For maintenance of antinociception during general anesthesia, we use simultaneously multiple antinociceptive agents, including opioids (Table 1, column II, row A). Use of multiple antinociceptive agents in addition to an opioid creates the opioid-sparing effect of these agents. Each agent targets a different component of the nociceptive system so that together, they suppress more completely nociceptive transmission. The hypnotic agents reduce the ability to perceive pain, and thereby, contribute implicitly to antinociception (Table 1, column III, row A).
During general anesthesia, uncon sciousness is maintained primarily by using a single titratable agent such as propofol or sevoflurane (Table 1, column II, row B). The antinociceptive agents profoundly contribute to unconsciousness by arresting nociceptive-induced arousal (Table 1, column III, row B). Because each of the antinociceptive agents decreases arousal, their combination reduces appreciably the hypnotic dose required to maintain unconsciousness. When considering the use of an inhaled ether to maintain unconsciousness, the fact that less is required when multiple antinociceptive agents are administered is the commonly cited special case of the minimal alveolar concentration–sparing effect of the antinociceptive drugs. Amnesia is maintained by ensuring unconsciousness because a patient who is truly unconscious and not simply unresponsive is also amnestic.
A single muscle relaxant (nicotinic anticholinergic agent) can be used to maintain immobility (Table 1, column II, row C). The GABAergic hypnotic agents contribute to muscle relaxation by blocking α motor neurons at the level of the spinal cord (Table 1, column III, row C). Magnesium, administered as part of an antinociceptive regimen (Table 1, column II, row A), also enhances muscle relaxation significantly (Table 1, column III, row C). In this case, the muscle relaxant dose has to be reduced accordingly.
In addition to standard monitors required for tracking the physiological state during general anesthesia, electroencephalogram monitoring is essential to track level of unconsciousness and to guide hypnotic dosing. The ability to apply our multimodal strategy would be substantially enhanced by a monitor to track level of antinociception and guide dosing of the antinociceptive agents.25 Such monitors are becoming commercially available.60–63 At present, we use heart rate and blood pressure changes as a measure of the nociceptive medullary adrenergic circuit response to nociceptive stimuli.64
To illustrate our multimodal general anesthesia strategy, we summarize the perioperative management of 4 surgeries: laminectomy, total knee replacement, cesarean delivery, and exploratory laparotomy (Table 2). The strategy requires an explicit plan for preoperative, intraoperative, postoperative, and discharge antinociception/pain management. The drug doses and combinations are ones the anesthesiologist chose for the particular case. They are intended solely as examples. The management strategy, anesthetic choices, and anesthetic doses must be adapted to the needs of the individual patient.
The preoperative anesthetic management for the lumbar laminectomy with instrumentation (Table 2, column I) started 30 minutes before the surgery by administering low-dose infusions of dexmedetomidine and magnesium. These infusions, which initiate the patient’s antinociceptive regimen, commonly induce substantial sedation and muscle relaxation. Unconsciousness was induced with propofol and maintained with a low-rate propofol infusion and a low concentration of sevoflurane. After a ketamine bolus, ketamine and lidocaine infusions were added to complete simultaneous multimodal targeting of nociception. Muscle relaxation was maintained with rocuronium, which was reversed with sugammadex before the start of the instrumentation. The magnesium, lidocaine, and dexmedetomidine infusions were stopped 15–30 minutes before the projected end of the surgery to avoid prolonged recovery of consciousness. For postoperative antinociceptive management, a field block was performed by combining ropivacaine, dexmedetomidine, and ketorolac. Half of the volume was administered in the muscle layer along the wound, and the remaining half was administered in the subcutaneous tissue. This field block provided postoperative analgesia for approximately 24 hours.
We (M.N.) used the visual analog scale to allow the patient to describe their level of postoperative pain. Intravenous ketorolac and acetaminophen were the primary agents used for pain control, and morphine was administered to treat breakthrough pain. Before discharge, we counseled the patient on the benefits of taking pain medication on a set schedule and on the potential adverse effects of opioids. Our (M.N.) goal is to discharge patients using just NSAIDs, such as either ketorolac or acetaminophen to control pain.65 This patient was also discharged on pregabalin as he had been taking it for neuropathic pain before his surgery.
