Multimodal General Anesthesia: A Principled Approach to Producing the Drug-Induced, Reversible Coma of Anesthesia

A map of the Harvard Medical School campus in Boston in 1906 emphasizes the primacy of the 2 foundational sciences in medicine. The first 3 structures of the newly constructed site, designated Buildings A, B, and C, were situated together at the top of the main quadrangle (and still stand today).1 Building A, now known as “Gordon Hall,” is the administrative center. On one side of the main quad, adjacent to the administration facility, one finds Building B, originally dedicated to the study of anatomy. Directly opposite on the other side of the plaza, one sees Building C, originally reserved for the study of physiology. Although the anatomy and physiology classrooms and laboratories have since been relocated, the legacies of Vesalius and Harvey still loom large on the main quadrangle of Harvard Medical School. All of biomedical science is an outgrowth of these 2 fundamental disciplines relating to form and function. In this issue of Anesthesia& Analgesia, Brown et al2 propose a principled approach to producing the drug-induced, reversible coma that is the anesthetized state. They call this refinement of existing methods “multimodal general anesthesia.” Anchoring the intellectual framework of their proposal in the relevant anatomy and physiology, they detail the multiplicity of neuroanatomical circuits and neurophysiological mechanisms that can be leveraged to produce anesthesia. There is a natural provinciality at play here; the authors’ arguments pay homage to the prominence of the buildings formerly known as A and B on the nearby quad. At the heart of the thinking by Brown et al2 is the acknowledgment that producing the anesthetized state with a single anesthetic agent is problematic. Although it is possible to produce unconsciousness and immobility with a single anesthetic agent such as isoflurane or propofol alone, controlling autonomic nervous system (ANS) responses to noxious stimulation with a single agent is more challenging and requires much higher concentrations. Hypnotic agents used in isolation cannot prevent heart rate and blood pressure increases in response to nociception without severe prestimulus hemodynamic depression and prolonged recovery.3,4 Thus, practically speaking, in the modern era, the practice of anesthesia is at least a 2-drug process consisting of an inhaled agent or propofol in combination with a second agent to control ANS responses to surgical stimulation.5 In recent decades, opioids have been, by far, the most commonly used second drug; opioids are very effective in controlling ANS responses to nociception and have traditionally played an important role in postoperative pain control. Other drugs such as esmolol or adenosine have also been used to control ANS responses, although these techniques never gained much traction in the trenches of daily practice presumably, in part, because they were not useful for postoperative pain management.6,7 The multimodal general anesthesia proposal by Brown et al2 extends the well-entrenched concept of “balanced anesthesia”8,9 to include more drugs that target different neuroanatomical circuits and multiple neurophysiological mechanisms. The suggested pharmacopeia includes a host of anesthetic adjuncts, including opioids (remifentanil), α-2 agonists (dexmedetomidine), local anesthetics (lidocaine), cations (magnesium), and N-methyl-D-aspartate receptor antagonists (ketamine). The pharmacological foundation of the concept is grounded in the firmly established observation that when anesthetic drugs of different mechanisms are administered together, they typically interact with synergism.10 This synergy theoretically affords certain advantages, including faster recovery because the slope of the concentration–effect relationship steepens with synergy, meaning that small decreases in drug concentration lead to larger decreases in drug effect.11 The opioid abuse epidemic has provided some of the motivation to move away from opioids toward other adjunct drugs for the provision of general anesthesia. Data suggest that perioperative opioid usage patterns may contribute to opioid abuse postoperatively, although how the administration of intraoperative opioids may influence this problem is unclear.12,13 In any case, the proposal by Brown et al2 does not call for the total abandonment of intraoperative opioids but rather a more eclectic pharmacological assortment that increases the resulting synergy and decreases the total opioid exposure. This approach will certainly reduce dose-related opioid adverse effects perioperatively and may have some impact on postoperative opioid abuse, although this notion is still speculative. Conceptualizing the multimodal general anesthesia technique within the context of fundamental anesthesia pharmacology constructs is instructive. The conventional goals of general anesthesia are unconsciousness, immobility, and the control of ANS responses to surgical stimulation (Figure, panel A). Amnesia, also an essential outcome, is presumed when patients are rendered unconscious. We promise our patients safe oblivion, and we must deliver on all 3 of these goals to keep our promise. At any given point during a procedure, the anesthetic state is either adequate or it is not.14 From the patient’s vantage point, referring to periods of inadequate anesthesia as “light” anesthesia is a disconcerting and inept euphemism.Figure.: The clinical goals and corresponding pharmacological concepts of general anesthesia. A, A triangle representing the conventional goals of general anesthesia. Amnesia is another essential outcome presumed to be present when a patient is clearly unconscious. B, An idealized, graphical representation of the concentration–effect relationships of inhaled anesthetic agents in terms of MAC, MACawake, and