The Membrane Lipid Cholesterol Modulates Anesthetic Actions on a Human Brain Ion Channel

Background: Molecular theories of general anesthesia often are divided into two categories: (l) Anesthetics may bind specifically to proteins, such as ionic channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane. Recent studies have provided evidence that anesthetics can bind to proteins and modify their function directly, bringing into question the role of the membrane in anesthetic interactions. To reexamine the role of membrane lipids in anesthetic interactions, an experimental approach was used in which the membrane lipid composition could be systematically altered and the impact on anesthetic interactions with potential targets examined.

Methods: Sodium channels from human brain cortex were incorporated into planar lipid bilayers with increasing cholesterol content. The anesthetic suppression of these channels by pentobarbital was quantitatively examined by single channel measurements under voltage-clamp conditions.

Results: Changes in cholesterol content had no effect on measured channel properties in the absence of anesthetic. In the presence of pentobarbital, however, cholesterol inhibited anesthetic suppression of channel ionic currents, with 1.9% (weight/weight, corresponding to 3.5 mol%) cholesterol decreasing anesthetic suppression of sodium channels by half.     

Propofol and Sevoflurane in Subanesthetic Concentrations Act Preferentially on the Spinal Cord: Evidence from Multimodal Electrophysiological Assessment

Background: Animal experiments in recent years have shown that attenuation of motor responses by general anesthetics is mediated at least partly by spinal mechanisms. Less is known about the relative potency of anesthetic drugs in suppressing cortical and spinal electrophysiological responses in vivo in humans, particularly those, but not only those, connected with motor responses. Therefore, we studied the effects of sevoflurane and propofol in humans using multimodal electrophysiological assessment.

Methods: We studied nine healthy volunteers in two sessions during steady state sedation with 0.5, 1.0, and 1.5 [mu]g/l (targeted plasma concentration) propofol or 0.2 and 0.4 vol% (end-tidal) sevoflurane. Following a 15-min equilibration period, motor responses to transcranial magnetic stimulation and peripheral (H-reflex, F-wave) stimulation were recorded, while electroencephalography and auditory evoked responses were recorded in parallel.

Results: At concentrations corresponding to two thirds of C50 awake, motor responses to transcranial magnetic stimulation were reduced by approximately 50%, H-reflex amplitude was reduced by 22%, F-wave amplitude was reduced by 40%, and F-wave persistence was reduced by 25%. No significant differences between sevoflurane and propofol were found. At this concentration, the Bispectral Index was reduced by 7%, and the middle-latency auditory evoked responses were attenuated only mildly (Nb latency increased by 11%, amplitude PaNb did not change). In contrast, the postauricular reflex was suppressed by 77%.     

Electroencephalogram approximate entropy correctly classifies the occurrence of burst suppression pattern as increasing anesthetic drug effect

BACKGROUND: Approximate entropy, a measure of signal complexity and regularity, quantifies electroencephalogram changes during anesthesia. With increasing doses of anesthetics, burst-suppression patterns occur. Because of the high-frequency bursts, spectrally based parameters such as median electroencephalogram frequency and spectral edge frequency 95 do not decrease, incorrectly suggesting lightening of anesthesia. The authors investigated whether the approximate entropy algorithm correctly classifies the occurrence of burst suppression as deepening of anesthesia. METHODS: Eleven female patients scheduled for elective major surgery were studied. After propofol induction, anesthesia was maintained with isoflurane only. Before surgery, the end-tidal isoflurane concentration was varied between 0.6 and 1.3 minimum alveolar concentration. The raw electroencephalogram was continuously recorded and sampled at 128 Hz. Approximate entropy, electroencephalogram median frequency, spectral edge frequency 95, burst-suppression ratio, and burst-compensated spectral edge frequency 95 were calculated offline from 8-s epochs. The relation between burst-suppression ratio and approximate entropy, electroencephalogram median frequency, spectral edge frequency 95, and burst-compensated spectral edge frequency 95 was analyzed using Pearson correlation coefficient. RESULTS: Higher isoflurane concentrations were associated with higher burst-suppression ratios. Electroencephalogram median frequency (r = 0.34) and spectral edge frequency 95 (r = 0.29) increased, approximate entropy (r = -0.94) and burst-compensated spectral edge frequency 95 (r = -0.88) decreased with increasing burst-suppression ratio. CONCLUSION: Electroencephalogram approximate entropy, but not electroencephalogram median frequency or spectral edge frequency 95 without burst compensation, correctly classifies the occurrence of burst-suppression pattern as increasing anesthetic drug effect.     

