Stover et al. (1998)

Germany

Case Control

N=52

Population: TBI; Thiopental (n=23): Mean Age=27 yr; Severity: Severe. Control (n=29): Mean Age=44 yr; Severity: Severe.

Intervention: Patients were included in retrospective analysis. Some received intravenous thiopental (5-11 mg/kg bolus, followed by continuous infusion of 4-6 mg/kg/hr and 4-6 bursts/min). Others received sedation with fentanyl and midazolam. ICP was targeted <20 mmHg and mean ar-terial pressure > 90 mmHg.

Outcome Measures: Infection rate, Granulocyte Count, Leukocyte Count, Bone Marrow Production.

1.        Patients requiring barbiturates were significantly younger than those not requiring it (27 yr versus 44 yr, p<0.01).

2.        Barbiturates were shown to induce reversible leukopenia and granulocytopenia as well as an increased infection rate.

3.        Several patients showed suppressed bone marrow production on histological examination.

Schalen et al. (1992)

Sweden

Case Series

N=38

Population: TBI; Median Age=20 yr; Gender: Male=30, Female=8.

Intervention: Patients received high-dose intravenous thiopental at 5-11 mg/kg, followed by a continuous infusion at 4-8 mg/kg/hr for at least 12 hr.

Outcome Measures: Intracranial Pressure (ICP), Mean Arterial Pressure (MAP), Cerebral Perfusion Pressure (CPP).

1.        There was a decrease in MAP in 31 patients, a small increase in 3, and no change in 4.

2.        There was a decrease in ICP in 26 patients, a small increase in 2, and no change in 3.

3.        There was a decrease in CPP in 18 patients, an increase in 10, and no change in 3.

4.        Though the fall in ICP immediately following infusion of thiopentone reduced the number of patients with decreased CPP (≤60 mmHg), continued treatment led to a fall in MABP, ultimately contributing to the decrease in CPP.

Nordby & Nesbakken (1984)

Norway

PCT

N=38

Population: TBI; Thiopental (n=16): Mean Age=20 yr; Mean GCS Score=4.3. Control (n=15): Mean Age=26 yr; Mean GCS=5.2.

Intervention: Patients received continuous intravenous thiopental: a loading infusion of 10-20 mg/kg and a maintenance infusion of 3-5 mg/kg/hr to maintain ICP<30 mmHg. Mild hypothermia (32-35º C) was maintained as soon as barbiturate loading was achieved. Controls consisted of patients not requiring barbiturate infusion.

Outcome Measure: Glasgow Outcome Scale (GOS).

1.        Better GOS outcomes at 9-12 mo were noted for the thiopental group compared with the control group (p=0.03).

2.        Thiopental resulted in 6 patients with good/moderate outcomes, 3 with severe outcomes, and 7 with dead/vegetative outcomes.

3.        In contrast, conventional therapy resulted in 2 patients with good/moderate outcomes, and 13 with dead/vegetative outcomes.

Eisenberg et al. (1988)

USA

RCT

PEDro=4

N=73

Population: TBI; Pentobarbital (n=37): Mean Age=25.3 yr; Gender: Male=29, Female=8; Mean Time Post Injury=83.3 hr; GCS Range=4-7. Conventional Therapy (n=36): Mean Age=24.3 yr; Gender: Male=33, Female=3; Mean Time Post Injury=89.0 hr; GCS Range=4-7.

Intervention: Patients were randomized to receive pentobarbital in addition to ongoing conventional therapy or conventional therapy alone. Pentobarbital was administered first asan initial bolus of 10 mg/kg over 30 min, then as an infusion (5 mg/kg/1hr for 3 hr), and finally as a maintenance dose (1 mg/kg).

Outcome Measures: Intracranial Pressure (ICP), Glasgow Outcome Scale (GOS), Survival.

1.        Patients receiving barbiturates were nearly twice as likely to achieve adequate ICP control as those receiving only conventional therapy (OR=1.94, p=0.12).

2.        The advantage of barbiturate therapy in those without prior cardiovascular complications was over 4-fold (OR=4.40).

3.        After declaration of treatment failure (ICP>20 mmHg), 26 of the patients randomized to conventional therapy were crossed over to receive barbiturates.

4.        The likelihood of survival at 1 mo was 92% for those who responded to barbiturates. In contrast, 83% of the patients who did not respond to barbiturates died.

5.        At 6 mo follow-up, 36% of the responders and 90% of the non-responders were vegetative or had died.

Ward et al. (1985)

USA

RCT

PEDro=6

N=53

Population: TBI; Pentobarbital (n=27): Mean Age=31.1 yr; Gender: Male=25, Female=2; Mean GCS=5.1. Conventional Therapy (n=26): Mean Age=35.1 yr; Gender: Male=21, Female=5; Mean GCS=4.9.

