>20mmHg).

There is level 4 evidence that enteral urea may lower elevated intracranial pressure in ABI patients with syndrome of in-appropriate antidiuretic hormone secretion.

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

There is level 4 evidence that midazolam may have no effect on intracranial pressure, and may decrease mean arterial pressure and cerebral perfusion pressure, in TBI patients.

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

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

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

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

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

There is level 4 evidence that paracetamol may lower elevated intracranial pressure post ABI.

There is level 4 evidence that ventricular cerebrospinal fluid drainage may effectively lower elevated intracranial pressure post ABI.

There is level 4 evidence that ventricular cerebrospinal fluid drainage may increase cerebral perfusion pressure and cerebreal blood flow.

There is level 4 evidence that lumbar cerebrospinal fluid drainage may effectively lower elevated intracranial pressure post ABI.

There is level 4 evidence that continuous cerebrospinal fluid extractions through an external lumbar device may effectively lower intracranial pressure in patients refractory to standard intracranial pressure treatment.

There is conflicting level 3 and level 4 evidence regarding whether or not a decompressive craniectomy compared to no treatment effectively reduces elevated intracranial pressure post ABI.

There is conflicting level 4 evidence regarding whether or not a decompressive craniectomy effectively improves cerebral perfusion pressure post ABI.

There is level 2 evidence that head elevations of 15° and 30° compared to 0° may, effectively reduce elevated intracranial pressure post ABI when compared to a flat position.

There is level 4 evidence that head elevation of 45o and 60o may effectively reduce elevated intracranial pressure post ABI when compared to a flat position.

There is conflicting (level 2 and level 4) evidence regarding whether or not head elevation can improve cerebral perfusion pressure post ABI.

There is level 4 evidence that head elevation of 10o-60o may decrease mean arterial pressure post ABI.

There is conflicting (level 1b and level 2) evidence that therapeutic hypothermia may improve intracranial pressure compared to controls in ABI patients.

There is level 1b evidence that hypothermia interventions may be more effective at decreasing intracranial pressure and improving long-term outcomes when administered for long-term (120 h) compared to short term (48 h)

There is level 1b evidence that intracranial pressure/cerebral perfusion pressure and brain tissue oxygen managed hypothermia are similar at reducing intracranial pressure in individuals with an ABI when compared to controls.

There is level 2 evidence that selective hypothermia may be superior to systemic hypothermia in improving intracranial pressure post ABI when compared to controls.

There is level 4 evidence that hypothermia treatment combined with mannitol may be more effective at sustaining improved intracranial pressure, cerebral perfusion pressure, and oxygenations compared to hypothermia alone post ABI.

There is level 4 evidence that the positions supine with head down 30º; 75% supine; and 75% prone may increase intracranial pressure more than the supine position in patients post ABI.

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

There is level 1b evidence that the use of hypertonic solution results in similar ICP clinical outcomes when compared to Ringer’s lactate solution post ABI.

There is level 1b evidence that the use of hypertonic solution may be more effective than mannitol in increasing cerebral perfusion pressure, cerebral blood flow, and brain tissue oxygen tension.

There is level 2 evidence that the use of hypertonic solution may be similar to Ringer’s lactate solution and sodium bicarbonate in lowering elevated intracranial pressure.

There is level 1b evidence that mannitol is no more effective than hypertonic saline in improving intracranial pressure or cerebral perfusion pressure in individuals with an ABI.

There is level 1b evidence that mannitol is less effective than Ringer’s (sodium) lactate in controlling elevated intracranial pressure post ABI.

There is level 2 evidence that early versus late administration of mannitol may not effectively lower elevated intracranial pressure in individuals with an ABI, but does not adversely affect blood pressure.

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

There is level 1b evidence that propofol may be more effective at reducing intracranial pressure compared to morphine, specially at high propofol doses, 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 2 evidence that midazolam may not differ from propofol in its effect on intracranial pressure or cerebral perfusion pressure post ABI.

There is conflicting level 1a and level 1b evidence as to whether morphine, fentanyl, and sufentanil increase intracranial pressure, and decrease cerebral perfusion pressure, compared to controls post ABI.

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 4 evidence that sufentanil with midazolam decreases intracranial 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.

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

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

There is level 1b evidence that high-dose KN38-7271 (a dual cannabinoid agonist) may increase intracranial pressure and cerebral perfusion pressure, and improves survival post TBI compared to low-dose KN38-7271.

There is level 1b evidence that conivaptan may be similar to standard care (e.g. osmolar therapy, sedation, analgesia) in lowering elevated intracranial pressure post ABI.

