There are insufficient data to support a Level I recommendation for this topic.

Prophylactic administration of barbiturates to induce burst suppression EEG is not recommended.

High-dose barbiturate administration is recommended to control elevated ICP refractory to maximum standard medical and surgical treatment. Hemodynamic stability is essential before and during barbiturate therapy.

Propofol is recommended for the control of ICP, but not for improvement in mortality or 6 month outcome. High-dose propofol can produce significant morbidity.

A variety of pharmacological agents have been advocated to treat pain and agitation in the traumatic brain injury (TBI) patient. It is felt beneficial to minimize painful or noxious stimuli as well as agitation as they may potentially contribute to elevations in ICP, raises in blood pressure, body temperature elevations and resistance to controlled ventilation. Until recently the primary concern over the utilization of these agents has been related to their tendency to obscure the neurologic exam, with a secondary concern over potential adverse hemodymanic effects. In the previous edition of these guidelines,2 little information was provided regarding analgesic and sedation utilization in severe TBI. It was noted that there have been relatively few outcome studies and therefore "decisions about . . . use . . . and the choice of agents are left to the practitioner to make based on individual circumstances."

Since the 1930s, high-dose barbiturates have been known to lower ICP.10 However their well known risks and complications, as well as the ongoing controversy over their ultimate benefits, have limited their use to the most extreme of clinical situations. Both cerebral protective and ICP-lowering effects have been attributed to barbiturates: alterations in vascular tone and resistance, suppression of metabolism, inhibition of free radical-mediated lipid peroxidation and inhibition of excitotoxicity. The most important effect may relate to coupling of cerebral blood flow (CBF) to regional metabolic demands such that the lower the metabolic requirements, the less the CBF and related cerebral blood volume with subsequent beneficial effects on ICP and global cerebral perfusion.

A number of barbiturates have been studied, with the most information available on pentobarbital. All suppress metabolism, however little is known about comparative efficacy to recommend one agent over another except in relationship to their particular pharmacologic properties. Considerably more is known, however, about the potential complications of a therapy that is essentially the institution of a general anesthetic in a non-operating room environment.

The use of barbiturates is based on two postulates: (1) they can affect long-term ICP control when other medical and surgical therapies have failed, and (2) absolute ICP control improves ultimate neurologic outcome.

This chapter combines information from the previous guideline about barbiturates with new information about sedatives and analgesics. Medline was searched from 1966 through April of 2006 (see Appendix B for search strategy). Results were supplemented with literature recommended by peers or identified from reference lists. Of 92 potentially relevant studies, one new study was included as evidence and added to the existing table (Evidence Table I).

Only one study fulfilling the predetermined inclusion criteria for this topic provides an evidence base for recommendations about sedatives and analgesics. In 1999, Kelly et al. conducted a double-blind, randomized controlled trial (RCT) comparing multiple endpoints for patients who received either propofol or morphine sulfate.

Propofol has become a widely used neuro-sedative as this sedative-hypnotic anesthetic agent has a rapid onset and short duration of action. In addition, propofol has been shown to depress cerebral metabolism and oxygen consumption and thus has a putative neuroprotective effect. Several studies found no statistically or clinically acute significant changes in MAP or ICP with propofol infusions, but they suggest that ICP might decrease slightly (mean, 2.1 mm Hg) after several hours of dosing.

The primary end-point of the trial by Kelly et al. was determining drug safety, but they also evaluated clinically relevant end-points, including ICP control, CPP, therapeutic intensity level (TIL) for ICP/CPP control, 6-month neurological outcome and treatment-related adverse events. Sixty-five patients with a GCS of 3-12 were randomized to receive either morphine sulfate (average infusion rate of 1.3 ± 0.7 mg/hour) or propofol (average infusion rate of 55 ± 42 mcg/kg/min). Twenty-three patients were excluded for various reasons from the efficacy analysis, leaving 23 in the propofol and 19 in the morphine group. Daily mean ICP and CPP were similar between the two groups; however, on day 3 ICP was lower in the propofol group (p < 0.05), and the TIL overall was higher in the morphine group.

There were no significant differences between groups in mortality or GOS. A favorable neurological outcome based on the GOS occurred in 52.5% of propofol treated patients compared to 47.4% of those receiving morphine, with mortality rates of 17.4% and 21.1%, respectively. In a post hoc, analysis, authors compared outcomes for patients receiving "high-dose" (total dose of >100 mg/kg for >48 h) versus "low-dose" propofol. While there were no significant differences in ICP/CPP between these groups, there was a significant difference in neurological outcome: high-dose favorable outcome 70% versus low-dose 38.5% (p < 0.05).

