Neurocognitive performance under combined regimens of ketamine-dexmedetomidine and ketamine-fentanyl in healthy adults: A randomised trial

Analgesic doses of ketamine affects neurocognition; however, deficits under co-administration regimens are unknown. This study evaluated the effects of ketamine, alone and in combination with dexmedetomidine or fentanyl on neurocognition. Using a randomised, within-subjects gender stratified design, 39 participants (mean age = 28.4, SD ± 5.8) received a ketamine bolus of 0.3 mg/kg followed by 0.15 mg/kg/h infusion of ketamine (3 h duration). At 1.5 h post-ketamine infusion commencement, participants received either: i) 0.7 μg/kg/h infusion of dexmedetomidine (n = 19) (KET/DEX) or (ii) three 25 μg fentanyl injections over 1.5 h (n = 20) (KET/FENT). Reaction and Movement time (RTI, Simple and 5Choice), Visuospatial Working Memory (SWM) and Verbal Recognition Memory (VRM) were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Whole blood drug concentrations were determined during ketamine-only infusion, at co-administration (KET/DEX or KET/FENT) and at 2-h post-treatment. Ketamine-only administration impaired psychomotor response speed (Simple and 5Choice) and impaired memory (all p < .001), however did not alter executive function abilities. Independent of sedation, co-administration of dexmedetomidine produced synergistic performance and memory deficits which persisted at post-treatment (KET/DEX) (all p < .001), and were comparatively greater than for KET/FENT (all p < .05). Ketamine, norketamine and dexmedetomidine concentrations were modestly associated with reduced psychomotor speed and accuracy (all p < .05), and an inverse relationship was found between blood concentrations of ketamine, norketamine and dexmedetomidine and performance on memory tasks. Co-administration of ketamine with dexmedetomidine but not with fentanyl exerts synergistic effects on psychomotor performance and memory without executive dysfunction. Assessment of these effects in clinical groups is warranted.