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 saline as a primary measure for ICP control (Horn et al. 1999; Ware et al. 2005).
Hypertonic saline (HTS) exerts its effect mainly by increasing serum sodium and osmolarity, thereby establishing an osmotic gradient. This allows water to passively diffuse from the cerebral intracellular and interstitial space into blood capillaries, which causes a reduction in water content and a subsequent reduction in ICP (Khanna et al. 2000). While mannitol works similarly, HTS has a better reflection coefficient (1.0) than mannitol (0.9) (Suarez 2004). Since the blood-brain barrier is better able to prevent entry of HTS, it makes it a more ideal osmotic agent. 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.
An abundance of retrospective studies have found that HTS treatment following ABI yields a significant decrease in ICP (Colton, Yang, et al. 2014b; Colton et al. 2016; Colton, et al. 2014; 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). In one comparative study, it was shown that HTS was more effective than no treatment at reducing elevated ICP (Tan et al. 2016). 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. Despite these favourable results, Coritsidis et al. (2015) suggested that treatment should be administered with caution in patients with severe TBI (GCS<8), as they had significantly increased odds for developing pulmonary infections.
HTS administration was found to have improved cerebral blood flow in two studies (Cottenceau et al. 2011; 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.
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). 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 (Jagannatha et al. 2016).
HTS 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.
Albumin and sodium bicarbonate solutions have been compared to HTS for managing acute ABI. A large trial by Myburgh et al. (2007) found that patients receiving HTS had significantly lower rate of mortality at two years than those who received albumin, although rates of favourable outcomes on the GOS Extended were similar between groups. In a smaller 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.
There is Level 3 evidence that the use of hypertonic saline is effective in lowering elevated intracranial pressure.
There is Level 3 evidence that the use of hypertonic saline leads to an increased rate of infection in severe ABI.
There is Level 4 evidence that the use of hypertonic saline is effective in increasing cerebral perfusion pressure.
There is Level 1b evidence that the use of hypertonic saline results in similar clinical outcomes when compared to Ringer’s lactate solution.
There is Level 2 evidence that the use of hypertonic saline is similar to Ringer’s lactate solution and sodium bicarbonate in lowering elevated intracranial pressure.
There is Level 1b evidence that the use of hypertonic saline results in lower rates of mortality when compared to albumin.
There is conflicting evidence (Level 1b) as to whether hypertonic saline lowers elevated intracranial pressure more effectively than mannitol.
There is Level 2 evidence that the use of hypertonic saline is more effective than mannitol in increasing CPP, Cerebral Blood Flow, and Brain Tissue Oxygen Tension.
Hypertonic saline effectively lowers elevated intracranial pressure and increases cerebral perfusion pressure; however, it may increase rate of infection in severe ABI.
Hypertonic saline has similar effects on intracranial pressure when compared to Ringer’s lactate solution, sodium bicarbonate, and mannitol.
Rapid administration of mannitol is among the first-line treatments recommended for the management of increased ICP. However, this treatment is reported to be associated with significant diuresis and can cause acute renal failure, hyperkalemia, hypotension, and in some cases rebound increments in ICP (Battison et al. 2005; Doyle et al. 2001). For these reasons, the Brain Trauma Foundation recommends that mannitol only be used if a patient has signs of elevated ICP or deteriorating neurological status. Under such circumstances the benefits of mannitol for the acute management of ICP outweigh any potential complications or adverse effects. There is also some evidence that with prolonged dosage, mannitol may penetrate the blood brain barrier, thereby exacerbating the elevation in ICP (Wakai et al. 2013). Despite the effectiveness of mannitol in ICP management, recent evidence points to HTS as a potentially more effective hyperosmotic agent.
Although mannitol is commonly used in acute ABI, the AANS concluded that there was insufficient evidence available to support a formal recommendation (Carney et al. 2017). The EBIC recommended mannitol as the preferred osmotic therapy, with administration via repeated bolus infusions or as indicated by monitoring to a serum osmolarity of ≤315 (Maas et al. 1997).
