氯胺酮对大鼠丘脑一氧化氮合酶活性和一氧化氮含量的影响

目的：观察不同剂量的氯胺酮对大鼠丘脑一氧化氮合酶（NOS）和一氧化氮（NO）含量的影响。方法：Sprague Dawley(SD)大鼠32只，雌雄不限，体重200－300g。随机分为四组（n=8):组I为对照组，给予生理盐水10ml/kg腹腔注射；组Ⅱ、组Ⅲ和组Ⅳ分别给予氯胺酮35ml/kg,100ml/kg和200ml/kg。组I和组Ⅱ在用药后5min后断头取材，组Ⅲ和组Ⅳ在大鼠翻正反射消失后立即断头取材。在低温操作箱内生理盐水冰面上取脑，以分光光度法测定NOS活性和NO量，Lawry法测蛋白含量。结果：大鼠腹腔注射氯胺酮35ml/kg后，其丘脑的NOS活性和NO量与对照组相比均无明显变化（P＞0．05）而腹腔注射氯胺酮100ml/kg和200ml/kg后，NOS活性明显降低，分别较对照组降低了44．3％和40％（P＜0．05）和P＜0．01），NO量也明显减少，分别较对照组减少了42．9％和47．1％（P＜0．05）或（P＜0．01）；且这两组的NOS活性和NO量也明显低于氯胺酮35ml/kg组，NOS活性分别降低了47．3％和43．2％（P＜0．01），NOS量降低了47．4％和51．3％（P＜0．01）；此两组之间相比较，丘脑的NOS活性和NO量无统计学意义（P＞0．05）。结论：NO在氯胺酮的中枢作用机制中可能发挥重要作用。     

大鼠肝移植的麻醉

目的研究氯胺酮在大鼠肝移植中的合适剂量.方法对100只雄性Wister大鼠行40例肝移植,观察供受体麻醉过程、药物剂量和效果. 结果供体手术氯胺酮麻醉的剂量以100～125 mg/kg合适,受体手术氯胺酮麻醉的剂量以75～100 mg/kg合适.结论在大鼠肝移植的手术中,氯胺酮是一种理想的麻醉药品.     

POSSIBLE PARTICIPATION OF NMDA AND GLYCINE RECEPTORS BUT NOT GABAA RECEPTORS IN ENFLURANE-INDUCED OPISTHOTONUS IN MICE

1. We previously reported that volatile anaesthetics produce incidences of a transient opisthotonus in mice, a sign of CNS stimulation. This study was performed to investigate mechanisms by which enflurane-induced opisthotonus (EIO) occurs. 2. The effects of pretreatment of N-methyl-d-aspartate (NMDA) antagonists dizocilpine (MK-801; DIZ) and ketamine (KET), GABA_A antagonists picrotoxin (PIC), pentylenetetrazol (PTZ) and glycine antagonist strychnine (STR) on the incidence of EIO were determined. Prior to exposure to 2.0% enflurane in air, male ddN mice were given intraperitoneal injections of 0.2 mL saline (control), 0.5–5.0 mg/kg DIZ, 20–80 mg/kg KET, 2.9 mg/kg PIC, 40.0 mg/kg PTZ and 0.75 mg/kg STR. After the injection, the behavioural state of the mice was observed for 20 min (the pre-enflurane period). During the exposure to enflurane the time for immobilization, that is, anaesthetic induction time (IT), and the incidence of EIO were measured. 3. Dizocilpine (1.0–5.0 mg/kg) and KET (80 mg/kg) significantly (P<0.01) reduced both the incidence of EIO and IT in a dose-dependent manner. During the pre-enflurane period DIZ produced incidences (5–40%) of transient seizures in a dose-dependent manner, while KET did not induce them at all. The two GABA_a antagonists had no detectable effect on the EIO. Strychnine significantly enhanced the EIO. These CNS stimulants resulted in a 3–10% incidence of transient seizure and/or opisthotonus during the pre-enflurane period, but there was no correlation between DIZ-induced seizure and EIO. 4. These results suggest that the EIO is mediated by the NMDA and the STR-sensitive glycine receptors, but not the GABA_A receptor. We speculate that DIZ acts on the NMDA-receptor and/or disrupts the balance between the inhibitory and the excitatory systems.     