The multimodal strategy also applies to surgeries such as total knee replacements (Table 2, column II) and cesarean deliveries (Table 2, column III), which were conducted using regional anesthetic techniques. For the total knee replacement, a low-dose propofol infusion was used for sedation during placement of the spinal and during the surgery. During the cesarean delivery, a low-dose propofol infusion was used for sedation until delivery then discontinued at the end of the surgery. The spinal anesthetics for both cases used a combination of bupivacaine, clonidine, and morphine to achieve multimodal antinociception and muscle relaxation. Both patients received field blocks using a combination of ropivacaine, dexmedetomidine, and ketorolac at the completing of their surgeries before closing the skin incisions. For the field block, the anesthetic solution is injected in a systematic way around the length of the incision. Postoperative pain management relied on ketorolac and acetaminophen, with morphine as the rescue agent after the total knee replacement and tramadol as the rescue agent after the cesarean delivery. Both patients were discharged home on ketorolac 10 mg every 8 hours for 3 days and acetaminophen 1 g every 8 hours for 5 days. In addition to the ketorolac and acetaminophen, the patient who had the total knee replacement was given tramadol 50 mg every 8 hours for breakthrough pain.
For many years after the initial use of ether as the first anesthetic in the 1840s, anesthesiologists relied almost exclusively on this single agent for anesthetic management. With time, anesthesiologists learned that using balanced general anesthesia to create the anesthetic state offered a greater likelihood of achieving the beneficial effects while minimizing side effects. The several undesirable side effects of the opioids and the recent opioid epidemic have catalyzed efforts to develop new balanced anesthesia paradigms, which reduce or eliminate opioid use.10,66
For example, a recent review proposes an opioid-free multimodal balanced general anesthesia strategy that provides unconsciousness with amnesia and muscle relaxation while maintaining appropriate tissue perfusion and sympathetic stability to protect organs.10 This strategy emphasizes use of medications other than opioids to create stress-free intraoperative conditions and asserts that analgesia is only important postoperatively and can be achieved with medications other than opioids. In contrast, we believe that nociception should be maintained intraoperatively and postoperatively using multiple antinociceptive agents.
A recent report has summarized the modalities (nonanesthetic and anesthetic adjuncts, and regional techniques) that can be used to reduce opioid use perioperatively.67 Our framework offers a principled approach for designing and implementing multimodal strategies for use in anesthesiology practice. The fundamental feature of our strategy is administration of multiple antinociceptive agents simultaneously to suppress nociceptive trafficking during both general and regional anesthesia (Table 2). Each agent targets a different component of the nociceptive system. Our neural circuit analyses provide a neurophysiologically based approach for understanding the effects of each anesthetic and for choosing the anesthetic combinations (Figures 2–6). As stated in the “Introduction,” surgically induced nociception is the primary reason for administering general anesthesia and the primary source of the patient’s hemodynamic and stress responses. If nociceptive control is adequate, the stress responses will be minimized and sympathetic stability will be achieved. Moreover, our approach also takes account of the implicit effects of the anesthetics being administered (Table 1). Suppression of nociceptive transmission has the significant added benefit of decreasing arousal, which appreciably reduces the hypnotic doses required to maintain unconsciousness and amnesia. We postulate that reduction in hypnotic use may facilitate faster recovery and help reduce the contribution of general anesthesia to postoperative cognitive dysfunction. Similarly, muscle relaxants decrease arousal by decreasing proprioceptive feedback. Under our strategy, opioid use need not be eliminated. Instead, other agents are used along with opioids to achieve antinociception control intraoperatively and pain control postoperatively (Tables 1 and 2).
To achieve adequate postoperative pain control, multimodal pain management has to be continued in the immediate postoperative period and after discharge (Table 2). This formal planning that provides an explicit way to reduce postoperative opioid use requires coordinated management during the perioperative period among the anesthesiology, surgical, and nursing teams. Our experience suggests that this multimodal strategy has important potential. We will test our strategy further in clinical practice and in clinical trial comparisons with existing approaches.
APPENDIX Glossary of Terms
α-2 adrenergic receptor is a subtype of G-protein–coupled, presynaptic receptor through which catecholamines like norepinephrine and epinephrine signal in the central and peripheral nervous systems.
Arousal system (arousal pathways) is (are) a collection of nuclei located primarily in the brainstem and their ascending neuronal projections to the thalamus and cortex that is (are) responsible for creating the awake component of consciousness. Inactivation of these nuclei and/or their pathways is a mechanism for producing unconsciousness.
Basal forebrain (BF) is an area of the cortex located in at the base of the frontal cortex that is a major source of excitatory cholinergic projections to the thalamus and cortex.