Overall, findings of single group interventions suggest that mannitol is effective in significantly reducing ICP following TBI (Diringer et al. 2012; Scalfani et al. 2012; Tang et al. 2015). Cruz and colleagues conducted three separate trials to investigate the effects of high dose mannitol on clinical outcomes in patients with ABI at six months post injury (Cruz et al. 2001, 2002, 2004). All three trials reported that high dose mannitol (1.4 g/kg) was superior to conventional mannitol (0.7 g/kg) in lowering elevated ICP and improving clinical outcomes. In a retrospective study, Sorani et al. (2008) found that for every 0.1 g/kg increase in mannitol dosage there was a 1.0 mmHg drop in ICP.
In a later trial, Francony et al. (2008) found that equimolar doses of mannitol and HTS were comparable in reducing ICP in stable patients with intact autoregulation post ABI. Mannitol was shown to improve brain circulation through possible improvements in blood rheology, but also significantly increased urine output. The authors suggested that both treatments may be effective, but patient pre-treatment factors should be considered before selection. In another trial, Ichai et al. (2009) reported that an equimolar dose of sodium lactate had a significantly greater effect on lowering elevated ICP that lasted longer than treatment with mannitol. Sodium lactate was also successful in reducing elevated ICP more frequently. Based on these results, further research into the effectiveness of sodium lactate in reducing ICP is warranted.
Most reports have recommended administering mannitol only when elevated ICP is proven or strongly suspected. Hartl et al. (1997) indicated that mannitol was only effective in diminishing ICP when the initial ICP was hypertensive (>20 mmHg). However, an RCT by Smith et al. (1986) reported that patients who received mannitol only after the onset of intracranial hypertension (>25mmHg) were not significantly different from those who received mannitol irrespective of ICP measurements in terms of mortality rates or neurological outcomes. Thus it is unclear whether the use of mannitol as a prophylactic measure against potential elevations in ICP is appropriate.
Other reports have discouraged the use of mannitol before volume resuscitation and patient stabilization, due to potential osmotic diuresis and hypotension. These adverse effects could further compromise CPP, but such an approach may deprive patients of the potential benefits of mannitol on ICP. With this in mind, Sayre et al. (1996) conducted an RCT to investigate the effects of early mannitol administration in an out-of-hospital emergency care setting. The authors reported that mannitol did not significantly affect blood pressure when compared to saline.
In a 2013 Cochrane review, Wakai et al. (2013) suggested that mannitol may have beneficial effects on mortality when compared to pentobarbital but detrimental effects when compared to HTS. However, there was a small benefit when mannitol treatment was monitored by a measurement of ICP when compared to standard care. The authors also reported that there was insufficient data on the effectiveness of pre-hospital administration of mannitol.
There is Level 4 evidence that mannitol is effective in controlling elevated intracranial pressure.
There is Level 2 evidence that early administration of mannitol does not effectively lower elevated intracranial pressure, but does not adversely affect blood pressure.
There is Level 2 evidence that high-dose mannitol is more effective than conventional mannitol in reducing mortality rates and improving clinical outcomes.
There is Level 1b evidence that mannitol is no more effective than hypertonic saline in controlling elevated intracranial pressure.
There is Level 1b evidence that mannitol is less effective than sodium lactate in controlling elevated intracranial pressure.
Mannitol may effectively lower elevated intracranial pressure; furthermore, high doses may yield lower mortality rates and better clinical outcomes.
Mannitol may be equally effective as hypertonic saline and less effective than sodium lactate for reducing elevated intracranial pressure.
Propofol is a fast acting sedative that is absorbed and metabolized quickly, leading to pronounced effects of short duration. Its beneficial effects occur via decreases in peripheral vascular tension resulting in potential neuroprotective effects, which may be beneficial in acute ABI care. Experimental results have shown positive effects on cerebral physiology including reductions in cerebral blood flow, cerebral oxygen metabolism, electroencephalogram activity, and ICP (Adembri et al. 2007). However, administration of high doses can result in propofol infusion syndrome, which has been characterized by severe metabolic acidosis, rhabdomyolosis, cardiac dysrhythmias, and potential cardiovascular collapse (Corbett et al. 2006).