There is level 1b evidence that vasopressin and catecholamine may be similarly effective in lowering elevated intracranial pressure post ABI.

There is level 1b evidence that ventricular cerebrospinal fluid drainage, regardless of amount drained, may effectively lower elevated intracranial pressure, and may increase cerebral perfusion pressure post ABI.

There is level 3 evidence that continuous cerebrospinal fluid drainage is superior to intermittent cerebrospinal fluid drainage at lowering intracranial pressure post ABI compared to intermittent drainage.

There is level 3 evidence that an intraparenchymal fiberoptic monitor may yield lower intensive care unit length of stay, device complications, need for surgical decompressions, and need for intracranial pressure monitoring compared to an external ventrical drainage post ABI.

There is level 1a evidence that decompressive craniectomy may be more effective than standard care at reducing elevated intracranial pressure post ABI.

There is level 1b evidence that a decompressive craniectomy may be similar to controlled decompression in reducing elevated intracranial pressure and improving Glasgow Outcome Scale scores post ABI.

There is level 1b evidence that a decompressive craniectomy with a unilateral frontotemporoparietal bone flap (12×15 cm) may be superior to a limited decompressive craniectomy with a temporoparietal bone flap (6×8 cm) in lowering intracranial pressure and improving Glasgow Outcome Scale scores post ABI.

There is level 3 evidence that decompressive craniectomy and craniotomy interventions may be similar at decreasing intracranial pressure post ABI.

There is conflicting (level 3) evidence as to whether decompressive craniectomies have better mortality outcomes compared to a craniotomy post ABI.

There is level 2 evidence that structured auditory sensory stimulation may improve Sensory Stimulation Assessment Measure and Disability Rating Scale, but not Glasgow Outcome Scale scores compared to controls in individuals in a coma post ABI.

There is level 3 evidence that multi-sensory stimulation has no effect on emergence from coma, Glasgow Outcome Scale scores, or recovery post ABI compared to controls.

There is conflicting (level 3 and level 4) evidence that multi-sensory stimulation may reduce heart rate in patients in a coma post ABI.

There is level 4 evidence that multi-sensory stimulation may reduce respiratory frequency in patients in a coma post ABI.

There is level 2 evidence that musical therapy may improve consciousness and brain activity compared to silence in individuals in a coma post ABI.

There is conflicting level 1b and level 2 evidence that median nerve electrical stimulation may not improve consciousness and arousal from coma compared to sham post ABI.

There is level 4 evidence that median nerve electrical stimulation may increase cerebral perfusion pressure and dopamine levels in individuals in a coma post ABI.

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

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

There is level 2 evidence that citicoline or antiepileptics may not be effective at restoring consciousness post ABI compared to controls.

There is level 1a evidence that multisensory stimulation may be more effective than standard care at improving consciousness and cognitive function post ABI.

There is level 1b evidence that familiar auditory stimulation may be more effective than standard care at imroving consciousness post ABI.

There is level 1b evidence that multisensory stimulation delivered five times per day may be more effective at improving consciousness and cognitive function post ABI than stimulation delivered twice a day.

There is level 1b evidence that multisensory stimulation delivered by a family member may be more effective at improving consciousness and cognitive function post ABI when compared to stimulation delivered by a nurse.

There is level 2 evidence that specific, directed, and regulated sensory stimulation may be more effective at improving consciousness and cognitive function post ABI than indiscriminate stimulation.

There is level 2 evidence that multimodal stimulation may be superior to unimodal stimulation at improving consciousness and behaviours associated with arousal from coma post ABI.

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

There is level 2 evidence that systemic hypothermia may improve favourable and reduces unfavourable outcomes compared to control in patients post ABI.

There is level 2 evidence that very mild hypothermia (35-36°C) may more effective than mild hypothermia (32-34°C) at improving neurological outcomes with fewer complications in patients post ABI.

There is level 2 evidence that hypothermia may reduce mortality compared to in patients post ABI.

There is level 2 evidence that conventional physiotherapy alone, or in combination with verticalization may improve Glasgow Coma Scale, Coma Recovery Scale-Revised, Level of Cognitive Functioning, and Disability Rating Scale scores compared to controls in patients post ABI.

There is level 2 evidence that verticalization plus conventional physiotherapy may be superior to conventional physiotherapy alone at improving Coma Recovery Scale-Revised scores in patients post ABI.

There is level 2 evidence that verticalization using the Erigo robot may cause less sympathetic stress in ABI patients compared to the verticalization using the MOTOmed machine, or conventional therapy.

