Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose–response study

Rationale Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that has medical indications but is also used as a recreational drug. Previous research has found persisting cognitive and psychotogenic effects of ketamine in chronic abusers of this drug 3 days after an acute dose.Objective The present study aimed to investigate the effects of ketamine on two processes related to drug abuse, response inhibition and reinforcement, and to examine whether an acute dose of ketamine produced residual cognitive effects in healthy volunteers.Methods Fifty-four healthy volunteers were given an 80-min infusion of one of two doses (0.4, 0.8 mg kg^–1) of ketamine or placebo. Subjects completed a battery of tests at three time points: pre-infusion, during the infusion and 3 days later at follow-up. The battery consisted of tests of episodic and semantic memory, schizophrenic-like and dissociative symptoms, response inhibition and measures of subjective effects, including mood, bodily symptoms and enjoyment of and desire for the drug.Results Ketamine acutely impaired response inhibition and had related biphasic effects on the subjective reinforcing effects of the drug. Ketamine also acutely impaired episodic but not semantic memory and increased schizophrenic-like and dissociative symptoms. No residual cognitive effects were observed 3 days following an acute dose.Conclusions The lack of residual effects in healthy volunteers on day 3 indicates that impairments found on day 3 in ketamine abusers are chronic effects. The abuse of ketamine may be related to its capacity both to reinforce and to decrease response inhibition.     

Propofol for pediatric radiotherapy

Objective : Pediatric radiotherapy is a day care procedure. In children, anaesthesia is necessary to prevent movement during the therapy. Traditionally intramuscular ketamine is used for these procedure because of its inherent safety in a child who used to be left alone in the cobalt room.Methods : This study was designed to explore the efficacy of propofol and ketamine in pediatric radiotherapy in nineteen children. The inclusion criteria was a child fasting for six hours with no fever or URTI in the past week. A child coming to the radiotherapy (RT) unit without an intravenous cannula was given intramuscular ketamine 10 mg/kg and taken for the procedure. Before the child recovered from anaesthesia an intravenous cannula, 20–22G, Vasofix was inserted for subsequent sittings of RT. The child coming with an intravenous cannula was given propofol 2.5 mg/kg with xylocaine (0.1 mg/kg) without adrenaline. The parameters recorded were pulse rate, oxygen saturation and respiratory rate-baseline to every 30 seconds till five minutes. Onset time, recovery time, oral feeding time and any untoward effects like nausea, vomiting, nystagmus were also noted.Result: The drug was graded on a scale of 0–10 according to parental acceptability where 0 is the worst and 10 is the best acceptability. The mean (±SD) of all the measured parameters were calculated and compared between the two groups.Conclusion : Propofol was associated with faster onset, better recovery, early oral feeding time, no nausea and vomiting and better parental acceptability. There was no hypotension, bradycardia and oxygen saturation at 60 seconds, which was betwen 94–95%, was easily treatable with supplementation of oxygen by face mask     

Low dose ketamine increases prepulse inhibition in healthy men

The N-methyl-D-aspartate (NMDA) antagonist, ketamine, produces neurobehavioural symptoms that mimic aspects of schizophrenia. Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in chronically ill, medicated schizophrenic patients and in animals treated acutely with NMDA antagonists. We tested the hypothesis that ketamine would produce psychotic symptoms and reduce PPI in healthy humans. Twenty male volunteers received placebo and ketamine in a within-subject, double-blind, cross-over design with 0.23 mg/kg ketamine hydrochloride or saline as a loading dose, followed by 0.5 mg/kg ketamine or saline over 45 min. Prepulse to pulse intervals were 30 ms and 120 ms. The Brief Psychiatric Rating Scale (BPRS) and the Clinician Administered Dissociative States Scale (CADSS) were administered. Ketamine produced a significant increase in PPI and significantly reduced startle magnitude, but did not alter habituation. Ketamine produced significant increases in BPRS and CADSS scores, with symptoms mimicking the negative and disorganisation symptoms of psychosis. In contrast to effects in rodents, this low dose of ketamine produced an increase in PPI despite producing psychopathological symptoms consistent with the NMDA psychosis model. These findings suggest that the cognitive and PPI changes of NMDA antagonists are not consistently linked at a phenomenological or neurochemical level.     