The AANS reported Level II evidence for the recommendation of propofol in controlling of ICP, but not for improvement in mortality or long-term outcomes (Carney et al. 2017). They also indicated that high-dose propofol can produce significant morbidity. The EBIC recommended sedation as part of the treatment course for ABI but make no specific mention of propofol (Maas et al. 1997).
In two earlier studies, propofol was reported to provide satisfactory sedation with few side effects. . Farling et al. (1989) reported that propofol reduced ICP, increased CPP, and provided safe and effective sedation. Stewart et al. (1994) found that propofol provided sedation similar to a combination of midazolam and morphine with no differences in changes to ICP, CPP, and MAP or in outcomes at six months. However, both of these studies had small sample sizes and were lower quality. In a retrospective review, Smith et al. (2009) identified three patients with propofol infusion syndrome. The authors noted that each of these patients was receiving both propofol and vasopressors, and that no patient on either propofol or vasopressors alone developed propofol infusion syndrome.
An RCT by Kelly et al. (1999) compared propofol to morphine for safety and efficacy. Patients were randomly assigned to either a morphine group or a propofol group where they received three simultaneous injections: injection one had propofol or placebo, injection two had morphine or placebo, and injection three had low-dose morphine. This particular design allowed for the comparison of propofol dosing and its effectiveness while maintaining blinding, although all patients received propofol in conjunction with morphine. Propofol was found to reduce ICP when compared to morphine, and higher doses were shown to be more effective than lower doses. As well, patients in the propofol group showed less need for additional therapies for elevated ICP. At six months, there were no significant differences in mortality rates or GOS scores between the two groups. The authors suggested that propofol is a safe, acceptable, and possibly desirable alternative to opiate-based sedation (Kelly et al. 1999).
In a crossover RCT, patients with ABI received both propofol and dexmedetomidine, each over a six-hour period (James et al. 2012). The authors reported no significant differences between the groups after treatment in terms of ICP and CPP. As a result of these findings, they recommend that the “choice of sedative regimen be based on the profile of the sedative and the individual goals for a patient”.
There is Level 1b evidence that propofol reduces intracranial pressure and the need for other intracranial pressure interventions when used in conjunction with morphine compared to morphine alone.
There is Level 1b evidence that a high dose of propofol improves intracranial pressure and cerebral perfusion pressure compared to a low dose of propofol.
There is Level 2 evidence that propofol is not significantly different from dexmedetomidine in its effect on ICP.
There is Level 2 evidence that propofol is not significantly different from morphine and midazolam in its effect on intracranial pressure, cerebral perfusion pressure , mean arterial pressure, and long-term outcomes.
There is Level 4 evidence that propofol improves ICP and CPP.
Propofol, especially at higher doses may improve intracranial pressure and cerebral perfusion pressure; furthermore, propofol may reduce intracranial pressure and the need for other intracranial pressure interventions when used in conjunction with morphine.
Propofol may be no different than dexmedetomidine or morphine with midazolam in its effect on intracranial pressure.
Midazolam is a fast-acting benzodiazepine with a short half-life and inactive metabolites (McCollam et al. 1999). It 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 within 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 cerebrospinal fluid 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).
An early retrospective study by Papazian et al. (1993) reported that midazolam yielded non-significant reductions in ICP. In patients with severe TBI, those receiving midazolam had similar levels of ICP and CPP after treatment when compared to those receiving propofol, although was propofol associated with a shorter wake-up time (Sanchez-Izquierdo-Riera et al. 1998). The two medications were also found to provide similar long-term outcomes (Ghori et al. 2008). It should be noted that increased doses of midazolam have been associated with significant hypotension (Davis et al. 2001) and decreased levels of CPP and MAP (Papazian et al. 1993).
There is Level 4 evidence that midazolam reduces mean arterial pressure, cerebral perfusion pressure, and systolic blood pressure, but has no effect on intracranial pressure.
