Multimodal General Anesthesia: Theory and Practice

Abstract

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.

Conflict of interest statement

Conflicts of Interest: See Disclosures at the end of the article.

Figures

Figure 1.

Ascending and descending nociception pathways. A, Nociceptive signals enter the spinal cord through nociceptive neurons that have specialized sensory receptors which lie in the tissue and cell bodies which lie in the dorsal root ganglia. These neurons synapse in the dorsal horn of the spinal cord onto primary projection neurons that travel in the anterolateral fasciculus through the spinal reticular tract (to the NTS and the amygdala) and spinal thalamic tract (to the thalamus). Projections from the thalamus continue to primary sensory cortex. B, The descending pathways begin in the sensory cortex and project to the hypothalamus and amygdala. Projections from the hypothalamus and amygdala synapse in the PAG, NTS, and RVM. Projections from the RVM carried in the reticular spinal tract modulate incoming nociceptive information by synapsing onto inputs to nociceptive neurons at the level of the dorsal horn. NTS indicates nucleus of the tractus solitarius; PAG, periaqueductal gray; RVM, rostral ventral medulla.

Figure 2.

Opioids. The mechanisms of opioid-induced antinociception are produced by opioid binding to opioid receptors in the brainstem and spinal cord. Opioid-induced decrease in arousal is produced by blockade of cholinergic arousal projections from the brainstem to the thalamus and cortex. The symbol denotes an excitatory effect. The symbol denotes an inhibitory effect. The symbols and denote inhibition of the indicated effects. ACh indicates acetylcholine; DRG, dorsal root ganglia; Glu, glutamate; LDT, laterodorsal tegmental area; mPRF, medial pontine reticular formation; NE, norepinephrine; PAF, peripheral afferent fiber; PAG, periaqueductal gray; PN, projection neuron; PPT, pedunculopontine tegmental area; RVM, rostral ventral medulla.

Figure 3.

Ketamine and magnesium. The mechanisms of ketamine- and magnesium-induced antinociception are produced primarily by blockade of glutamatergic receptors in the spinal cord and in arousal projections emanating from the brainstem. Ketamine at low doses blocks GABAergic interneurons. DRG indicates dorsal root ganglia; GABA, γ-aminobutyric acid; Glu, glutamate; mPRF, medial pontine reticular formation; PAF, peripheral afferent fiber; PB, parabrachial nucleus; PN, projection neuron.

Figure 4.

Dexmedetomidine and clonidine. Dexmedetomidine- and clonidine-induced antinociception occur primarily through enhanced inhibitory activity in the descending nociceptive pathways. Sedation induced by dexmedetomidine or clonidine and loss of consciousness induced by dexmedetomidine occur through NE-mediated disinhibition of the POA of the hypothalamus and decreased noradrenergic signaling in the thalamus and cortex. 5HT indicates serotonin; ACh, acetylcholine; DA, dopamine; DR, dorsal raphé; DRG, dorsal root ganglia; GABAA, γ-aminobutyric acid receptor subtype A; Gal, galanin; His, histamine; ILN, intralaminar nucleus of the thalamus; LC, locus coeruleus; LDT, laterodorsal tegmental area; NE, norepinephrine; PAF, peripheral afferent fiber; PN, projection neuron; POA, preoptic area; PPT, pedunculopontine tegmental area; RVM, rostral ventral medulla; TMN, tuberomammillary nucleus; vPAG, ventral periaqueductal gray.

Figure 5.

NSAIDs and lidocaine. Surgical insults induce rupture of cell membranes, leading to release of arachidonic acid, which, through the action of COX-1 and COX-2, is converted into prostaglandins, which are potent inflammatory and nociceptive mediators. NSAIDs modulate the nociceptive response by blocking the actions of COX-1 and COX-2, and lidocaine exerts their nociceptive effects by inactivating sodium channels, thus inhibiting excitation of nerve endings and blocking conduction of action potentials in peripheral nerves. Lidocaine also impedes neutrophil degranulation, thereby impeding the amplification of the inflammatory response. COX indicates cyclooxygenase; DRG, dorsal root ganglion; NSAID, nonsteroidal anti-inflammatory drug; PAF, peripheral afferent fiber; PGE2, prostaglandin E2; PGH2, prostaglandin H2; PGG2, prostaglandin G2; PN, projection neuron.

Figure 6.

Propofol and sevoflurane. Propofol and sevoflurane induce unconsciousness by enhancing inhibitory GABAergic activity of inhibitory interneurons in the cortex, in the thalamus, and at the inhibitory GABAergic projections from the POA of the hypothalamus onto the arousal centers in the brainstem. 5HT indicates serotonin; ACh, acetylcholine; DA, dopamine; DR, dorsal raphé; GABA, γ-aminobutyric acid; Gal, galanin; His, histamine; LC, locus coeruleus; LDT, laterodorsal tegmental area; LH, lateral hypothalamus; NE, norepinephrine; POA, preoptic area; PPT, pedunculopontine tegmental area; TMN, tuberomammillary nucleus; TRN, thalamic reticular nucleus; vPAG, ventral periaqueductal gray.