Intervention: Patients were randomized to receive pentobarbital or conventional therapy. Barbiturates were administered first as a bolus (5-10 mg/kg), subsequently as a 1 hr bolus and continuous infusion for at least 72 hr, and finally as a maintenance dose of 1-3 mg/kg.

Outcome Measures: Intracranial Pressure (ICP), Glasgow Outcome Scale (GOS), Mortality.

1.        During the first 4 days, there was no significant difference in hr levels of ICP or mortality.

2.        Clinical outcomes on the GOS and mortality did not differ between groups at 1 yr.

Schwartz et al. (1984)

Canada

RCT

PEDro=5

N=59

Population: TBI; Gender: Male=47, Female=12. Evacuated Hematoma (n=29): Pentobarbital (n=15): Mean Age=32.8 yr; Mean GCS=5.1; Mannitol (n=14): Mean Age=35.7 yr; Mean GCS=4.9. No Hematoma (n=30): Pentobarbital (n=13): Mean Age=24.9 yr; Mean GCS=4.2; Mannitol (n=17): Mean Age=24.4 yr; Mean GCS=4.4.

Intervention: Patients were randomized to receive either 20% mannitol (1 gm/kg) or pentobarbital (initial bolus of 10 mg/kg, then continuous infusion at 0.5-3 mg/kg/hr). The other treatment was initiated on top of initial one if ICP proved refractory to maximal doses of the original drug.

Outcome Measures: Intracranial Pressure (ICP), Mortality.

1.        For patients with evacuated hematomas, no significant difference was observed in mortality at 3 mo between pentobarbital and mannitol groups (40% versus 43%).

2.        Nearly twice as many patients in the pentobarbital group required the other regimen (mannitol) to control raised ICP compared to those in the mannitol group (p=0.04).

3.        For patients without evacuated hematoma, significantly higher proportion of patients treated with pentobarbital died compared to those treated with mannitol initially (77% versus 41%, p=0.03).

4.        In these patients, there was a higher rate of failure to control ICP in the pentobarbital group than in the mannitol group (p<0.001).

Fried et al. (1989)

USA

PCT

N=7

Population: TBI; Mean Age=31 yr; Gender: Male=4, Female=3; Time Post Injury≤1 wk; Mean GCS=4.7.

Intervention: Patients unresponsive to conventional therapy received pentobarbital administered as a bolus followed by a continuous infusion to achieve serum concentrations of 20-40m g/L (n=4). Patients responsive to conventional therapy formed the control group (n=7).

Outcome Measures: Energy Expenditure, Urinary Nitrogen Excretion, Nitrogen Balance, Urinary 3-Methylhistidine Excretion.

1.        Patients treated with pentobarbital had significantly lower energy expenditure (p<0.01), lower urinary total nitrogen excretion (p<0.01), and improved nitrogen balance (p<0.05) than the control group.

2.        There was no significant difference in urinary 3-methylhistidine excretion between groups.

Perez-Barcena et al. (2008)

Spain

RCT

PEDro=4

N=44

Population: TBI; Thiopental (n=22): Median Age=26 yr; Gender: Male=19, Female=3; Median GCS=6.5. Pentobarbital (n=22): Median Age=32 yr; Gender: Male=19, Female=3; Median GCS=7.

Intervention: Participants were randomized to receive thiopental or pentobarbital. Thiopental was delivered in an initial bolus of 2 mg/kg over 20s. A second bolus of 3-5 mg/kg was administered if ICP>20mmHg. Once ICP<20mmHg was achieved, a continuous infusion was administered (3 mg/kg/hr). Pentobarbital was delivered in an initial dose of 10 mg/kg for 30 min, followed by continuous infusion of 5 mg/kg/hr for 3 hr, and then a dose of 1 mg/kg/hr for the last hr

Outcome Measure: Intracranial Pressure (ICP).

1.        Uncontrolled ICP was significantly lower with thiopental than pentobarbital (50% versus 82%, p=0.03).

2.        Thiopental was more effective than pentobarbital for controlling ICP (OR=5.1, p=0.027).

3.        Relative risk for good control of ICP between thiopental and pentobarbital was 2.26 in patients with focal lesions and 3.52 in patients with diffuse lesions.

Perez-Barcena et al. (2005)

Spain

RCT

PEDro=5

N=20

Population: TBI; Mean Age=33 yr; Gender: Male=16, Female=4; GCS≤8.

Intervention: Participants were randomized to receive Thiopental (n=10) or Pentobarbital (n=10). Thiopental was delivered in an initial bolus of 2 mg/kg over 20s A second bolus of 3-5 mg/kg was administered if ICP>20mmHg, followed by continuous infusion of 3 mg/kg/hr once ICP<20 mmHg. Pentobarbital was delivered in an initial dose of 10 mg/kg for 30 min, followed by continuous infusion of 5 mg/kg/hr for 3hr. For the last hour a dose of 1 mg/kg/hr was administered. Outcomes were assessed at discharge and 6mo.