There is Level 2 evidence that midazolam is not different from propofol in its effect on intracranial pressure or cerebral perfusion pressure.
There is Level 1b evidence that midazolam is not different than propofol in its effect on long-term outcomes.
Midazolam may have no effect on ICP, but may reduce mean arterial pressure, cerebral perfusion pressured, and systolic blood pressure.
Midazolam is not different than propofol in its effect on intracranial pressure, cerebral perfusion pressure, or long-term outcomes.
Opioids are substances that produce morphine-like effects by binding to opioid receptors, found principally in the central nervous system and gastrointestinal tract. Each opioid has a distinct binding affinity to groups of opioid receptors that determines its pharmacodynamic response. Morphine has been the most commonly used opioid following ABI, while fentanyl and its derivatives have gained popularity owing to their more rapid onset and shorter duration of effect (Metz et al. 2000). However, controversy persists regarding the effect of opioids on ICP and CPP. It has been reported that opioids can increase cerebral blood flow (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.
Analgesic sedation with opioids is commonly used in conjunction with hypnotic agents (i.e., midazolam, propofol) to reduce nociceptive stimulation, which makes it difficult to evaluate the effects of opioids in isolation. Five studies reported increases in ICP after opioid administration (Albanese et al. 1993,1999; de Nadal et al. 2000; Sperry et al. 1992; Werner et al. 1995), while two found no increase in ICP (Engelhard et al. 2004; Karabinis et al. 2004; Lauer et al. 1997) and one reported a decrease (Scholz et al. 1994). However, the mode of administration has been suggested as a determining factor for increases in ICP (Albanese et al. 1993, 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).
There is Level 1a evidence that morphine, sufentanil, and alfentanil result in increased intracranial pressure post ABI.
There is conflicting evidence (Level 1b) regarding the effects of fentanyl on intracranial pressure post ABI.
There is Level 2 evidence that remifentanil does not affect intracranial pressure post ABI.
Different opioids may have different intracranial pressure effects post ABI; where morphine, sufentanil, and alfentanil may increase intracranial pressure, remifentanil may not affect intracranial pressure, and the effect of fentanyl on intracranial pressure post ABI is unclear.
Barbiturates have long been proposed as a useful intervention in the control of ICP. They are thought to reduce ICP by suppressing cerebral metabolism and reducing metabolic demands and cerebral blood volume (Roberts 2000). Early reports indicated that barbiturates reduced ICP in patients reported to be unresponsive to rigorous treatments with conventional ICP management techniques, including mannitol and hyperventilation (Marshall et al. 1979; Rea & Rockswold 1983; Rockoff et al. 1979). However, most of these early investigations provided only anecdotal or poor evidence, as they were conducted in very small cohorts of patients lacking control comparisons. Later studies explored the negative side effects associated with barbiturate coma, such as adrenal insufficiency (Llompart-Pou et al. 2007) and bone marrow suppression (Stover & Stocker 1998).
The AANS made Level II B recommendations that high-dose barbiturates can be used to control elevated ICP that is refractory to maximum standard medical and surgical treatment (Carney et al. 2017). They also reported Level II evidence against the use of prophylactic barbiturates for inducing electroencephalogram burst suppression. The EBIC guidelines recommended barbiturate use to increase sedation only after previous sedation, analgesia, hyperventilation, osmotic therapy, and CSF drainage have failed to control ICP (Maas et al. 1997).
The findings of an RCT by Eisenberg et al. (1988) suggested that pentobarbital was an effective adjunctive therapy for the management of elevated ICP refractory to conventional therapeutic measures. However, this study only supported the use of the high dose barbiturate for a small subgroup of patients with severe ABI (GCS≤7). In contrast, the findings of an RCT by Ward et al. (1985) suggested that pentobarbital was no better than conventional ICP management measures, which was corroborated by Schwartz et al. (1984) in an RCT 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. Schalen et al. (1992) also noted that decreased ICP was associated with decreased CPP and MAP. More recently, Majdan et al. (2013) found that barbiturate administration was associated with a significant increase in the amount of time spent with low MAP, despite a decrease in the amount of time with elevated ICP. Furthermore, the authors reported that high doses of barbiturate were associated increased intubation days, days in the ICU, and did not improve clinical outcomes.
