Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications.

Gasser S, Khan N, Yonekawa Y, Imhof HG, Keller E.

Department of Neurosurgery, University Hospital Zurich, Switzerland.

The purpose was to evaluate the feasibility and intensive care complications of long-term hypothermia (>72 hours) in the treatment of severe brain edema after poor-grade subarachnoid hemorrhage (SAH) Hunt and Hess grade 4 to 5. Among 156 patients with SAH, 21 patients were treated with mild hypothermia (33.0 to 34.0 degrees C) combined with barbiturate coma because of severe brain edema and elevated intracranial pressure (>15 mm Hg) after early aneurysm clipping. Hypothermia was sustained for at least 24 hours after maintaining an intracranial pressure of <15 mm Hg. Nine patients were treated for <72 hours (group 1: mean 42.2 hours, range 8-66 hours) and 12 for >72 hours (group 2: mean 153.9 hours, range 78-400 hours). Three patients (14%) died during the hypothermia treatment. Good functional outcome after 3 months (Glasgow Outcome Score 4-5) was achieved in 10 patients (48%). The outcome did not differ between the two groups. All patients developed severe infections. In group 2 the mean value of minimal leukocyte counts during hypothermia was significantly lower (6.9 vs. 11.8 x 109/L; P = 0.001), and thrombocytopenia (<150 x 109/L) occurred significantly more often (48 vs. 33%; P = 0.032). In 48% of patients with poor-grade SAH, good functional outcome was achieved with combined mild hypothermia and barbiturate coma after early aneurysm surgery. This may be a feasible treatment even for longer than 72 hours. All patients developed severe infections as potentially hazardous side effects. To determine whether mild hypothermia alone is effective in the treatment of severe SAH patients, controlled studies to compare the effects of barbiturate coma alone, mild hypothermia alone, and combined barbiturate coma with hypothermia are needed.

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Selectivity in generalization to GABAergic drugs in midazolam-trained baboons.

Ator NA.

Department of Psychiatry and Behavioral Sciences, Behavioral Biology Research Center, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Suite 3000, Johns Hopkins Bayview Campus, Baltimore, MD 21224, USA. ator jhmi.edu

When barbiturates have been tested in animals trained to discriminate the intravenous benzodiazepine (Bz) anesthetic midazolam, squirrel monkeys and pigeons did not reliably generalize to barbiturates but rats did. To explore this unexpected phenomenon in another species and to extend the midazolam generalization profile to GABAergic compounds not previously tested, five baboons were trained to discriminate midazolam maleate (0.32 mg/kg i.v.) from saline under a two-lever procedure. In tests 10 min after dose delivery, the partial agonist imidazenil, the full agonist chlordiazepoxide, and the receptor-subtype-selective hypnotic zolpidem fully shared discriminative effects with midazolam. The barbiturate pentobarbital did so in only one of five baboons, and the intravenous anesthetic propofol failed to do so in the three baboons tested. Testing 1 min after dose delivery shifted midazolam and zolpidem curves to the left and increased generalization to propofol but not pentobarbital. Taken together with previous published data, partial or full agonism at the Bz binding site appears sufficient for midazolam-like discriminative effects in nonhuman primates, pigeons, and rodents, and modulation through the anesthetic site is sufficient in baboons. However, to date, positive modulation of GABA through the barbiturate site is not generally sufficient for this effect in nonhuman primates and pigeons although it is in rodents.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12873636&dopt=Abstract barbiturate Butalbital Fioricet





Thiopental inhibits tumor necrosis factor alpha-induced activation of nuclear factor kappaB through suppression of kappaB kinase activity.

Loop T, Humar M, Pischke S, Hoetzel A, Schmidt R, Pahl HL, Geiger KK, Pannen BH.

Department of Anesthesiology and Critical Care Medicine, University Hospital, Freiburg, Germany.