Outcome Measures: Intracranial Pressure (ICP), Mortality.

1.        Thiopental was able to control ICP in 50% of patients while pentobarbital was only able to control ICP in 20% (p=0.16).

2.        50% of patients in the thiopental group died at discharge while 80% died in the pentobarbital group (p=0.16).

Llompart-Pou (2007)

Spain

Case Control

N=40

Population: TBI; Barbiturates (n=17): Mean Age=35 yr; Gender: Male=16, Female=1; Mean GCS Score=7. Control (n=23): Mean Age=27 yr; Gender: Male=20, Female=3; Mean GCS=7.

Intervention: Patients were included in retrospective analysis. Those with elevated Intracranial Pressure (ICP) refractory to first tier measures received thiopental (n=10) or pentobarbital (n=7). The remaining patients showed controlled ICP in response to first tier measures.

Outcome Measure: Adrenal function.

1.        Within 24 hr, adrenal function was similar in both groups.

2.        After treatment with barbiturates, patients demonstrated higher adrenal insufficiency compared to the control group (53% versus 22%, p=0.03).

3.        94% of patients treated with barbiturates received norepinephrine (NE), while only 39% of those without received NE (p<0.001).

4.        Those treated with barbiturates had higher NE doses than those without (1.07 µg/kg/min versus 0.31 µg/kg/min, p=0.03).

5.        There was a trend toward a higher incidence of adrenal insufficiency among patients treated with pentobarbital than those treated with thiopental (71% versus 40%, p=0.20).

Colton et al.

(2014b)

USA

Case Series

N=117

Population: TBI; Mean Age=40.0 yr; Gender: Male=93, Female=24; Median GCS=6.

Intervention: Participants were included in retrospective analysis after having received one of the following ICP therapies: hypertonic saline (HTS), mannitol, propofol, fentanyl, and barbiturates.

Outcome Measure: Intracranial Pressure (ICP).

1.        Treatment with HTS resulted in the largest ICP decrease of the treatments examined.

2.        Propofol and fentanyl escalations resulted in smaller but significant ICP reductions.

3.        Mannitol resulted in statistically insignificant reductions in the first hr but rebounded by the second hr.

Slovakia

Case Control

N=1172

Population: TBI; High Barbiturate Group (n=71): Median Age=36 yr; Gender: Male=51, Female=20; Median GCS=6. Low Barbiturate Group (n=140): Median Age=41; Gender: Male=113, Female=27. No Barbiturate Group (n=961): Median Age=45 yr; Gender: Male=737, Female=224.

Intervention: Participants were categorized into high barbiturate (>2 g/day), low barbiturate (<2 g/day), or no barbiturate groups for retrospective analysis.

Outcome Measures: Intracranial Pressure (ICP), Mean Arterial Pressure (MAP), Glasgow Outcome Scale (GOS), Mortality, Hospital days.

1.        Patients treated with high doses of barbiturate had significantly longer intubation days, days on ICU, and days in hospital compared to patients treated with low doses or no barbiturate (all p<0.001).

2.        Barbiturate administration was associated with a significant reduction in the daily hr of ICP>25 mmHg, but was also associated with a significant elevation in daily hr of MAP <70 mmHg (p<0.05).

3.        The effect of barbiturate use to treat ICP was not associated with improved outcomes as rates of ICU death, hospital death, 6 mo death, and poor outcome were not significantly different between responders and non-responders.

Thorat et al. (2008)

Singapore

Case Series

N=12

Population: TBI; Mean Age=38.58 yr; Gender: Male=10, Female=2; Median GCS=6.

Intervention: Patients received a 250 mg bolus of barbiturates followed by continuous infusion of 4-8 mg/kg/hr.

Outcome Measures: Intracranial Pressure (ICP), Mean Arterial Pressure (MAP), Cerebral Perfusion Pressure (CPP), Brain Tissue Oxygen Pressure (P_tiO₂), Pressure Reactivity Index (PRx).

1.        Mean duration of barbiturate coma was 61.25 hr.

2.        No significant reductions in mean ICP, MAP, CPP, P_tiO₂, or PRx were reported.

3.        Eight of 12 patients experienced reductions in ICP, but only 4 had levels below 20 mmHg and only 3 of them survived.

4.        Improved P_tiO₂was seen in 6 of the 8 patients with initial P_tiO₂ >10 mmHg.

5.        There were no significant differences in initial ICP or P_tiO₂ levels between survivors and non-survivors, but the difference became significant after treatment (p=0.012 and p=0.042, respectively).

6.        Favourable and significant changes in PRx were observed among survivors (p=0.020), but not among non-survivors.