In accordance with recommendations made by the Brain Trauma Foundation, Perez-Barcena et al. (2005, 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.
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.
There is conflicting (Level 1b, Level 2, Level 3) evidence regarding the efficacy of pentobarbital in improving intracranial pressure over conventional management measures.
There is Level 2 evidence that thiopental is more effective than pentobarbital for controlling elevated intracranial pressure.
There is Level 2 evidence that pentobarbital is not more effective than mannitol for controlling elevated intracranial pressure.
There is Level 3 evidence that high-dose barbiturate results in increase length of stay and does not improve outcomes when compared to low-dose barbiturate.
There is Level 4 evidence that barbiturate therapy may cause reversible leukopenia, granulocytopenia, and systemic hypotension, as well as supressed bone marrow production.
There is Level 4 evidence that a combination barbiturate therapy and therapeutic hypothermia may result in improved clinical outcomes up to 1 year post injury.
There are conflicting reports regarding the efficacy of pentobarbital and thiopental for controlling elevated intracranial pressure; however, thiopental may be more effective than pentobarbital for controlling elevated intracranial pressure.
Pentobarbital may be less effective than mannitol for controlling elevated intracranial pressure.
Barbiturate therapy should be avoided until all other measures for controlling elevated intra cranial pressure are exhausted; patients undergoing barbiturate therapy should have their immunological response monitored.
Dexanabinol (HU-211) is a synthetic, non-psychotropic cannabinoid (Mechoulam et al. 1988). It is believed to act as a non-competitive N-methyl-D-aspartate receptor antagonist to decrease glutamate excitotoxicity (Feigenbaum et al. 1989). It is also believed to possess antioxidant properties (Eshhar et al., 1995) and has shown encouraging neuroprotective effects in animal models of TBI (Shohami et al. 1995).
The AANS and the EBIC made no recommendations regarding cannabinoids in acute ABI.
In an early RCT, Knoller et al. (2002) found that dexanabinol (50mg or 150mg) showed significant improvements in ICP and CPP over placebo for patients with TBI. Despite showing significant improvements on the GOS and Disability Rating Scale at one month post treatment, these benefits progressively lost significance over the 6-month follow-up. Maas et al. (2006) conducted a large-scale multicenter RCT to better establish the efficacy of dexanabinol in the treatment of TBI. Patients admitted to 86 different centres from 15 countries were randomized to receive dexanabinol or placebo within six hours of injury. The authors reported that dexanabinol did not significantly improve outcomes on the GOSE, Barthel Index, or quality of life measures (SF-36, CIQ) at six months when compared to placebo. Moreover, dexanabinol failed to provide any acute control of ICP or CPP. These findings suggest that the initial benefits reported by Knoller et al. (2002) may have been due to their small sample size. In a more recent RCT, Firsching et al. (2012) utilized a dual cannabinoid agonist as means of reducing ICP. When compared to placebo, the authors reported significant increases in CPP and greater survival at one month, but non-significant decreases in ICP. These results suggest that the dual cannabinoid agonist may an overall positive effect on patients post TBI and is worth exploring in future research.
There is conflicting evidence (Level 1b) as to whether dexanabinol in cremophor-ethanol solution effectively lowers intracranial pressure, increases cerebral perfusion pressure, and improves long-term clinical outcomes post TBI when compared to placebo.
There is Level 1b evidence that a dual cannabinoid agonist significantly increases cerebral perfusion pressure and improves survival post TBI when compared to placebo.
Dexanabinol in cremophor-ethanol solution may not be effective in controlling intracranial pressure or improving clinical outcomes post TBI; however, dual cannabinol agonists may be effective in increasing cerebral perfusion pressure and reducing mortality post TBI.
