| 1. |
- Laaksonen, L., et al.
(författare)
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Comparative effects of dexmedetomidine, propofol, sevoflurane, and S-ketamine on regional cerebral glucose metabolism in humans : a positron emission tomography study
- 2018
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Ingår i: British Journal of Anaesthesia. - : Elsevier. - 0007-0912 .- 1471-6771. ; 121:1, s. 281-290
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The highly selective α2-agonist dexmedetomidine has become a popular sedative for neurointensive care patients. However, earlier studies have raised concern that dexmedetomidine might reduce cerebral blood flow without a concomitant decrease in metabolism. Here, we compared the effects of dexmedetomidine on the regional cerebral metabolic rate of glucose (CMRglu) with three commonly used anaesthetic drugs at equi-sedative doses.Methods: One hundred and sixty healthy male subjects were randomised to EC50 for verbal command of dexmedetomidine (1.5 ng ml-1; n=40), propofol (1.7 μg ml-1; n=40), sevoflurane (0.9% end-tidal; n=40) or S-ketamine (0.75 μg ml−1; n=20) or placebo (n=20). Anaesthetics were administered using target-controlled infusion or vapouriser with end-tidal monitoring. 18F-labelled fluorodeoxyglucose was administered 20 min after commencement of anaesthetic administration, and high-resolution positron emission tomography with arterial blood activity samples was used to quantify absolute CMRglu for whole brain and 15 brain regions.Results: At the time of [F18]fluorodeoxyglucose injection, 55% of dexmedetomidine, 45% of propofol, 85% of sevoflurane, 45% of S-ketamine, and 0% of placebo subjects were unresponsive. Whole brain CMRglu was 63%, 71%, 71%, and 96% of placebo in the dexmedetomidine, propofol, sevoflurane, and S-ketamine groups, respectively (P<0.001 between the groups). The lowest CMRglu was observed in nearly all brain regions with dexmedetomidine (P<0.05 compared with all other groups). With S-ketamine, CMRglu did not differ from placebo.Conclusions: At equi-sedative doses in humans, potency in reducing CMRglu was dexmedetomidine>propofol>ketamine=placebo. These findings alleviate concerns for dexmedetomidine-induced vasoconstriction and cerebral ischaemia.
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| 2. |
- Radek, L., et al.
(författare)
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Dreaming and awareness during dexmedetomidine- and propofol-induced unresponsiveness
- 2018
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Ingår i: British Journal of Anaesthesia. - : Elsevier. - 0007-0912 .- 1471-6771. ; 121:1, s. 260-269
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Tidskriftsartikel (refereegranskat)abstract
- Background: Experiences during anaesthetic-induced unresponsiveness have previously been investigated by interviews after recovery. To explore whether experiences occur during drug administration, we interviewed participants during target-controlled infusion (TCI) of dexmedetomidine or propofol and after recovery. Methods: Healthy participants received dexmedetomidine (n = 23) or propofol (n = 24) in stepwise increments until loss of responsiveness (LOR1). During TCI we attempted to arouse them for interview (return of responsiveness, ROR1). After the interview, if unresponsiveness ensued with the same dose (LOR2), the procedure was repeated (ROR2). Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness (LOC), infusion terminated, and the participants interviewed upon recovery (ROR3). An emotional sound stimulus was presented during LORs and LOC, and memory for stimuli was assessed with recognition task after recovery. Interview transcripts were content analysed. Results: Of participants receiving dexmedetomidine, 18/23 were arousable from LOR1 and LOR2. Of participants receiving propofol, 10/24 were arousable from LOR1 and two of four were arousable from LOR2. Of 93 interviews performed, 84% included experiences from periods of unresponsiveness (dexmedetomidine 90%, propofol 74%). Internally generated experiences (dreaming) were present in 86% of reports from unresponsive periods, while externally generated experiences (awareness) were rare and linked to brief arousals. No within drug differences in the prevalence or content of experiences during infusion vs after recovery were observed, but participants receiving dexmedetomidine reported dreaming and awareness more often. Participants receiving dexmedetomidine recognised the emotional sounds better than participants receiving propofol (42% vs 15%), but none reported references to sounds spontaneously. Conclusion: Anaesthetic-induced unresponsiveness does not induce unconsciousness or necessarily even disconnectedness.