MACBAR (see text for complete explanation). ANS indicates autonomic nervous system; MAC, minimum alveolar concentration; MACawake, minimum alveolar concentration inhibiting voluntary response to verbal command; MACBAR, minimum alveolar concentration blocking adrenergic response to skin incision.These 3 deliverables that constitute adequate anesthesia can be mapped to well-established, widely understood pharmacological concepts in anesthesiology (Figure, panel B). Minimum alveolar concentration (MAC),15 which relates anesthetic concentration to the immobility deliverable (sometimes referred to as the “somatic” response to nociception), is perhaps the most unifying idea in anesthesia pharmacology. MACawake is an analogous concept relating to the unconsciousness deliverable16; MACawake is approximately 1/3 of MAC. MACBAR (block of adrenergic response) extends this concept of MAC to the third deliverable of anesthesia, the control of ANS responses to the surgeon’s knife.17 MACBAR is approximately 2 times MAC. Some refer to the control of ANS responses during general anesthesia as analgesia, although this is philosophically clumsy because, by definition, the study of pain in humans requires conscious patients to tell us about their unpleasant affective experiences stemming from the noxious stimuli. That is, we do not have a well-developed theoretical construct to understand or study pain in the comatose patient, although we often have clinical evidence that some nociception is occurring during anesthesia (eg, heart rate and blood pressure increases arising from surgical stimuli). In any case, the relationships among these variants of the MAC concept have simple and important clinical implications. As anesthetic concentrations rise, unconsciousness precedes immobilization, which precedes control of ANS responses. At MACBAR, only 50% of patients exhibit adequate anesthesia, and yet the hemodynamic consequences of these levels of volatile anesthetics (and equivalent concentrations of propofol) are intolerable in many patients. Thus, the antinociceptive effects of opioids and other adjuncts are key to the multimodal general anesthesia concept. As Brown et al2 emphasize, these adjuncts profoundly contribute to unconsciousness (and other anesthetic end points) by mitigating nociceptive-induced arousal. In clinical pharmacology terms, these adjunct anesthetic agents shift the concentration–effect relationships of the primary anesthetic agents leftward (both volatile agents and propofol). This idea is the well-known and often clinically exploited concept of “MAC reduction.”18 Viewed from an evidence-based medicine perspective, the proposal by Brown et al2 must be regarded as a hypothesis to be tested. They have put forward a principle-based proposal that outlines a theoretical framework for multimodal general anesthesia, but many studies need to be done to confirm that their proposal will yield the desired results. Brown et al2 acknowledge the need to confirm their clinical impressions and solidify the scientific foundation and evidence basis of the multimodal general anesthesia concept though investigation. The necessary studies fit into at least 2 categories, perhaps among others. First, there is work to be done in the clinical pharmacology arena to better characterize the pharmacodynamic interactions between the anesthetic adjuncts and primary anesthetics (ie, inhaled agents and propofol). The current state of the art for the study of such interactions employs the response surface technique, an observational, 3-dimensional method that relates the drug concentrations of both agents (from low to high) to drug effect (from low to high).11,19 Fully understanding the multiple drug interactions implied by the multimodal general anesthesia approach may require the development of new multidimensional interaction models. An important advantage of undertaking this clinical pharmacology work is that it might be possible to identify optimal ratios of the drug combinations based on computer simulation.20 The second category of study relates to outcomes. An infinite number of clinical trials could be proposed to vet and validate the multimodal general anesthesia concept in terms of anesthetic outcomes. Designing trials that assess the clinical consequences of the most commonly used combinations and techniques compared to standard practice will be a reasonable place to start this hypothesis testing work. Of course there are important practical limitations to the multimodal general anesthesia concept. Perhaps chief among them is that the technique calls for multiple intravenous infusions; many practitioners will find this necessity cumbersome in the daily trenches of a busy anesthesia practice. Also, from a technological perspective, many practitioners do not have the recommended processed electroencephalography machines available to them. And, it is fair to conclude that the antinociception monitoring technologies advocated by Brown et al2 are in their infancy and not yet fully validated. The multimodal general anesthesia concept is rooted in the legacies of Buildings B and C of the newly constructed Harvard Medical School Campus of the early 1900s. The neuroanatomical circuitry and neurophysiological mechanisms at the foundation of the proposal are sound, but it will take time and effort for investigators to confirm the hypothesis generated by Brown et al.2 In the meantime, clinicians on the frontlines of everyday practice will make their own observations and draw their own conclusions about the technique. DISCLOSURES Name: Talmage D. Egan, MD. Contribution: This author helped write the manuscript and direct creation of the artwork. Name: Christer H. Svensen, MD, PhD. Contribution: This author helped review the manuscript and artwork and provide comments and suggestions. This manuscript was handled by: Ken B. Johnson, MD.