Numerous corticosteroids have been used in brain injury care including dexamethasone, methylprednisolone, prednisolone, prednisone, betamethasone, cortisone, hydrocortisone, and triamcinolone (Alderson & Roberts 2005). Using such a broad spectrum of agents within diverse patient groups has made understanding corticosteroid efficacy difficult. Adding to this difficulty is a lack of understanding regarding the mode of steroid action. Grumme et al. (1995) reported that laboratory studies have associated corticosteroid use with reductions in wet brain weight, facilitation of synaptic transmission, reduction of lipid peroxidation, preservation of electrolyte distribution, enhanced blood flow, and membrane stabilization (Grumme et al. 1995). While it had been thought that the benefits of corticosteroids could arise from reductions in ICP, as well as neuroprotective activity, several studies have suggested limitations in their usage. Focal lesions seem to respond well to corticosteroid therapy, while diffuse intracerebral lesions and hematomas are less responsive (Cooper et al. 1979; Grumme et al. 1995).
In the wake of several large scale trials, questions regarding the safety of corticosteroid administration have been brought to light. Alderson and Roberts (1997) conducted a systematic review of corticosteroid literature and concluded that there was a 1.8% improvement in mortality associated with corticosteroid use. However, their 95% confidence interval ranged from a 7.5% reduction to a 0.7% increase in deaths. Roberts et al. (2004) studied corticosteroid use in acute brain injury with the goal of recruiting 20,000 patients with TBI; after 10,008 patients were recruited it became clear that corticosteroid use caused significant increases in mortality and the trial was halted.
The AANS stated that steroid use was not recommended for reducing ICP or improving outcomes, and that high-dose methylprednisolone was associated with increased mortality (Carney et al. 2017). The EBIC stated that there was no established indication for the use of steroids in acute head injury management (Maas et al. 1997).
In light of a series of inconclusive studies into the effectiveness and safety of corticosteroid use, a very large multinational randomized collaboration for assessment of early methylprednisolone administration was initiated in 1999 (Roberts et al. 2004). To achieve 90% power, recruitment of 20,000 patients in the Corticosteroid Randomization after Severe Head Injury (CRASH) trial was the goal. After the random allocation of 10,008 patients, the experiment was halted. Of 4,985 patients allocated corticosteroids, 1052 died within two weeks compared to 893 of 4979 patients in the placebo group. This indicated a relative risk of death equal to 1.8 in the steroid group (p=0.0001). Further analysis showed no differences in outcomes between eight CT subgroups or between patients with major extracranial injury compared to those without. The authors also conducted a systematic review and meta-analysis of existing trials using corticosteroids for head injury. Before the CRASH trial, a 0.96 relative risk of death was seen in the corticosteroid group. Once the patients from the CRASH trial were added, the relative risk changed to 1.12. The authors suggest that based on this large multinational trial, corticosteroids should not be used in head injury care no matter what the severity of injury.
Two other studies assessed methylprednisolone in acute ABI management. Giannotta et al. (1984) conducted an RCT of patients with GCS≤8 treated with methylprednisolone. Patients were divided into one of three groups: a high dose, low dose or placebo group, then assessed at six months based on the GOS grading system. They reported no differences in mortality rates between groups. The authors then compressed the low dose and placebo groups and performed further analyses. They found that patients less than 40 years old in the high dose group showed significant decreases in mortality when compared to the low dose/ placebo group; further, they found no significant differences between these groups in beneficial outcomes. Saul et al. (1981) conducted another RCT where patients received methylprednisolone or no drug at all. They noted that there were no differences between the two groups in GOS scores at 6 months.