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| 3. |
- Kallionpää, Roosa E., et al.
(författare)
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Alpha band frontal connectivity is a state-specific electroencephalographic correlate of unresponsiveness during exposure to dexmedetomidine and propofol
- 2020
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Ingår i: British Journal of Anaesthesia. - : Elsevier. - 0007-0912 .- 1471-6771. ; 125:4, s. 518-528
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Tidskriftsartikel (refereegranskat)abstract
- Background herent alpha electroencephalogram (EEG) rhythms in the frontal cortex have been correlated with the hypnotic effects of propofol and dexmedetomidine, but less is known about frontal connectivity as a state-specific correlate of unresponsiveness as compared with long-range connectivity. We aimed to distinguish dose- and state-dependent effects of dexmedetomidine and propofol on EEG connectivity. thods rty-seven healthy males received either dexmedetomidine (n=23) or propofol (n=24) as target-controlled infusion with stepwise increments until loss of responsiveness (LOR). We attempted to arouse participants during constant dosing (return of responsiveness [ROR]), and the target concentration was then increased 50% to achieve presumed loss of consciousness. We collected 64-channel EEG data and prefrontal–frontal and anterior–posterior functional connectivity in the alpha band (8–14 Hz) was measured using coherence and weighted phase lag index (wPLI). Directed connectivity was measured with directed phase lag index (dPLI). sults efrontal–frontal EEG-based connectivity discriminated the states at the different drug concentrations. At ROR, prefrontal–frontal connectivity reversed to the level observed before LOR, indicating that connectivity changes were related to unresponsiveness rather than drug concentration. Unresponsiveness was associated with emergence of frontal-to-prefrontal dominance (dPLI: –0.13 to –0.40) in contrast to baseline (dPLI: 0.01–0.02). Coherence, wPLI, and dPLI had similar capability to discriminate the states that differed in terms of responsiveness and drug concentration. In contrast, anterior–posterior connectivity in the alpha band did not differentiate LOR and ROR. nclusions cal prefrontal–frontal EEG-based connectivity reflects unresponsiveness induced by propofol or dexmedetomidine, suggesting its utility in monitoring the anaesthetised state with these agents. inical trial registration
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| 4. |
- Lim, Elaine T, et al.
(författare)
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Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10-8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10-117). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10-4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.
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| 5. |
- Scheinin, Annalotta, et al.
(författare)
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Differentiating Drug-related and State-related Effects of Dexmedetomidine and Propofol on the Electroencephalogram
- 2018
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Ingår i: Anesthesiology. - : Lippincott Williams & Wilkins. - 0003-3022 .- 1528-1175. ; 129:1, s. 22-36
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDDifferentiating drug-related changes and state-related changes on the electroencephalogram during anesthetic-induced unconsciousness has remained a challenge. To distinguish these, we designed a rigorous experimental protocol with two drugs known to have distinct molecular mechanisms of action. We hypothesized that drug- and state-related changes can be separated.METHODS: Forty-seven healthy participants were randomized to receive dexmedetomidine (n = 23) or propofol (n = 24) as target-controlled infusions until loss of responsiveness. Then, an attempt was made to arouse the participant to regain responsiveness while keeping the drug infusion constant. Finally, the concentration was increased 1.5-fold to achieve presumable loss of consciousness. We conducted statistical comparisons between the drugs and different states of consciousness for spectral bandwidths, and observed how drug-induced electroencephalogram patterns reversed upon awakening. Cross-frequency coupling was also analyzed between slow-wave phase and alpha power.RESULTS: Eighteen (78%) and 10 (42%) subjects were arousable during the constant drug infusion in the dexmedetomidine and propofol groups, respectively (P = 0.011 between the drugs). Corresponding with deepening anesthetic level, slow-wave power increased, and a state-dependent alpha anteriorization was detected with both drugs, especially with propofol. Negative phase-amplitude coupling before and during loss of responsiveness frontally and positive coupling during the highest drug concentration posteriorly were observed in the propofol but not in the dexmedetomidine group.CONCLUSIONS: Electroencephalogram effects of dexmedetomidine and propofol are strongly drug- and state-dependent. Changes in slow-wave and alpha activity seemed to best detect different states of consciousness.
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