The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients

Studies on pharmacokinetics and pharmacodynamics of high-dose methotrexate chemotherapy (HD-MTX) in elderly primary central nervous system lymphoma (PCNSL) patients are rare. MTX exposure time has recently been proposed as an outcome determining factor in PCNSL. We investigated 49 immunocompetent PCNSL patients (female N=30, male N=19, median age 73 years) who were treated according to HD-MTX-based protocols. A two-compartment pharmacokinetic model was used to describe the MTX clearance. Response to treatment was assessed by MRI. We used multivariable models to investigate the association between MTX exposure and tumor response as well as survival. Dose normalized MTX peak serum levels [C (max), μmol/L g] and dose normalized area under the curve [AUC(dn), μmol h/L g] were higher in females than in males, respectively [59.4 (f) vs. 48.1 (m), P<0.001; 373.2 (f) vs. 271.9 (m), P=0.008]. Increasing AUC was inversely correlated with tumor response. AUC values above 2,126 h?μmol/L were independently associated with shorter overall and progression-free survival [hazard ratio (HR), 4.56, 95 % CI 1.74-11.94; HR 2.87, 95 % CI 1.18-7.00]. Exceedingly high MTX AUC levels can have a negative impact on progression-free and overall survivals in elderly PCNSL patients.     

Effects of prophylactic or therapeutic application of bovine haemoglobin HBOC-200 on ischaemia-reperfusion injury following acute coronary ligature in rats

Background. Haemoglobin-based oxygen carriers (HBOCs) are assessedas blood substitutes in patients with perioperative anaemiaincluding patients at risk for perioperative cardiac ischaemia.There is controversy as to whether HBOCs are beneficial or deleteriousduring ischaemia–reperfusion (I–R). Therefore theeffects of HBOC-200 on I–R injury were evaluated in arandomized placebo-controlled animal trial. Methods. Animals were randomized to receive either placebo i.v.without I–R (sham group, n=9), placebo i.v. with I–R(control group, n=10), HBOC-200 0.4 g kg^–1 i.v. priorto I–R (prophylaxis group, n=12) or HBOC-200 0.4 g kg^–1i.v. during I–R (therapy group, n=15). I–R consistedof 25 min of acute ligature of the left coronary artery followedby 120 min of reperfusion. Measurements included assessmentof the area at risk and infarct size using triphenyl tetrazoliumchloride (TTC) stain, DNA single-strand breaks (in situ nicktranslation with autoradiography/densitometry) and cardiac arrhythmias. Results. Infarct size within the area at risk was 62 (SD 15)%(control), 46 (10)% (prophylaxis, P<0.025 vs control) and61 (9)% (therapy, P<0.85 vs control). The frequency of DNAsingle-strand breaks was reduced vs control in the sham (P<0.01)and prophylaxis (P<0.04) groups and was almost the same inthe therapy group (P<0.75). The severity of cardiac arrhythmiasduring ischaemia was lower compared with control in the sham(P<0.001) and prophylaxis (P<0.039) groups, but therewas no difference in the therapy group. Conclusion. This study demonstrates that neither prophylacticnor therapeutic application of the cell-free haemoglobin solutionHBOC-200 aggravates cardiac I–R injury. Furthermore, theprophylactic approach may offer a new opportunity for pretreatmentof patients at risk for perioperative ischaemic cardiac events. The results were presented in part at the Congress of the EuropeanSociety of Anaesthesia, Glasgow, UK, June 2003 (‘BestAbstract Award’), and at the Annual Meeting of the AmericanSociety of Anesthesiologists, San Francisco, CA, USA, October2003. Declaration of interest. T. G. Standl has received lecture honorariaand travel fees from Biopure Corporation, Boston, MA, the manufacturerof HBOC. The Department of Anaesthesiology, University Hospital,Hamburg-Eppendorf, received restricted grants from Biopure Corporation,Boston, MA, between 1994 and 1998 for animal and clinical phaseII and III trials. M.A. Burmeister is Vice President Researchand Development, Hospital Care Division, B. Braun MelsungenAG, Melsungen, Germany. B. Braun, a global health care supplier,cooperated with Biopure Corporation, Boston, MA, on HBOC developmentuntil 1996. The work presented in this paper was done independentlyof and without any support from B. Braun.     

Seromukotympanon bei Neugeborenen mit Down-Syndrom

Hintergrund: Bei mehr als der H?lfte der Kinder mit Down-Syndrom tritt eine H?rst?rung auf. Als h?ufigste Ursache gelten chronische bzw. rezidivierende Paukenergüsse (Seromukotympanon), die mit einer H?ufigkeit von etwa 60% beobachtet werden.