Significant concerns have subsequently arisen regarding the safety of high dose propofol infusions. Propofol Infusion Syndrome was first identified in children, but can occur in adults as well. Common clinical features include hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, rhabdomyolysis, and renal failure resulting in death. Thus extreme caution must be taken when using doses greater than 5 mg/kg/h or when usage of any dose exceeds 48 h in critically ill adults.

The following section contains information about sedatives and analgesics from small studies that do not provide an evidence base for recommendations.

The most widely used narcotic in the acute setting has been morphine sulfate. Limited studies suggest a high level of analgesic efficacy and safety in this setting, however it provides minimal if any sedation and tachyphylaxis is extremely common, thus leading to continuous need for dose escalation and a prolonged period of "withdrawal" when therapy is discontinued. At least one study demonstrated a significant rebound increase in CBF and ICP with pharmacologic reversal of morphine.

The rapidly metabolized synthetic narcotics, fentanyl and sufentanyl, have become increasingly popular because of their brief duration of action. However, multiple studies have shown a mild but definite elevation in ICP with their utilization.1,20 deNadal et al. showed a significant fall in mean arterial pressure (MAP) and rise in ICP (p < 0.05) lasting for up to 1 h after a single bolus dose of fentanyl (2 mcg/kg) in 30 severe TBI patients. Patients with preserved autoregulation experienced the largest elevations in ICP.

One study suggested that the slow, titrated administration of fentanyl and sufentanyl may minimize ICP elevations. Thus utilization of the synthetic narcotics should be undertaken with caution in potentially hemodynamically unstable patients and those with poor intracranial compliance. No studies were found examining the effects of continuous use of these agents on ICP or hemodynamics. Tachyphylaxis and withdrawal symptoms may occur after prolonged use of these agents.

Traditionally, benzodiazepines have been avoided in the TBI population because of their neuro-depressant effects and their long duration of action. However, Midazolam has gained wide popularity in neurosurgical intensive care units, especially to control agitation associated with mechanical ventilation. Papazian et al. studied 12 patients with GCS < 6 with a 0.15 mg/kg midazolam bolus. All had a baseline ICP of <18 mm Hg. Up to a 50% decrease in MAP (p < 0.0001) was observed with 33% of patients with a significant and sustained elevation in ICP, and a similar percentage with a sustained drop in cerebral perfusion pressure (CPP) below 50 mm Hg (p < 0.0001).17 Nevertheless, caution must be exercised when using this agent as well. A test bolus of 2 mg can be used to ascertain efficacy and systemic response before initiating a continuous infusion. If necessary, midazolam can be reversed with flumazenil.

There have been three randomized controlled trials of barbiturate therapy in severe TBI.

Prophylactic use of barbiturates. Two RCTs examined early, prophylactic administration and neither demonstrated significant clinical benefit. In 1984, Schwartz et al. compared barbiturates to mannitol as the initial therapy for ICP elevations and found no improvement in outcome, noting that when diffuse injury was present, barbiturate-treated patients fared much worse. Patients with ICPs of >25 mm Hg for more than 15 min were randomly assigned to a pentobarbital or mannitol treatment group. In patients who underwent evacuation of mass lesions, mortalities were 40% and 43%, respectively. However, in patients with diffuse injury, there was 77% mortality in those on pentobarbital compared to 41% receiving mannitol. Additionally, these authors noted significant decrements in CPP in the pentobarbital group.

In 1985, Ward et al. reported results of an RCT of pentobarbital in 53 consecutive TBI patients who had an acute intradural hematoma or whose best motor response was abnormal flexion or extension. There was no significant difference in 1-year GOS outcomes between treated patients and controls, while six in each group died from uncontrollable ICP. The undesirable side effect of hypotension (SBP < 80 mm Hg) occurred in 54% of the barbiturate-treated patients compared to 7% in the control group (p < 0.001).

Refractory intracranial hypertension.In 1988, Eisenberg et al. reported the results of a five-center RCT of highdose barbiturate therapy for intractable ICP elevation in patients with a GCS of 4-8.7 ICP control was the primary outcome measure, although mortality was also assessed. The patients were randomly allocated to barbiturate treatment when standard conventional therapy failed.