Antinociceptive interactions of ketamine with morphine or methadone in mononeuropathic rats

To study the antinociceptive synergy resulting from the combination of opioid receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists on neuropathic pain, an isobolographic analysis of equianalgesic combinations of ketamine with methadone or morphine was performed in rats with mononeuropathy produced by placing four constrictive ligatures around the common sciatic nerve. Two weeks later, the antinociceptive effect of subcutaneous administration of the drugs alone or combined was evaluated by using the paw pressure test. Drugs and their combinations produced dose-dependent antinociception. Combinations produced synergy of a supra-additive nature in the neuropathic paw, but only additive antinociception in the normal paw. The ketamine/methadone combination was more effective to produce antinociception in the neuropathic paw than was the ketamine/morphine association, as revealed by the lower ED25. The results indicate supra-additive synergy between NMDA receptor antagonists and opioids, especially methadone, to produce antinociception in experimental neuropathy.     

Effects of local and intravenous anesthetics on the activity of glutamate transporter type 2

Glutamate transporters may be important targets for anesthetic action in the central nervous system. The authors investigated the effects of the intravenous anesthetics, thiopental and ketamine, and the local anesthetics, lidocaine and bupivacaine, on the activity of glutamate transporter type 2, EAAT2. EAAT2 was expressed in Xenopus oocytes by injection of its mRNA. By using two-electrode voltage clamping, membrane currents were recorded after the application of L-glutamate (30 microM) in the presence or absence of various concentrations of anesthetics. Lidocaine and bupivacaine did not change glutamate-induced inward currents at the tested concentrations (1-1000 microM). Thiopental and ketamine also did not affect the activity of EAAT2 at the tested concentrations (0.3-300 microM). Our results suggest that the two commonly used local anesthetics (lidocaine and bupivacaine) and intravenous anesthetics (thiopental and ketamine) do not affect the activity of EAAT2 expressed in oocytes. EAAT2 may not be a target for these anesthetics.     

Effects of ketamine on voltage-dependent calcium currents and membrane potentials in single bullfrog atrial cells

Purpose. This study was undertaken to assess the effect of ketamine on L-type calcium channel current (I_Ca) and membrane action potential in the bullfrog single atrial myocyte. Methods. Bullfrog single atrial myocytes were prepared by enzymatic dispersion. Whole-cell voltage-clamp technique and current clamp technique were used to monitor I_Ca, membrane resting potential, and action potential. Results. Ketamine (10⁻⁵–10⁻³ M) showed dose-dependent inhibition of I_Ca in a reversible manner. The 50% inhibitory concentration (IC₅₀) of ketamine on I_Ca was estimated to be 0.92 × 10⁻⁵ M. Use-dependent block of I_Ca was not observed. The resting membrane potential was depolarized at a high concentration (10⁻⁴ M) of ketamine. Reduction of the plateau phase and prolonged duration of the action potential were observed in the presence of a high concentration of ketamine (10⁻⁴ M). Conclusion. Ketamine has an inhibitory effect on I_Ca in the bullfrog single atrial myocyte, and a high dose (10⁻⁴ M) of ketamine prolonges the duration of the action potential. The mechanism of inhibition of I_Ca seems to be a direct effect on the L-type calcium channel, not like an open channel blocker. Received: October 2, 2000 / Accepted: February 19, 2001     

大鼠肺鳞癌模型两种麻醉方法的比较

目的 探讨不同麻醉方法建立大鼠肺鳞癌模型的差异.方法 体重180～220 g Wistar大鼠,依不同麻醉方法分为2组实验I组(110只)用0.3%戊巴比妥钠麻醉;实验Ⅱ组(80只) 基础麻醉用盐酸氯胺酮44 mg/kg,然后乙醚吸入麻醉.两组均采用额镜直视法,灌注3-甲基胆蒽(MCA)、二乙基亚硝胺(DEN)与普通碘油混悬液于大鼠左下叶支气管.结果 麻醉显效时间和维持时间分别为Ⅰ组,(23.50±1.98) min,(246.56±15.46) min,Ⅱ组,(3.05±0.45) min,(12.47±1.35) min,两组间有显著性差异(P＜0.01);灌注成功率、存活率、诱癌率分别为Ⅰ组94.55%,48.08%,90.00%,Ⅱ组93.75%,90.67 %,92.65%,两组成功率、诱癌率差异无显著性(P ＞ 0.05),存活率有显著差异(P ＜0.01).分别于不同时间处死大鼠,2组基本病理过程相同.结论 戊巴比妥钠麻醉剂量易控制,以小剂量灌注雄性大鼠为佳;盐酸氯胺酮与乙醚复合麻醉较难控制,但速度快,实用性强.     

