Ketamine: a controversial drug for neonates

Ketamine is widely used for anesthesia and analgesia in neonates and children. It provides potent sedation, analgesia, and amnesia, a short duration of action, supporting hemodynamic and respiratory stability. Noncompetitive antagonism of NMDA receptors produces its primary therapeutic effects, but it also alters receptor function at dopaminergic, serotonergic, cholinergic, and opioidergic sites. Recent interest in ketamine stems from its potential to block excitotoxic cell death, although concerns have been raised about anesthetic neurotoxicity in neonatal animal models. The development of ketamine, its clinical profile, toxic effects in the immature brain, and future applications in neonates and children are reviewed in this article.     

Bioerodable Ketamine-Loaded Microparticles Fabricated Using Dissolvable Hydrogel Template Technology

For severe cancer-related pain that is not relieved adequately by escalating doses of oral or parenterally administered strong opioid analgesics such as morphine, alone or in combination with an adjuvant drug such as ketamine, more invasive dosing routes may be warranted. One such approach involves surgical implantation of an intrathecal pump to deliver small doses of analgesic or adjuvant drugs in close proximity to the receptors that transduce their pain-relieving effects. However, the use of implanted devices is associated with a range of catheter-related problems. To address this, we have developed biodegradable microparticles loaded with the analgesic adjuvant drug, ketamine, for sustained release after a single bolus intrathecal injection. Drug-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared using a dissolvable hydrogel template. Using PLGA with 3 different ratios of lactic acid to glycolic acid (L/G), relatively high ketamine loading and homogenous particle shape and size were achieved. Specifically, ketamine loading of PLGA5050, PLGA7525, and PLGA8515 in ester-terminated microparticles was 20.0%, 20.4%, and 18.9%, respectively. The microparticles were within the desired size range (20 μm diameter and 30 μm height) and in vitro release was sustained for ≥14 days with an acceptable initial burst release (～10%-20%) achieved.     

Ketamine for chronic pain: risks and benefits

The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (4–14 days) show long-term analgesic effects up to 3 months following infusion. The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain.     

Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia.     

阈下剂量的氯胺酮用于剖宫产术麻醉中的探讨

目的 :探讨阈下剂量氯胺酮应用于剖宫产术麻醉中的可行性。方法 :80例产妇在连续硬膜外麻醉下行剖宫产手术 ,随机分成对照组和试验组。于切皮前分别静注 0 .4m g/kg的生理盐水和氯胺酮 ,观察并记录术中低血压和阻滞不全、新生儿 Apgar评分及产妇 Sp O2 情况。结果 :试验组低血压和阻滞不全的发生率分别为 0和 5 % ,明显较对照组 30 % ,2 5 %低 ( P<0 .0 5 ) ;两组新生儿 Apgar评分及产妇 Sp O2 则无明显差异 ( P>0 .0 5 )。结论 :阈下剂量的氯胺酮应用于剖宫产术麻醉是可行的。     

Quantifying the Psychological Effects of Ketamine: From Euphoria to the k-Hole

52 ketamine users were “opportunistically” recruited to take part in a survey of the psychological effects of the drug, in Manchester, United Kingdom in 2008. Twenty-seven ketamine-naïve respondents were also recruited for comparison in respect of “other” recreational drug use and level of schizotypy. Ketamine users attributed a wide range of appetitive, aversive, after-effect, and dissociative experiences to the drug. They also reported using a much wider range of other recreational drugs than ketamine non-users. Former users reported significantly fewer positive or dissociative experiences than current users.     

Are Sexes Affected Differently by Ketamine? An Exploratory Study in Ketamine Users

One hundred primary ketamine users and 100 controls were recruited in Hong Kong between December 2009 and December 2011. Cognitive assessment included general intelligence, working, verbal, and visual memory, and executive functions. A Univariate General Linear Model was used to compare cognitive performance between the male and female ketamine users and controls. The female users appeared to have a higher risk of visual memory impairment than their male counterparts. Further studies are warranted to clarify the mechanism of the sex-specific effect of ketamine on cognitive functions.     

氯胺酮导致下尿路症研究进展与相关动物试验的系统评价

目的探讨氯胺酮导致下尿路症状的临床症状案例报告相关研究的病因以及治疗方案,并对动物模型可靠性进行系统评价。方法计算机检索Pubmed,Embase,Elsevier,CNKI和Google Scholar,查找所有研究氯胺酮导致下尿路症状的文献,包括动物实验,检索时限为2007-01-01/2013-10-30。同时手检纳入文献的参考文献,按纳入排除标准由两人独立进行RCT的筛选,资料提取和质量评价后,进行定性分析。并采用STAIR清单和CAMARADES清单进行质量评价。结果 12篇个案均报道氯胺酮导致下尿路症状,主要临床表现为尿频、尿急、耻骨上疼痛。共纳入3个动物实验,且动物试验的方法学质量均不高,由于纳入研究的数量少和研究方法间的差异,本系统评价不适合采用Meta分析,有限的证据表明氯胺酮会导致小鼠膀胱壁增厚。结论本系统评价显示并没有可信服的证据证明动物试验在研究氯胺酮导致下尿路症状的可靠性。     

临床药师对1例氯胺酮相关性尿路系统损害病例的药学监护

目的:探讨临床药师参与氯胺酮相关性尿路系统损害患者的治疗并开展药学监护的意义。方法:根据对患者的药学监护,重点分析氯胺酮相关性尿路损害患者的诊疗过程,开展药学监护。结果:临床药师通过对患者的药学监护,结合疾病诊疗,提出合理化治疗建议,实现对氯胺酮相关性泌尿道损害的个体化治疗。结论:临床药师和临床医师协作治疗,制定个体化治疗方案,提高了临床治疗的安全有效性,同时提出心身药学概念。