Four RCTs were found that assessed dexamethasone in ABI. Dearden et al. (1986) assessed consecutively admitted patients with ABI treated with dexamethasone. They noted that patients experiencing ICP levels >20mmHg showed significantly poorer outcomes on the GOS at six months. Braakman et al. (1983) found no differences between patients treated with dexamethasone compared to placebo in one month survival rates or six month GOS scores. Similarly, Cooper et al. (1979) performed a double blind randomized controlled study of the effects of dexamethasone on outcomes in severe head injuries. Patients were divided into three groups and no significant differences were seen in outcomes. The authors performed several post-mortem examinations and indicate that often, patients initially diagnosed with focal lesions were in fact suffering from diffuse injuries which are not amenable to corticosteroid treatment. Finally, Kaktis & Pitts (1980) assessed the effects of low-dose (16mg/day) and high-dose (14mg/day) dexamethasone on ICP levels in patients with ABI. They noted no differences in ICP at any point during the 72 hour follow-up period.
In a cohort study conducted by Watson et al. (2004) patients receiving any form of glucocorticoid therapy (dexamethasone 98%, prednisone 2.4%, methylprednisone 1.6%, or hydrocortisone 1.6%) were compared two patients treated without corticosteroids for risk of development of post-traumatic seizures. Their inclusion criteria allowed for patients with only one of a list of complications to be included resulting in a diverse group of patients with TBI. They noted that patients receiving glucocorticoid treatment on the first day post injury were at increased risk of developing first late seizures compared to patients receiving no treatment. They also saw no improvement in patients receiving glucocorticoids after the first day. The authors suggest that this ads further strength to the argument against routine corticosteroid use in TBI (Watson et al. 2004).
Grumme et al. (1995) conducted an RCT in which GOS scores were assessed one year after injury in patients treated with the synthetic corticosteroid triamcinolone. While no overall effect between groups was found, further analysis was performed on subsets of patients. A significant increase in beneficial outcomes was seen in patients who had both a GCS<8 and a focal lesion. The authors suggest that in light of this evidence, patients with both GCS<8 and a focal lesion would benefit from steroid administration immediately after injury.
There is Level 1a evidence that methylprednisolone increases mortality rates in patients post ABI and should not be used.
There is Level 1b evidence that dexamethasone does not lower elevated intracranial pressure levels and may worsen outcomes.
There is Level 2 evidence that triamcinolone may improve outcomes in patients with a GCS<8 and a focal lesion.
There is Level 3 evidence that glucocorticoid administration may increase the risk of developing first late seizures.
Corticosteriods such as methylprednisolone, dexamethasone, and glucocorticoids may worsen outcomes, with no effect on intracranial pressure levels, and should not be used.
Triamcinolone may improve outcomes in patients with a Glasgow Coma Scale<8 and a focal lesion.
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.
In an RCT, Wright et al. (2007) evaluated patients receiving the medication over three days and found no significant improvement in ICP levels over placebo. However, these patients showed a decreased 30-day mortality rate without an increased rate of complications. As well, less severe patients in this group also showed significantly greater rates of favourable outcomes on the GOSE. Noting limitations in group distribution within their study, the authors recommended a larger clinical trial. Xiao et al. (2008) conducted such a trial with patients receiving progesterone or placebo over five days. They similarly reported a lack of improvement in ICP over placebo, but significantly greater GOS and FIM scores at three months and six months, and lower mortality at six months. They also reported no complications associated with progesterone administration.
In contrast, more recent trials have reported no significant differences in outcomes between those receiving progesterone or placebo after three months (Shakeri et al. 2013) and six months (Shakeri et al. 2013; Skolnick et al. 2014; Wright et al. 2014). However, in a subgroup analysis of patients with initial GCS>5, Shakeri (2013) found a significant improvement in GOS scores associated with progesterone. As well, one study reported that progesterone was not associated with increased rate of serious adverse events (Wright et al. 2014). Given the conflicting findings between studies, the evidence regarding progesterone in acute ABI should be taken with caution.
There is Level 1a evidence that progesterone does not lower intracranial pressure levels post TBI when compared to placebo.
There is Level 1a evidence that progesterone is not associated with adverse events when compared to placebo.
There is conflicting evidence (Level 1a) as to whether progesterone improves long-term outcomes and reduces mortality post TBI when compared to placebo.
Progesterone may improve Glasgow Outcome Scale scores and reduce mortality rates up to 6 months post injury, without an increased rate of adverse events.