Cyclooxygenase (COX) is an important enzyme for biosynthesis of prostaglandins that promote inflammation and fever. COX-1 and COX-2 are 2 important types COX enzymes, the actions of which are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).
Dorsal raphé is a brainstem area located in the central pons that sends primarily excitatory serotonergic projections to the cortex.
Frequency bands are electroencephalogram frequency ranges that have been established by convention. The commonly used bands, characterized in cycles per second or Hertz (Hz), are as follows: slow-delta, 0.1–4 Hz; theta, 4–7 Hz; alpha, 8–12 Hz; beta, 13–25 Hz; gamma, >25 Hz.
Galaninergic pathways are inhibitory pathways that project from the preoptic area of the hypothalamus onto nearly each one of the major arousal nuclei in the pons and midbrain. The neuropeptide galanin is the neurotransmitter in these pathways.
γ-amino butyric acid is the primary inhibitory neurotransmitter in the central nervous system.
Laterodorsal tegmentum is a brainstem area located in the superior posterior region of the midbrain that is a major source of excitatory cholinergic projections to the thalamus and cortex.
Locus ceruleus is a brainstem area located in the central pons that sends primarily noradrenergic projections to the cortex, central thalamus, BF, and the preoptic area of the hypothalamus.
Neutrophil priming is the process by which polymorphonuclear lymphocytes are activated, and as a consequence, readily degranulate inducing amplification of an inflammatory response.
N-methyl-D-aspartate receptors are a pharmacologically identified subset of glutamate receptors and ion channel proteins that are primarily excitatory.
Nociception is the propagation through the sensory system of potentially noxious and harmful chemical, mechanical, or thermal stimuli. The nociceptive system or pathways consist of the nociceptors in the periphery and in the viscera, the ascending nociceptive pathways and the descending nociceptive pathways. The ascending pathways transmit nociceptive stimuli from the periphery to the spinal cord to the brainstem (medulla and midbrain), the amygdala, the thalamus, and on to the primary and secondary sensory cortices. The brainstem descending component of the nociceptive pathway begins in the periaqueductal gray located in the midbrain, and projects through the rostral ventral medulla in the medulla to the spinal cord. The descending pathways are activated immediately by the nociceptive inputs from the ascending pathways and modulate (upregulate and downregulate) the nociceptive information.
Nociceptors are unspecialized bare nerve cell endings that initiate nociception or pain. Their cell bodies arise in the dorsal horn of the spinal cord and send one axonal process to the periphery and the other to the spinal cord or brainstem through the spinothalamic tract.
NSAIDs are pharmacological agents that block specifically the COX-1 and COX-2 enzymes that play a major role in prostaglandin synthesis. Because prostaglandins are primary mediators of inflammation, NSAIDs are key agents for blocking inflammation and thereby reducing inflammation-induced nociception and pain.
Pain is the conscious perception of nociceptive information.
Parabrachial nucleus is a brainstem area located in the dorsolateral pons that surrounds the superior cerebellar peduncle as it enters the brainstem from the cerebellum. The parabrachial nucleus provides important glutamatergic projections to the central thalamus and the BF.
Pedunculopontine tegmentum is brainstem area located in the superior posterior region of the midbrain that is a major source of excitatory cholinergic projections to the thalamus and to the cortex.
Periaqueductal gray is the midbrain relay of the descending pathways for modulating nociceptive inputs into the central nervous system.
Pyramidal neurons are multipolar, commonly teardrop-shaped excitatory neurons that are located primarily in the amygdala, the hippocampus, and the cortex.
Rostral ventral medulla is a brainstem area located in the upper ventral part of the medulla that relays descending modulation of nociceptive information from the periaqueductal gray to the spinal cord.
Rostral and caudal ventral lateral medulla are brainstem areas located respectively in the upper and lower ventral lateral parts of the medulla. These areas relay sympathetic signals from the nucleus of the tractus solitarius—also in the medulla—to the sympathetic ganglia in the thoracolumbar trucks.
Spindles are waxing and waning oscillations in the 9–15 Hz range that are a defining feature of stage 2 nonrapid eye movement sleep. These oscillations are also observed in the EEG of patients receiving low-dose dexmedetomidine.
Striatum is a general term used to denote the putamen and caudate in the basal ganglia. It plays a critical role in motor control.
Thalamic reticular nucleus is a network of inhibitory neurons that surround the thalamus and modulate nearly all thalamic output, particularly to the cortex.
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