There is level 3 evidence that thawed plasma may be superior to packed red blood cells at improving neurological function and disability at both discharge and follow up in patients with multiple injuries post TBI.

There is level 3 evidence that hypertonic solution may increase hospital length of stay and rates of infections compared to controls post ABI.

There is level 3 evidence that hypertonic solution may increase the risk of pulmonary infections in individuals with an ABI and a Glasgow Coma Scale score less than 8 compared to hypertonic solution.

There is level 1b evidence that mannitol may increase urine output, lowers serum sodium, transiently decreases systolic blood pressure, but may have the same effect on mortality compared to hypertonic solution post ABI.

There is level 1b evidence that albumin may increase mortality, specifically in individuals with an ABI and a Glasgow Coma Scale score less than 9, compared to hypertonic solution.

There is level 1b evidence that albumin may not differ from hypertonic solution for improving Glasgow Outcome Scale Extended scores in patients 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 midazolam may be no different than propofol at improving Glasgow Outcome Scale scores, mortality, or disability in patients post ABI.

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

There is level 2 evidence that pentobarbital my decrease 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 1b evidence that methylprednisolone may increase mortality rates compared to placebo in individuals post ABI and should not be used.

There is level 2 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 3 evidence that glucocorticoid administration 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 progesterone treatment may be associated with adverse events such as phlebitis and thrombophlebitis.

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

There is level 1b evidence that recombinant erythropoietin administration may improve neurological outcomes and transiently decreases markers of brain cell destruction compared to saline post ABI.

There is level 1b evidence that recombinant erythropoietin administration may decrease mortality compared to saline, especially in patients who have undergone an operation previously, post ABI.

There is level 1b evidence that Anatibant, regardless of dose, may not cause serious adverse events, affect mortality, Glasgow Coma Scale, Modified Oxford Hanicap Scale, or Disability Rating Scale in individuals post ABI.

There is level 1b evidence that tranexamic acid in combination with standard care may be superior to standard care alone at reducing intracranial hemorrhage growth in patients post TBI.

There is level 1b evidence that selenium in addition to standard care may not be different than standard care alone at improving morbidity and neurological outcomes in patients post TBI.

There is level 3 evidence that statin use prior to injury may not improve mortality or neurological outcomes compared to no prior statin use in patients post TBI.

There is level 3 evidence that early propranolol intervention may decrease mortality and increases time spent on a ventilator compared to late intervention in patients post TBI.

There is level 4 evidence that dexmedetomidine may decrease blood pressure and heart rate, increases Glasgow Coma Scale and Richmond Agitation-Sedation Scale scores, and reduces the need for opiod administration in patients post TBI.

There is level 4 evidence that diclofenac sodium may decrease core body temperature, blood pressure, heart rate, and cerebral perfusion pressure in patients post TBI.

There is level 3 evidence that individuals with ABI receiving a tracheostomy may have improved mortality compared to individuals not receiving a tracheostomy.

There is level 4 evidence that decompressive craniectomy may be associated with increased mortality, low recovery rates, and expansion of hemorrhagic contusions in patients post ABI.

There is level 4 evidence that younger age, higher intital Glasgow Coma Scale score, and earlier decompressive craniectomy may be associated with positive long-term outcomes in patients post ABI.

There is level 3 evidence that a larger decompressive craniectomy may associated with positive long-term outcomes compared to routine care in patients post ABI.

There is conflicting (level 2 and level 4) evidence as to whether decpmpressive craniectomy is superior to craniotomy at improving mortality, long-term outcomes, and hospital length of stay in patients post ABI.

There is level 3 evidence that an intracranial hemorrhage evacuation with a decompressive craniectomy may cause an increase in additional treatment required, but is not different in terms of mortality and neurological outcomes, compared to an intracranial hemorrhage evacuation with a craniotomy post ABI.

There is level 3 evidence that a hematoma evacuation may be superior to a hematoma evacuation combined with decompressive craniectomy at producing favourable outcomes in patients post ABI.

There is level 4 evidence that trepination in patients with thick subdural intracranial hemorrhages may increase mortality post ABI.

There is conflicting (level 3) evidence as to whether decompressive craniectomy is associated with higher Glasgow Outcome Scale scores and lower mortality when compared to standard care post ABI.

There is level 2 evidence that a decompressive craniectomy with expansile duraplasty is not different than a decompressive craniectomy with dural-slits with respect to mortality or Glasgow Outcome Scale scores in patients post acute subdural hematoma.

References

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