Progesterone may not be effective in lowering intracranial pressure levels.
Any type of tissue injury or death following brain injury acts as a strong trigger for the initiation of an inflammatory response. The kinin-kallikrein pathway is one of the components of this acute inflammatory cascade (Marmarou et al. 1999; Narotam et al. 1998). The generation of bradykinin from this pathway leads to a detrimental 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 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 to these receptors (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.
We identified two trials that evaluated the efficacy of Bradycor in the acute treatment of ABI. In the smaller study, the authors reported that treatment with Bradycor resulted in a significant reduction in ICP elevations when compared to placebo (Narotam et al. 1998). They found that patients in the placebo group experienced a greater deterioration in GCS scores over the course of the study. As well, the need for other therapeutic interventions to control ICP was markedly lower in those who received Bradycor. A larger RCT conducted by Marmarou et al. (1999) similarly found that patients on Bradycor experienced a significant reduction in intracranial hypertension (ICP>15mmHg) over placebo. However, there were 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.
Anatibant is believed to be a more potent bradykinin antagonist than Bradycor, and was evaluated by Marmarou et al. (2005) in a later trial. 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. Shakur et al. (2009) conducted a large-scale multicenter trial of Anatibant. The authors reported an elevated risk of serious adverse events among patients receiving the medication, without improvements in morbidity or mortality. As such, the trial was terminated early on by the investigators, leading to a legal dispute with its sponsors.
There is Level 1a evidence that Bradycor is effective at preventing acute elevations in intracranial pressure and reducing therapeutic intensity levels post ABI when compared to placebo.
There is Level 1b evidence that Anatibant is no more effective than placebo in improving long-term outcomes and may result in serious adverse events post ABI.
Bradykinin antagonists such as Bradycor may prevent acute elevations in intracranial pressure and reduce therapeutic intensity levels post ABI; however, others such as Anatibant may not improve long-term outcomes and may result in serious adverse events.
Dimethyl sulfoxide (DMSO) has been suggested for the treatment of elevated ICP following ABI. Through its ability to stabilize cell membranes, DMSO protects cells from mechanical damage and reduces edema in tissue (Kulah et al. 1990). DMSO is also believed to act as a free radical scavenger and increase tissue perfusion, thereby improving cell oxygenation, neutralizing metabolic acidosis, and decreasing intracellular fluid retention (Kulah et al. 1990).
The AANS and the EBIC made no recommendations regarding DMSO in acute ABI.
Three retrospective studies have examined the effects of DMSO in the management of ICP post ABI. The findings of Marshall et al. (1984) suggested that rapid infusions of DMSO were effective in controlling elevated ICP that was refractory to standard measures. In a study by Kulah et al. (1990), patients with elevated ICP were treated with a single bolus injection of DMSO within 6 hours of injury. 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. 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.
There is Level 4 evidence that dimethyl sulfoxide temporarily reduces intracranial pressure elevations that may not be sustained over the long-term.
Dimethyl sulfoxide may cause temporary reductions in intracranial pressure elevations post ABI that may not be sustained over the long-term.
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.
In a retrospective study, paracetamol (acetaminophen) was found to significantly reduce ICP, CPP, MAP, and core body temperature post TBI (Picetti et al. 2014). 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). Finally, in another trial, it was reported that vasopressin and catecholamine yielded similar improvements to ICP and CPP post TBI (Van Haren et al. 2013). Given the limited research on each of these medications, additional clinical trials are required to make firm conclusions.
There is Level 1b evidence that conivaptan lowers elevated intracranial pressure post ABI when compared to standard acute care alone (e.g. osmolar therapy, sedation, analgesia).
There is Level 1b evidence that vasopressin and catecholamine are similarly effective in lowering elevated intracranial pressure post ABI.
There is Level 4 evidence that paracetamol effectively lowers elevated intracranial pressure post ABI.
Elevated intracranial pressure may be effectively reduced by other pharmacological interventions including paracetamol, conivaptan, vasopressin, and catecholamine. However, further research on each of these medications is required.