氯瑞合剂对小儿全身静脉麻醉心血管系统的影响

目的:观察瑞芬太尼复合氯胺酮在小儿全身麻醉中对心血管系统的影响。方法:将80例ASAⅠ级~Ⅱ级患儿随机分为A、B两组,每组各40例。A组用氯胺酮静脉注射泵维持,B组用氯胺酮以及瑞芬太尼静脉注射泵维持。术中监测患儿血压、心率及SpO2,观察并记录术后苏醒时间和氯胺酮的用量。结果:A组患儿血压和心率与麻醉前相比差异有显著性(P<0.05),B组差异无显著性,两组患儿SpO2较麻醉前差异均无显著性;B组术中氯胺酮用量和复苏时间均明显少于A组(P<0.05)。结论:瑞芬太尼复合氯胺酮用于小儿全身麻醉能更有效地维持心血管系统稳定,是一种较安全的麻醉方法。     

咪唑安定氯胺酮用于硬膜外腔超前镇痛观察

目的 探讨咪唑安定、氯胺酮硬膜外腔超前镇痛的临床效果及副作用。方法 择期硬膜外间隙阻滞下施行下腹部手术病人60例,ASAⅠ～Ⅱ级,随机分为三组,Ⅰ组(n=20例)氯胺酮1 mg·kg~(-1),Ⅱ组(n=20例)氯胺酮0.5 mg·kg~(-1),Ⅲ组(n=20例)氯胺酮0.5 mg·kg~(-1)、咪唑安定0.1 mg·kg~(-1),三组药液均以生理盐水稀释至4 ml,Ⅰ组于手术结束后注入硬膜外腔,Ⅱ、Ⅲ组于手术前(麻醉平面满意后)注入硬膜外腔。分别记录术中MAP、ECG、HR、SPO_2。术后4 h、8 h、12 h、24 h、48 h、72 h追踪观察镇痛(用视觉模拟评分法VSA 0～10cm)情况、杜冷丁用量及副作用。结果Ⅲ组效果优于Ⅰ、Ⅱ组,镇痛时间长,效果确切、有遗忘作用、副作用少。Ⅰ组有短暂的意识模糊、定向障碍。结论 氯胺酮伍用咪唑安定用于硬膜外腔超前镇痛效果较好。     

Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers

RATIONALE: Ketamine is an NMDA receptor antagonist with psychotogenic and cognitive effects in healthy volunteers and schizophrenic patients which has been proposed to be a useful tool to investigate neurobiological basis of schizophrenia. OBJECTIVE: The present study characterized the effects of a subanesthetic dose of ketamine on memory and related subjective states of awareness in healthy volunteers. METHODS: Twenty-six subjects were given either a 60-min ketamine (0.5 mg/kg per hour) or a placebo infusion. To obtain constant plasma ketamine throughout the experiment, ketamine was administered using a computer-controlled infusion system. Subjects carried out episodic memory tasks involving words presented before and during infusion. Memory performance was assessed with recognition and free recall tasks. Subjective states of awareness were assessed using an experiential approach. Levels of psychopathology were evaluated with BPRS. RESULTS: Ketamine impaired performance in free recall and recognition of words presented during, but not before, infusion. There were no differences between groups concerning states of awareness associated with recognition memory. Subjects under ketamine had higher BPRS total scores as well as BPRS negative and positive cluster scores than control subjects. CONCLUSIONS: Ketamine decreases episodic memory performance by impairing encoding, but not retrieval processes. It does not selectively impair subjective states of awareness associated with recognition memory as it has been seen in patients with schizophrenia. Ketamine might mimic the memory impairment associated with acute, but not chronic, forms of schizophrenia.