Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Br J Anaesth. 2021 Jul;127(1):23-31. doi: 10.1016/j.bja.2021.02.034. Epub 2021 Apr 22.
Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine.
Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites.
A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output.
S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner.
Dutch Cochrane Center 5359.
氯胺酮具有心脏兴奋的副作用。目前，关于氯胺酮及其代谢物浓度对心输出量的影响的数据很少。因此，我们开发了一种从随机临床试验数据中得出的药效动力学模型。本研究是一项更大的临床研究的一部分，该研究评估了硝普钠对氯胺酮致幻作用的潜在缓解作用。
20 名健康男性受试者在 4 次就诊时接受递增的 Esketamine 和外消旋 Ketamine 剂量，同时接受安慰剂或硝普钠：（i）Esketamine 和安慰剂，（ii）Esketamine 和硝普钠，（iii）外消旋 Ketamine 和安慰剂，和（iv）外消旋 Ketamine 和硝普钠。在每次就诊时，采集动脉血样并测量心输出量。使用非线性混合效应模型分析心输出量时间序列数据。以顺序方式向模型中添加氯胺酮代谢物，以评估代谢物的影响。
一个包含 S-氯胺酮和 S-去甲氯胺酮效应的模型最能描述数据。氯胺酮增加心输出量，而建模显示 S-去甲氯胺酮降低心输出量。对于 R-氯胺酮、除 S-去甲氯胺酮以外的代谢物或硝普钠，对心输出量均未检测到显著影响。
S-氯胺酮而非 R-氯胺酮以剂量依赖性方式增加心输出量。与 S-氯胺酮相反，其代谢物 S-去甲氯胺酮以剂量依赖性方式降低心脏兴奋。
荷兰 Cochrane 中心 5359。
