Barbiturates

It has long been proposed that barbiturates may be useful in the control of ICP. Barbiturates are thought to reduce ICP by suppressing cerebral metabolism to reduce metabolic demands and cerebral blood volume (Roberts 2000). Early reports indicated that barbiturates reduced ICP even in patients reported to be unresponsive to rigorous treatments with conventional ICP management techniques including mannitol and hyperventilation (Marshall et al. 1979). Further studies supported the therapeutic potential of barbiturates and suggested that failure to control ICP can lead to death (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. More recent studies have 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 American Association of Neurological Surgeons make Level II recommendations that prophylactic administration of barbiturates to induce electroencephalogram (EEG) burst suppression should not be performed. They also make Level II recommendations that high-dose barbiturate administration can be used to control elevated ICP that is refractory to maximum standard medical and surgical treatment (Bratton et al. 2007). The European Brain Injury Consortium (EBIC) guidelines recommend barbiturate use to increase sedation only after sedation, analgesia, hyperventilation, osmotic therapy, and CSF drainage have failed to control ICP (Maas et al. 1997).

Table: Effects of Barbiturates in the Management of Elevated Intracranial Pressure

Discussion

The findings from an RCT conducted by Eisenberg et al. (1988) suggest that the use of high-dose barbiturates during the acute phase post injury is more effective in the management of elevated ICP compared to conventional therapies, as patients receiving pentobarbital were twice as likely to achieve adequate ICP control as those receiving conventional therapies only. This finding however is in direct contrast to what had been reported in a previous RCT conducted by Ward et al. (1985) who failed to observe any significant differences between the pentobarbital group and the conventional therapy group in various measures of ICP control (e.g. hourly reductions in ICP, duration of ICP elevation, and number of patients succumbing to elevated ICP). The discrepancy between the two studies indicates there remains a level of uncertainty in establishing whether barbiturate therapy is more effective than conventional therapies for the management of elevated ICP post ABI.

An RCT also investigated whether pentobarbital was more effective than mannitol in alleviating elevated ICP post injury (Schwartz et al. 1984). The authors found that pentobarbital was generally ineffective compared to mannitol, citing that a far greater proportion of patients from the pentobarbital group needed to be reallocated into the mannitol group to achieve adequate ICP control.

Findings from two studies suggest that barbiturate use may not be effective at all in the management of elevated ICP (Colton et al. 2014; Thorat et al. 2008). The authors of respective studies have shown that treatment with barbiturates did not lead to significant reductions in ICP post injury. However given that these studies were performed retrospectively, their findings should be viewed with some caution. Further RCTs are warranted.

While one study noted that barbiturates (e.g. thiopentone) were helpful in decreasing elevated ICP, the same authors also cautioned that this might have occurred at the expense of lowered arterial pressure, which ultimately led to a reduction in CPP (Schalen et al. 1992). Similarly, Majdan et al. (2013) reported that even though barbiturate administration was able to reduce ICP in 69% (n=22) of the study participants, it was also associated with longer periods of reduced mean arterial pressure, leading to considerable hemodynamic instability.

Further potential complications related to barbiturate use have been reported. Llompart-Pou et al. (2007) for example found that barbiturate therapy with either thiopental or pentobarbital was associated with adrenal insufficiency secondary to brain injury. In another study, the use of thiopental led to significantly reduced white blood cell production and was shown to induce reversible leukopenia and granulocytopenia (Stover & Stocker 1998). The authors also noticed interactions between bone marrow suppressing antibiotics (specifically, tazobactum/piperacillin) and thiopental, further exacerbating the problem.

Nevertheless, barbiturates may be beneficial from a metabolic standpoint. For instance, Fried et al. (1989) in their retrospective study compared the energy expenditure and nitrogen excretion in patients treated with pentobarbital and those who received conventional ICP therapy without pentobarbital. They reported that pentobarbital helped lower energy expenditure and nitrogen excretion, thereby allowing the brain to achieve energy and nitrogen equilibrium during metabolic support of patients with acute head injury. 

There is some evidence that barbiturates may also affect long-term clinical outcomes. In a prospective controlled trial conducted by Nordby and Nesbakken (1984), the authors reported that thiopental combined with mild hypothermia resulted in better clinical outcomes as per the GOS 1 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. Further study is thus needed to shed such uncertainties.  

Conclusions

There is Level 2 evidence that pentobarbital is not effective for intracranial pressure management. 

Based on a single RCT, there is Level 2 evidence that pentobarbital is no better than mannitol for the control of elevated intracranial pressure.

Based on two case control studies, there is Level 3 evidence that barbiturate therapy may lead to adrenal insufficiency, reversible leukopenia and granulocytopenia.

Based on a single prospective controlled study, there is Level 2 evidence that barbiturates confer metabolic benefits.

Based on a single prospective controlled study, there is Level 2 evidence that a combination of barbiturate therapy and hypothermia may result in improved clinical outcomes up to 1 year post injury.

 

Pentobarbital is not effective for intracranial pressure management.

Pentobarbital is not better than mannitol for the control of elevated intracranial pressure.

Barbiturate therapy may improve metabolic functions.

Patients undergoing barbiturate therapy should have their immunological response and systemic blood pressure monitored.

Barbiturate therapy plus hypothermia may improve clinical outcomes.