Our single-center RCT revealed a significant reduction in the incidence of POD by a perioperative administration of dexmedetomidine among elderly patients undergoing either cardiac or noncardiac high-risk surgery (19). In the present secondary analysis, the perioperative coadministration of dexmedetomidine revealed significantly lower PSi indices, which were not associated with a reduced anesthetic agent or opioid application. Interestingly, despite lower anesthetic depth index values in the dexmedetomidine group, the incidence of POD was also significantly lower, which is a contradiction to previously published RCT trials showing that prolonged deep sedation during general anesthesia is associated with a higher risk of developing POD in elderly patients.(5)
The protective effects of dexmedetomidine in connection with delirium prevention and related outcome parameters have already been demonstrated in previous studies. (13, 19, 22) Nevertheless, the exact administration differs considerably between some of the existing studies, as well as the examined patient population. Earlier study results indicate that the patient population, as well as the dosage and timing of dexmedetomidine administration, influences its preventive effects.(23–25) Age seems to be a relevant risk factor not only for the manifestation of POD but also for the occurrence of deep anesthesia and burst suppression patterns in the EEG.(2, 26) In our cohort, we focused on an older (≥60 years of age) and high-risk surgical population of both noncardiac and cardiac patients undergoing mainly high-risk surgeries (CABG, PPPD, etc.). Accordingly, a high incidence of POD and POCD was expected, as this patient population is known to be most prone to developing cognitive dysfunctions.(27, 28) For example, the evaluation by Saczynski and colleagues for a cardio-surgical patient group after coronary bypass surgery (CABG) or valve replacement revealed a delirium incidence of 46% (29), which is in accordance with the delirium incidence of our placebo group.
In recent years, the depth of anesthesia and its possible consequences have increasingly become the focus of scientific work. Based on the results of large RCT trials, it is now recommended to monitor the depth of anesthesia with intraoperative frontal EEG neuromonitors in elderly patients to reduce the risk of developing POD by avoiding deep levels of anesthesia. (5, 30)
Dexmedetomidine, an alpha-2 adrenoceptor agonist, has sedative, anxiolytic, sympatholytic, analgesic-sparing effects with minimal depression of respiratory function and obtained arousal to stimuli.(15, 31) Therefore, it is widely used as a sedative or anesthetic adjunct. In addition to a significant reduction in POD in our trial, we would like to emphasize further effects of the perioperative administration of dexmedetomidine, as it seems to have an impact on anesthetic depth and PSi. In the present study population, over 70% of the patients examined were affected by deep anesthesia during the procedure, with an incidence of 85.2% in the dexmedetomidine group and 58.1% in the placebo group.
In our study, reduced PSi index values occurred despite a significant POD reduction in our dexmedetomidine group without opioid- and anesthetic agent-sparing procedures. This controversial finding may be interpreted in two ways: (1) either the algorithm within the SedLine monitor is not able to reliably indicate the depth of sedation under administration of alpha-2 adrenergic agents or (2) dexmedetomidine itself has a neural effect that prevents POD besides inducing deep sedation. Anesthetic agents inducing unconsciousness act at different molecular targets, including gamma-amino butyric acid type A (GABAA) agonists, opioid receptor agonists, N-methyl-D-aspartate receptor (NMDA) antagonists and alpha-2 adrenergic agonists. Dexmedetomidine is a highly selective alpha2-adrenergic agonist inducing an increase in delta-band power and coherent spindle oscillations in the frontal brain area during sedation.(18, 32) This is in contrast to most frequently used anesthetic agents, such as propofol or sevoflurane, which induce besides an increase of delta-band power a highly coherent frontal alpha-band power during unconsciousness.(33, 34) Since EEG neuromonitor indices depend on inbuilt raw EEG processing algorithms based on fast Fourier transformation and spectral data analysis of shifting EEG epochs, these algorithms have a major impact on the processed index presented during Anesthesia.(30) In detail, the PSi is derived from changes in the power spectrum in various EEG frequency bands, frontal hemispheric symmetry and synchronization.(20) Since the presented raw EEGs during sedation between GABAergic anesthesia (i.e., propofol, sevoflurane) and alpha-2 adrenergic agonist-induced unconsciousness differ significantly, we assume that the presented PSi during dexmedetomidine application does not reliably indicate the correct level of sedation in these patients. We deduce that patients in the dexmedetomidine group do not undergo deeper sedation levels compared to the placebo group, even though this is indicated by the PSi.
Dexmedetomidine selectively acts on the alpha2-adrenergic receptors of the locus coeruleus projecting to the preoptic area of the hypothalamus, disrupting thalamo-cortical functional connectivity, while maintaining cortico-cortical functional connectivity within the DMN network.(16) During NREM sleep states I and II in humans, the same neuronal functional changes occur: DMN cortico-cortical functional connectivity is preserved, while thalamo-cortical functional connectivity is disrupted.(35, 36) In many recent studies, the positive effect of sleep on memory consolidation has been shown (37, 38), and ICU-related delirium is also triggered by disruption of the circadian rhythm and sleep deprivation.(39) Hence, we propose that the application of dexmedetomidine triggers physiological sleep like neuronal oscillations, which improve postoperative cognitive functions in those patients and thereby prevent the development of POD.
In our study, there were no differences in the opiate and hypnotic requirements of the patients between the two groups. To adequately address opioid and hypnotic saving effects through our intervention, the anesthetic levels should have been identical. Since anesthesia was not primarily PSi-guided in our study, i.e., anesthetic depth in both groups was not directly comparable. In contrast, our study results indicate lower PSi values in the dexmedetomidine group. To be able to take advantage of possible dexmedetomidine-induced hypnotic- and opioid-saving effects, monitoring anesthetic depth, from our point of view, is essential. As our study population gathers different scopes of surgery, opioid requirements, in general, may not be comparable between the two groups or within each group.
Limitations
Intraoperative neurological monitoring was a secondary endpoint in the study and the relatively small sample size in our study is a restriction. One of the main limitations of this analysis is the fact that the PSi was being interpreted without considering the EEG raw data. Additionally, besides the controlled application of the study medication, all other anesthetic agents and opioids were given at clinical requirements by the anesthesiologists in charge. However, since medical applications follow standard operative procedures and we did not see a difference between the two groups, we think this would not have compromised our results.