Effects of propofol anesthesia on the processing of noxious stimuli in the spinal cord and the brain
Introduction
The intravenous agent propofol, commonly used as a hypnotic drug for general anesthesia, provides means to investigate the neural correlates of drug-induced unconsciousness in an experimental setting (MacDonald et al., 2015). In dependence of the applied dose, propofol can be used to induce a wide range of states of consciousness, reaching from drowsiness over the loss of responses following tactile or verbal stimuli to deep unconsciousness that remains stable even during intense noxious stimuli (Shafer and Stanski, 2008). As the mechanism conducting this gradual loss of responsiveness with increasing dose, it is assumed that propofol dose-dependently first impairs sensory processing in higher-order association cortices, followed by attenuation and eventual cessation of responses in primary cortical areas at higher doses (Colon et al., 2017, Hudetz, 2012). This progressive attenuation and disruption of cortical processing of stimuli with increasing anesthetic depth has been shown for a variety of innocuous stimuli like auditory (Adapa et al., 2014, Heinke et al., 2004, Liu et al., 2012, Plourde et al., 2006), visual (Heinke and Schwarzbauer, 2001) and tactile stimuli (Antognini et al., 1997, Bonhomme et al., 2001).
However, propofol-induced attenuation of the sensory processing of noxious stimuli differs from other sensory modalities in the way that propofol exhibits a strong attenuating effect in the spinal cord (Baars et al., 2009, Hudetz, 2012, Matute et al., 2004). Interpretations of the cerebral mechanisms of a progressive attenuation and disruption of cortical processing based on the results from previous studies investigating noxious stimuli during propofol-induced unconsciousness (Hofbauer et al., 2004, Ní Mhuircheartaigh et al., 2010, Ní Mhuircheartaigh et al., 2013) are therefore confounded by spinal effects of propofol. In this study, we sought to investigate the processing of noxious stimuli during propofol-induced unconsciousness using simultaneous monitoring of spinal and cerebral activations to differentiate between spinal and cortical dose-dependent effects of propofol on the processing of noxious stimuli. To that end, we performed experimental measurements in volunteers that received stepwise increasing doses of propofol ranging up to doses inducing electroencephalogram (EEG) burst suppression, which corresponds with the deepest levels reached during general anesthesia in clinical practice. In order to investigate the sensory processing of innocuous and noxious stimuli at every dose level, we applied a transcutaneous electrical stimulation paradigm to a peripheral nerve at the leg, which allows the application of sensory stimuli ranging from innocuous to intense noxious without the risk of tissue damage. To monitor the effects of propofol on the spinal processing of these stimuli we recorded nociceptive flexion reflex responses using electromyography (EMG) and to monitor the effects of propofol on the cerebral processing we used functional magnetic resonance imaging (fMRI) in combination with simultaneous EEG.
Section snippets
Sample size
As this was the first study to investigate the processing of noxious stimuli during deep propofol anesthesia, a formal sample size calculation based on estimates of the effects could not be performed. Therefore, the necessary minimum sample size was derived from previous similar studies conducting fMRI measurements during anesthesia (e.g. (Leppä et al., 2006, Plourde et al., 2006, Wise et al., 2004)). Ethical considerations and regulatory constraints limited the sample size to the minimum
Increasing propofol concentration after the loss of consciousness has little effect on spinal nociceptive reflex responses to intense noxious stimuli
As expected for a nociception-specific measure, innocuous stimuli did provoke significant nociceptive flexion reflex responses neither during wakefulness nor during any propofol level (Fig. 2). Moderate noxious stimuli triggered significant reflex responses during wakefulness, which were no longer detectable under the influence of propofol. In contrast, intense noxious stimuli triggered significant nociceptive flexion reflex responses at every propofol concentration level without significant
Discussion
Our results show that while spinal and brain responses to innocuous and moderate noxious stimulation are abolished completely at low to medium propofol concentrations, intense noxious stimuli provoke both spinal and brain neuronal activations even at the highest investigated propofol concentrations, which induced profound EEG burst suppression. Specifically, we found that increasing propofol levels after the loss of consciousness influenced neither spinal nociceptive processing of intense
Conclusion
In this study, we found that propofol changes the processing of somatosensory stimuli profoundly in a dose-dependent manner after the loss of consciousness. We found that intense noxious stimuli provoke responses in various brain regions including higher-order cortices even at concentration levels that cause nearly complete EEG burst suppression. While the spinal transmission of intense noxious input and its forwarding to the somatosensory cortex were not significantly altered by propofol after
Contributors
RA, FB, and FvD conceived and designed the study. GL, RA, HV, DM, MS, FB, and FvD acquired the data. GL, RA, EK, MS, FB, and FvD analyzed the data. GL and FvD drafted the article. GL, RA, EK, HV, DM, MS, FB, and FvD interpreted the data and critically revised the manuscript. All authors provided approval of the manuscript.
Declaration of interests
Gregor Lichtner was in student employment at Dolosys GmbH, a spin-off company of Charité - Universitätsmedizin Berlin developing reflex measurement devices.
Falk von Dincklage worked as consultant for Dolosys GmbH and received funding from Dolosys GmbH for a different research project.
No conflicts of interests regarding this study exist. No equipment of Dolosys GmbH has been used in this study.
Trial registration
Deutsches Register Klinischer Studien, DRKS (registration number DRKS00000663).
Acknowledgements
This study was funded by the German Research Foundation, Bonn, Germany (Deutsche Forschungsgemeinschaft, DFG, grant number DI1579/4-1).
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