Anesthesia and analgesia
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Anesthesia and analgesia · Mar 1999
The influence of anesthetic choice, PaCO2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts.
Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors. Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O2 protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [3H]-methotrexate. With isoflurane/O2 anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [3H]-methotrexate delivery compared with saline in the tumor (0.388 +/- 0.03 vs 0.135 +/-0.04; P = 0.0001), brain around the tumor (0.269 +/- 0.03 vs 0.035 +/- 0.03; P = 0.0001), brain distant to the tumor (0.445 +/- 0.05 vs 0.034 +/- 0.07; P = 0.001), and opposite hemisphere (0.024 +/- 0.00 vs 0.016 +/- 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O2 anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/ N2O regimen was compared with the isoflurane/O2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2O was superior to isoflurane/O2 by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N2O regimen was evaluated, and none was found. These data support the use of propofol/N2O along with maintaining hypocarbia to optimize BBBD in animals with tumors. ⋯ Propofol/N2O anesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.
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Anesthesia and analgesia · Mar 1999
The effects of general anesthetics on excitatory and inhibitory synaptic transmission in area CA1 of the rat hippocampus in vitro.
It is unclear whether general anesthetics induce enhancement of neural inhibition and/or attenuation of neural excitation. We studied the effects of pentobarbital (5 x 10(-4) mol/L), propofol (5 x 10(-4) mol/L), ketamine (10(-3) mol/L), halothane (1.5 vol%), and isoflurane (2.0 vol%) on both excitatory and inhibitory synaptic transmission in rat hippocampal slices. Excitatory or inhibitory synaptic pathways were isolated using pharmacological antagonists. Extracellular microelectrodes were used to record electrically evoked CA1 neural population spikes (PSs). In the presence of the gamma-aminobutyric acid type A (GABA(A)) receptor antagonist (bicuculline), the inhibitory actions of pentobarbital and propofol were completely antagonized, whereas those of ketamine, halothane, and isoflurane were only partially blocked. To induce the N-methyl-D-aspartate (NMDA) receptor-mediated PS (NMDA PS), the non-NMDA and GABA(A) receptors were blocked in the absence of Mg2+. Ketamine, halothane, and isoflurane decreased the NMDA PS, and pentobarbital and propofol had no effect on the NMDA PS. The non-NMDA receptor-mediated PS (non-NMDA PS) was examined using the antagonists for the NMDA and GABA(A) receptors. Volatile, but not i.v., anesthetics reduced the non-NMDA PS. These findings indicate that pentobarbital and propofol produce inhibitory actions due to enhancement in the GABA(A) receptor; that ketamine reduces NMDA receptor-mediated responses and enhances GABA(A) receptor-mediated responses; and that halothane and isoflurane modulate GABA(A), NMDA, and non-NMDA receptor-mediated synaptic transmission. ⋯ Volatile anesthetics modulate both excitatory and inhibitory synaptic transmission of in vitro rat hippocampal pathways, whereas i.v. anesthetics produce more specific actions on inhibitory synaptic events. These results provide further support the idea that general anesthetics produce drug-specific and distinctive effects on different pathways in the central nervous system.