BACKGROUND: Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury and is associated with immunosuppressive effects. The authors have recently reported that thiopental inhibits activation of nuclear factor (NF) kappaB, a transcription factor implicated in the expression of many inflammatory genes. Thus, it was the aim of the current study to examine the molecular mechanism of this inhibitory effect. METHODS: The authors tested gamma-aminobutyric acid (GABA), the GABA(A) antagonist bicuculline, and the GABA(B) antagonist dichlorophenyl-methyl-amino-propyl-diethoxymethyl-phosphinic acid (CGP 52432) in combination with thiopental for their influence on the activation of NF-kappaB. In addition, they investigated the direct effect of thiopental on activated NF-kappaB DNA binding activity. These experiments were conducted in Jurkat T lymphocytes using electrophoretic mobility shift assays. The presence of the phosphorylated and dephosphorylated NF-kappaB inhibitor IkappaBalpha (Western blotting) and IkappaB kinase activity were studied in Jurkat T cells and human CD3+ T lymphocytes. In addition, the authors tested the effect of the structural barbiturate analog pairs thiopental-pentobarbital and thiamylal-secobarbital and of thiopental in combination with the thio-group containing chemical dithiothreitol on the activation of NF-kappaB. RESULTS: GABA did not inhibit NF-kappaB activation, and the GABA(A) and GABA(B) antagonists bicuculline and CGP did not diminish the thiopental-mediated inhibitory effect on NF-kappaB activation. Thiopental did not inhibit activated NF-kappaB directly in a cell-free system. The phosphorylation of IkappaBalpha was prevented after incubation with 1,000 microg/ml thiopental. The same concentration of thiopental also inhibited IkappaB kinase activity in tumor necrosis factor-stimulated Jurkat T cells and human CD3+ T lymphocytes (60% suppression, P < 0.05 vs. tumor necrosis factor alpha alone). Thiobarbiturates (4 x 10(-3) m) inhibited NF-kappaB activity, whereas equimolar concentrations of the structural oxyanalogs did not. Preincubation of thiopental with dithiothreitol diminished the inhibitory effect. CONCLUSION: Thiopental-mediated inhibition of NF-kappaB activation is due to the suppression of IkappaB kinase activity and depends at least in part on the thio-group of the barbiturate molecule.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12883408&dopt=Abstract barbiturate Butalbital Fioricet





Effects of barbiturates on human platelet aggregation differ depending on their chemical structures.

Sato M, Hirakata H, Ikeda M, Fukuda K.

Department of Anesthesia, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan.

The effects of barbiturates on human platelet function are not fully understood. Since we have already revealed the effects and mechanisms of thiopental, thiamylal, and pentobarbital in platelets, the present study attempted to elucidate (i) the effects of other barbiturates on human platelet aggregation, (ii) the underlying mechanisms, and (iii) the structure-function relationship of barbiturates in platelets. Barbiturates, including amobarbital, butalbital, secobarbital, barbital, phenobarbital, metharbital, and primidone, were examined. Human platelet aggregation induced by adenosine diphosphate (ADP), epinephrine, and (+)-9,11-epithia-11,12-methano-thromboxane A2 (STA2), a thromboxane A2 analog, was measured using an 8-channel light-transmission aggregometer. The cytosolic free calcium concentration ([Ca2+]i) was measured by fluorometer using fura-2 loaded platelets. Inositol 1,4,5-trisphosphate (IP3) formation induced by STA2 was determined by a commercially available IP3 assay kit. Amobarbital, butalbital, and secobarbital suppressed ADP-, epinephrine- and STA2-induced platelet aggregation and the STA2-induced [Ca2+]i increase, even when Ca2+ influx was blocked by Ni2+. However, they did not affect STA2-induced IP3 formation. Barbital, phenobarbital, metharbital, and primidone (up to 1 mM) had no effect on ADP- and epinephrine-induced platelet aggregation. Thus, we conclude that amobarbital, butalbital, and secobarbital inhibit platelet aggregation by suppressing [Ca2+]i increase without affecting IP3 formation. However, these antiaggregatory effects may not have clinical importance, since the barbiturate concentrations used were higher than clinically relevant ones. The other tested barbiturates had no effects on platelet aggregation. The data indicate that the effects of barbiturates on platelet aggregation differ depending on their chemical structures.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12897810&dopt=Abstract barbiturate Butalbital Fioricet