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Balanced general anesthesia, the most common management strategy used in anesthesia care, entails the administration of different drugs together to create the anesthetic state. Anesthesiologists developed this approach to avoid sole reliance on ether for general anesthesia maintenance. Balanced general anesthesia uses less of each drug than if the drug were administered alone, thereby increasing the likelihood of its desired effects and reducing the likelihood of its side effects. To manage nociception intraoperatively and pain postoperatively, the current practice of balanced general anesthesia relies almost exclusively on opioids. While opioids are the most effective antinociceptive agents, they have undesirable side effects. Moreover, overreliance on opioids has contributed to the opioid epidemic in the United States. Spurred by concern of opioid overuse, balanced general anesthesia strategies are now using more agents to create the anesthetic state. Under these approaches, called "multimodal general anesthesia," the additional drugs may include agents with specific central nervous system targets such as dexmedetomidine and ones with less specific targets, such as magnesium. It is postulated that use of more agents at smaller doses further maximizes desired effects while minimizing side effects. Although this approach appears to maximize the benefit-to-side effect ratio, no rational strategy has been provided for choosing the drug combinations. Nociception induced by surgery is the primary reason for placing a patient in a state of general anesthesia. Hence, any rational strategy should focus on nociception control intraoperatively and pain control postoperatively. In this Special Article, we review the anatomy and physiology of the nociceptive and arousal circuits, and the mechanisms through which commonly used anesthetics and anesthetic adjuncts act in these systems. We propose a rational strategy for multimodal general anesthesia predicated on choosing a combination of agents that act at different targets in the nociceptive system to control nociception intraoperatively and pain postoperatively. Because these agents also decrease arousal, the doses of hypnotics and/or inhaled ethers needed to control unconsciousness are reduced. Effective use of this strategy requires simultaneous monitoring of antinociception and level of unconsciousness. We illustrate the application of this strategy by summarizing anesthetic management for 4 representative surgeries., National Institutes of Health (Grants R01 GM104948 and P01GM118269)

Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the α[subscript 2]-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness., National Institutes of Health (U.S.) (DP1-OD003646), National Institutes of Health (U.S.) (TR01-GM104948), National Institutes of Health (U.S.) (DP2-OD006454)

Background:: Electroencephalogram patterns observed during sedation with dexmedetomidine appear similar to those observed during general anesthesia with propofol. This is evident with the occurrence of slow (0.1 to 1 Hz), delta (1 to 4 Hz), propofol-induced alpha (8 to 12 Hz), and dexmedetomidine-induced spindle (12 to 16 Hz) oscillations. However, these drugs have different molecular mechanisms and behavioral properties and are likely accompanied by distinguishing neural circuit dynamics. Methods:: The authors measured 64-channel electroencephalogram under dexmedetomidine (n = 9) and propofol (n = 8) in healthy volunteers, 18 to 36 yr of age. The authors administered dexmedetomidine with a 1-µg/kg loading bolus over 10 min, followed by a 0.7 µg kg−1 h−1 infusion. For propofol, the authors used a computer-controlled infusion to target the effect-site concentration gradually from 0 to 5 μg/ml. Volunteers listened to auditory stimuli and responded by button press to determine unconsciousness. The authors analyzed the electroencephalogram using multitaper spectral and coherence analysis. Results:: Dexmedetomidine was characterized by spindles with maximum power and coherence at approximately 13 Hz (mean ± SD; power, −10.8 ± 3.6 dB; coherence, 0.8 ± 0.08), whereas propofol was characterized with frontal alpha oscillations with peak frequency at approximately 11 Hz (power, 1.1 ± 4.5 dB; coherence, 0.9 ± 0.05). Notably, slow oscillation power during a general anesthetic state under propofol (power, 13.2 ± 2.4 dB) was much larger than during sedative states under both propofol (power, −2.5 ± 3.5 dB) and dexmedetomidine (power, −0.4 ± 3.1 dB). Conclusion:: The results indicate that dexmedetomidine and propofol place patients into different brain states and suggest that propofol enables a deeper state of unconsciousness by inducing large-amplitude slow oscillations that produce prolonged states of neuronal silence., National Institutes of Health (U.S.) (Grant DP2-OD006454), National Institutes of Health (U.S.) (Grant DP1-OD003646), National Institutes of Health (U.S.) (Grant TR01-GM104948)

Anesthesia-induced altered arousal depends on drugs having their effect in specific brain regions. These effects are also reflected in autonomic nervous system (ANS) outflow dynamics. To this extent, instantaneous monitoring of ANS outflow, based on neurophysiological and computational modeling, may provide a more accurate assessment of the action of anesthetic agents on the cardiovascular system. This will aid anesthesia care providers in maintaining homeostatic equilibrium and help to minimize drug administration while maintaining antinociceptive effects. In previous studies, we established a point process paradigm for analyzing heartbeat dynamics and have successfully applied these methods to a wide range of cardiovascular data and protocols. We recently devised a novel instantaneous nonlinear assessment of ANS outflow, also suitable and effective for real-time monitoring of the fast hemodynamic and autonomic effects during induction and emergence from anesthesia. Our goal is to demonstrate that our framework is suitable for instantaneous monitoring of the ANS response during administration of a broad range of anesthetic drugs. Specifically, we compare the hemodynamic and autonomic effects in study participants undergoing propofol (PROP) and dexmedetomidine (DMED) administration. Our methods provide an instantaneous characterization of autonomic state at different stages of sedation and anesthesia by tracking autonomic dynamics at very high time-resolution. Our results suggest that refined methods for analyzing linear and nonlinear heartbeat dynamics during administration of specific anesthetic drugs are able to overcome nonstationary limitations as well as reducing inter-subject variability, thus providing a potential real-time monitoring approach for patients receiving anesthesia.