氯胺酮脑保护作用的可能机制

众多研究显示，氯胺酮对脑缺血缺氧性损伤具有保护作用。主要通过调节神经细胞凋亡；与NMDA受体结合，抑制兴奋性氨基酸毒性及钙离子内流；抑制炎性因子生成和蛋白激酶表达等几个方面发挥脑保护作用。     

Patch clamp studies on the kinetics and selectivity of N-methyl-d-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan)

Memantine (1-amino-3,5-dimethyladamantan) was tested as an antagonist of N-methyl-d-aspartate (NMDA) receptors on cultured superior collicular and hippocampal neurones using the patch clamp technique and its actions were compared to those of Mg²⁺ ions, ketamine, dextrorphan, dextromethorphan, phencyclidine and dizocilpine (MK-801). Memantine (2–33 μM) concentration-dependently antagonized responses to NMDA 100 μM with an IC₅₀ of 2.92 ± 0.05 μM. In contrast, current responses to (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (l-AMPA 50–100 μM) and γ-amino butyric acid (GABA 10 μM) were unaffected by Memantine 8 μM. Memantine 8 μM caused a non-parallel shift of the NMDA concentration-response curve to the right in a manner indicative of uncompetitive open channel block. The effects of memantine were similar to ketamine in that both antagonists were weakly use- and strongly voltage-dependent. In contrast, MK-801, phencyclidine and dextrorphan showed much slower kinetics that was reflected in their marked use- and weaker voltage-dependency. The antagonistic effects of memantine were not reversed by increasing concentrations of glycine (0.1–100 μM) ruling out the possibility of an interaction of memantine with the strychnine-insensitive glycine modulatory site associated with the NMDA receptor-channel complex. Memantine (1–100 μM) also selectively antagonized responses to NMDA (40 μM) in the cortical wedge preparation with IC₅₀ of 12.9 ± 1.5 μM.     

Anaesthetic experience with paediatric interventional cardiology

Anaesthetic and sedation techniques, complications and outcomes were reviewed in 176 children undergoing 184 interventional cardiologic procedures. Techniques included sedation only, and ketamine, inhalational or narcotic anaesthesia. Ketamine infusion was the technique most frequently used. Ketamine was associated with a higher incidence of respiratory complications (P < 0.05) than the other techniques. The higher incidence of hypercarbia (15.6 per cent), which did not affect outcome, may be attributable to the use of supplemental sedatives. The incidence of upper airway obstruction (7.8 per cent) was similar to that of previous studies. Vascular compromise resulted from the procedure in 33 patients, necessitating surgical correction in 16. Cardiac perforation occurred in four cases, causing one death. Pulmonary valve stenosis was most amenable to balloon dilatation and aortic valve stenosis least amenable. Ketamine was the anaesthetic agent preferred by cardiologists for use in the catheterisation suite when general anaesthesia was required. Vigilant monitoring by anaesthetic staff is necessary during the procedure, and avoidance of concomitant narcotics is recommended if a ketamine technique with spontaneous ventilation is used. Les techniques anesthésiques et de sédation ainsi que les complications et les issues ont été revues chez 176 enfants subissant 184 procedures cardiaques. Les techniques ont inctu soil la sédation seulement, soit l’anesthésie à la kétamine, aux agents d’inhalation ou aux narcotiques. La perfusion de kétamine était la technique la plus fréquemment utilisée. La ketamine était associée à une plus grande incidence de complication respiratoire (P < 0.05) comparativement aux autres techniques. La plus grande incidence d’hypercarbie (15.6 pour cent), n’ayant pas affecté l’issue, pourrait être attribuée à l’utilisation additionnelle de sédatifs. L’incidence d’obstruction des voies aériennes supérieures (7.8 pour cent) était similaire aux études préalables. Un problème vasculaire suite à la procédure fut observé chez 33 patients dont 16 ont requis une correction chirurgicale. Une perforation cardiaque est survenue dans quatre cas provoquant le décès d’un seul patient. La sténose de la valve pulmonaire était la procédure la plus susceptible d’être dilatée et la sténose de la valve aortique la moins susceptible. La kétamine était l’agent anesthésique préféré par les cardiologistes lors des cathétérisations quand une anesthésie générate était requise. Une surveillance vigilante par une équipe anesthésique fut nécessaire durant la procedure. Il faut aussi éviter l’administration de narcotiques si la kétamine est administrée en respiration spontanée.

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Presented in part at the Canadian Anaesthetists’ Society annual meeting in Halifax, June 1988.     