Patients in the control group were electively crossedover to barbiturate therapy at specific "ICP treatment failure" levels. There were 36 controls and 32 study patients, although 32 of the controls ultimately crossed-over and received barbiturates. The odds of ICP control were two times greater with barbiturate treatment and four times greater when adjusted for "cardiovascular complications." The likelihood of survival for barbiturate responders was 92% at 1 month compared to 17% for non-responders. Of all deaths, 80% were due to refractory ICP. At 6 months, 36% of responders and 90% of non-responders were vegetative or had died. Due to the study design, the effects of barbiturate treatment on any outcome other than mortality cannot be conclusively determined. Additionally, when one compares the noncrossover control patients (n = 10) with the patients initially randomized to barbiturates, the effect on mortality was lost: 100% versus 97.7% survival.

Prerandomization cardiac "complications" were evaluated and appeared to have an important interaction with barbiturate therapy and outcome. In those patients with prerandomization hypotension, control of ICP with either barbiturate or conventional treatment had a similar chance of success (24% vs. 29%).

It must be borne in mind that all of the RCTs of barbiturate therapy were undertaken when prolonged prophylactic hyperventilation, fluid restriction and steroids were considered the best available medical therapies for severe TBI.

Systematic review of barbiturate RCTs.In 1999 and 2004, the Cochrane Injuries Group undertook a systematic review of the three barbiturate RCTs. In all three trials, death was an outcome measure and the pooled relative risk for death was 1.09 (95% CI 0.81-1.47). In the two studies utilizing the GOS, the pooled relative risk for adverse neurologic outcome was 1.15 (95% CI 0.81-1.64). In the two studies examining the effect on ICP, the relative risk for refractory ICP with barbiturate therapy was 0.81 (95% CI 0.62-1.06). In the two studies examining the occurrence of hypotension, there was a substantial increase of occurrence of hypotension in barbiturate treated patients (RR = 1.80, 95% CI 1.19-2.70).

The Cochrane group thus concluded: "There is no evidence that barbiturate therapy in patients with acute severe head injury improves outcome. Barbiturate therapy results in a fall in blood pressure in one of four treated patients. The hypotensive effect of barbiturate therapy will offset any ICP lowering effect on cerebral perfusion pressure"

Sedatives and analgesics.Table 1 provides general dosing guidelines if the option to utilize these agents is exercised.

Barbiturates. A number of therapeutic regimens using pentobarbital have been applied, all requiring a loading dose followed by a maintenance infusion. The Eisenberg RCT7 used the following protocol:

Even though a goal of therapy is to establish serum pentobarbital levels in the range of 3-4 mg%, available pharmacologic literature suggests a poor correlation among serum level, therapeutic benefit and systemic complications. A more reliable form of monitoring is the electroencephalographic pattern of burst suppression. Near maximal reductions in cerebral metabolism and CBF occur when burst suppression is induced.

Analgesics and sedatives are a common management strategy for ICP control, although there is no evidence to support their efficacy in this regard and they have not been shown to positively affect outcome. When utilized, attention must be paid to potential undesirable side effects that might contribute to secondary injury.

High dose barbiturate therapy can result in control of ICP when all other medical and surgical treatments have failed. However it has shown no clear benefit in improving outcome. The potential complications of this form of therapy mandate that its use be limited to critical care providers; that patients be hemodynamically stable before its introduction; and that appropriate, continuous systemic monitoring be available to avoid or treat any hemodynamic instability. Utilization of barbiturates for the prophylactic treatment of ICP is not indicated.

More studies are needed to identify certain subsets of patients who might respond favorably to analgesic-sedative and/or barbiturate treatment, and to identify alternative agents, drug combinations, and dosing regimens.14 Continuous dosing regimens must be further refined to determine affect on outcome.

More research should be added to current studies of the novel sedative-anesthetic dexmedetomidine and its effects in patients with severe TBI.3 They should attempt to identify subsets of patients who might respond favorably or unfavorably to barbiturate treatment. For example, Cruz et al. suggested that certain patients may develop oligemic hypoxia if given barbiturates.4 Lobato et al., based on their experience with 55 patients, suggested that barbiturates increase the odds of survival in the setting of post-traumatic unilateral hemispheric swelling.15 And Nordstrom et al. demonstrated a correlation in 19 patients between cerebral vasoreactivity and the beneficial effects of barbiturate therapy on outcome.16

The effects of barbiturate-mediated ICP control on the quality of survival after severe TBI remain, for the most part, unknown. Further studies are required to adequately address outcomes utilizing the GOS, Disability Rating Scale, Functional Independence Measures, and neuropsychological testing.

Finally, additional studies examining the comparative clinical efficacy of different barbiturates or combinations of barbiturates are warranted.