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(–)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid E_max pharmacodynamic model, yielding estimates of both maximal effect (E_max) and sensitivity (IC₅₀) to the racemic and enantiomeric forms of ketamine. R(–)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (E_max)for R(–)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC₅₀) was 1.8±0.5g/mL for R(–)-ketamine; 2.0±0.5 g/mL for R,S(±)-ketamine; and 0.8±0.4 g/mL for S(+)-ketamine. Because the maximal effect (E_max) of the R(–)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC₅₀) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.This work was supported in part by a Starter Grant from the American Society of Anesthesiologists, the Biomedical Research Support Grant NIH 2S07RR5353-20, 1981, (P.F.W.); and NIH and NIA Research Grants NS-17956 and AG03104 (D.R.S., A.J.T., L.B.S). The research fellowship of Dr. Schüttler was made possible by a NATO Foundation Grant (300-402-511-3), awarded by the German Academic Exchange Service. This study is part of Dr. Schüttler's Habilitation Thesis for the Faculty of Medicine at the University of Bonn, West Germany. Dr. Verotta is a fellow of the program of advanced training established by EEC and Regione Lombardia on leave of absence from Mario Negri Institute of Pharmacological Research, Milan, Italy.     

异丙酚与氯胺酮联合应用的实验研究

目的;研究异丙酚（propofol,P)和氯胺酮（ketamine,K)的相互作用。方法：观察P对K引起的小鼠入睡率及睡眠时间的影响;研究P对K镇痛效应的影响;以序贯法研究不同剂量的P对小鼠静脉注射K的半数致死量（LD50）的影响,并探讨P对清醒家兔静注K的呼吸循环效应的影响。结果：P可增大K引起的小鼠入睡率（P＜0．01）;延长小鼠睡眠时间（P＜0．01）,且呈剂量依赖关系;种测痛方法均显示P增强K的镇痛作用（P＜0．05）;P可拮抗兔静注K所致的血压高和心率增快效应（P＜0．01）,而加重K的呼吸抑制作用（P＜0．01）。在所用剂量范围内P对小鼠静注K的LD50无明显影响。结论：P可增强K的催眠和镇痛作用,拮抗K的循环兴奋作用,而不减小K的LD50。提示二者合用于临床静脉复合全麻是合理的,但需注意呼吸的管理。     

异丙酚氯胺酮混合液静脉麻醉

选择 40例 ASA ～ 级病人行异丙酚氯胺酮 (1∶ 2 )复合静脉麻醉。结果麻醉诱导后血压、心率与麻醉前相比无明显变化 ,2 0 %病人出现一过性 SPO2 下降 (<94% )。麻醉诱导苏醒快 ,满意率高 ,恢复期无精神症状。表明异丙酚可控制氯胺酮的心血管兴奋作用和恢复期精神症状 ,氯胺酮可减轻异丙酚的心血管抑制作用。两者配伍是一种较好的短效静脉麻醉方式 ,但仍存在呼吸抑制作用 ,应引起注意。     

Ketamine for analgosedative therapy in intensive care treatment of head-injured patients

Summary Ketamine was supposed to be contra-indicated in head injured patients although it possesses numerous advantages over other commonly used analgosedative drugs. Referring to these potential advantages and the lack of definitive data about its effect upon ICP, CPP or neurological development, we conducted a prospective study in which moderate or severely head injured patients (n=35) were prospectively allocated to receive treatment either with a combination of ketamine and midazolam or fentanyl and midazolam. The initial dose was 6.5 mg/kg/day midazolam, 65 mg/kg/day ketamine or 65 g/kg/day fentanyl and was later adjusted due to clinical requirements for a period of 3 to 14 days. Comparably high dosages of detamine have been found necessary (104 mg/kg/day).Four patients from the ketamine group (n=17) and 5 from the control group (n=18) were withdrawn during treatment due to persistent ICP above 25 mm Hg, countermeasured by barbiturate coma. Two more patients were withdrawn due to development of cardiovascular arrest (ketamine group) and multi organ failure. A comparison of the remaining patients revealed a lower requirement of catecholamines (significant on first day, p<0.05), an on average 8 mm Hg higher cerebral perfusion pressure and a 2 mm Hg higher intracranial pressure in the fentanyl group. Enterai food intake was better in the study group. The outcome was comparable in both groups with or without inclusion of withdrawn patients.