Update on the Physiologic Effects of in General Anesthesia and Spinal Blockade: A Review of the Literature

Chelsea Ann Ragule, RN, BSN, CCRN Kristie Lee Wade, DNAP, CRNA Sebastian Rubino, MD

Ketamine, a analog and dissociative the primary scientific literature and discuss recent anesthetic, has been used in anesthesia since the studies that have implicated ketamine in inflammation 1960s. Serial subanesthetic administration has been and oxidative stress, inhibition of ion channels in dor- explored for treatment of depression and chronic pain; sal horn neurons, and in disruption of frontoparietal however, there has been a recent surge in its intraop- communication. Also discussed are the potential clini- erative and perioperative use among anesthesia pro- cal implications these effects may have for patients. viders. As ketamine becomes an important addition to multimodal acute pain regimens, it important that Keywords: Frontoparietal communication, ketamine anesthesia providers review the physiologic underpin- mechanism of action, mTOR, sodium/voltage-gated nings of ketamine administration. Herein, we review potassium channels.

etamine is a noncompetitive, N-Methyl-d- tiple mechanisms of action, and hemodynamic stabil- (NMDA) ity make ketamine a favorable agent to use in Enhanced antagonist.1 It was initially developed in 1962 Recovery After Surgery (ERAS) pathways and has led to its by Calvin Stevens, an organic chemist seeking increased intraoperative and perioperative use.2,8 to develop a structural analog of phencyclidine Interestingly, ketamine has also been shown to cause K(PCP) with similar anesthetic potential but less emergence a transient activation of glutamate neurotransmission in delirium.2 Since that time, the complex neuropharmacol- the prefrontal cortex (PFC, referred to as a glutamate ogy of ketamine has been found to also affect non-NMDA “surge”) and a sustained increase in PFC synaptic con- glutamate receptors, nicotinic and muscarinic cholinergic nectivity.9 This surge in glutamate causes hyperstimula- receptors, monoaminergic and opioid receptors, and volt- tion of neurons in corticolimbic brain regions and may age-dependent ion channels such as Na+ and L-type Ca2+ be responsible for the schizophrenia-like symptoms channels.3 Commercially available ketamine consists of a experienced by some patients.10 For this reason, recent racemic mixture of 2 optical enantiomers, R(−) and S(+), 2018 consensus guidelines consider active psychosis a and the preservative benzethonium chloride.2,3 When relative contraindication to ketamine use in acute pain ketamine is used intraoperatively and perioperatively, the control.11 More conservative providers may elect not to S(+) isomer produces less cardiac stimulation, less spon- use ketamine in patients with any psychiatric disorder or taneous motor activity, better analgesia, more rapid recov- cognitive impairment. However, the physiologic effect ery, fewer psychotomimetic side effects, and decreased of glutamate on NMDA receptors may vary depend- incidence of emergence delirium,2,4,5 whereas the R(−) ing on the location of the receptor. Synaptic NMDA isomer may be more potent with fewer side effects in the receptors promote synaptic formation and neuronal treatment of depression.6 survival, whereas extrasynaptic NMDA receptor activa- Used for more than a half century as an effective an- tion leads to synaptic and neuronal death by altering esthetic and analgesic,1 ketamine has dissociative proper- nuclear calcium.12 At low doses, ketamine is thought ties that elicit unique psychoactive effects.7 These effects to preferentially bind to and inhibit NMDA receptors include alterations in visual perception, out-of-body expe- on γ-aminobutyric acid (GABA)-ergic interneurons,13 riences, increased empathy, religious ecstasy, and transcen- decreasing their inhibitory effects on glutamate-releasing dence of time and space.7 Negative side effects of ketamine neurons. This disinhibition of glutamater- include anxiety, panic, paranoia, and cognitive impair- gic neurons and increased depolarization of the presyn- ments.7 A lack of respiratory depression as well as analge- aptic, glutamatergic neuron leads to a surge of glutamate sic properties, high bioavailability, fast time to maximum release, as reported in the medial PFC.14 plasma concentration, large volume of distribution, mul- Released glutamate subsequently binds to and ac-

www.aana.com/aanajournalonline AANA Journal  December 2019  Vol. 87, No. 6 489 tivates postsynaptic α-amino-3-hydroxy-5-methyl- brain and spinal cord, ketamine effects on neural networks, 4-isoxazolepropionic acid (AMPA) receptors,14 which and ketamine and neurobiology. Broad MeSH (Medical conduct Na+ and Ca2+ into the cell. High local intracel- Subject Headings) terms and Boolean operators were lular concentration of Ca2+ triggers the release of brain- selected for each database search. In addition, the same derived neurotrophic factor into the synaptic space, search terms were used to identify further relevant re- which subsequently activates its surface receptor, tropo- search. All research had to be completed within the past myosin receptor kinase B, which activates 2 downstream 13 years and was limited to publication in the English signaling cascades involving MEK-ERK and PI3K-Akt.15 language. Both human and animal studies were included These 2 pathways converge onto the mechanistic target of in the search. Three studies were chosen and are dis- rapamycin (mTOR), which is a key regulator of neuronal cussed in this literature review. protein synthesis, dendritic size and shape, and ultimately synaptic plasticity.16 These events lead to increased Review of the Literature synaptic protein translation, in part through the sup- Ketamine is used frequently in ERAS pathways and as pressed phosphorylation of eukaryotic elongation factor an analgesic adjunct in patients experiencing severe 2 (eEF2).17 These newly synthesized proteins are inserted perioperative pain. However, prior murine research has into the postsynaptic bouton, leading to further increases shown that low-dose ketamine increases oxidative stress in AMPA receptor activation, dendritic spine density, and in brain tissue. Abelaira et al24 examined the behavioral ultimately, increased synaptogenesis18 in key regions of and biochemical effects of ketamine in the murine PFC, the brain such as the PFC and limbic structures like the hippocampus, amygdala, and nucleus accumbens after hippocampus and amygdala.15 This increased synapto- inhibition of mTOR signaling in the PFC to further genesis may ultimately affect patients’ perception of acute elucidate the role of ketamine in inflammation and pain and subsequently contribute to patients’ emotional oxidative stress in the brain. Myeloperoxidase activity, affect and motivational drive during the postoperative thiobarbituric acid-reactive species (TBARS) formation, recovery period.19-21 Improving the patient’s perception of carbonyl protein formation, nitrite/nitrate concentration, pain can lead to earlier mobilization, decreased postopera- superoxide dismutase activity, and catalase activity were tive opioid use, and improved recovery. measured from the brain tissue homogenates as markers Although ketamine has been shown to increase of oxidative stress. Increased myeloperoxidase activ- protein translation and long-term synaptic plasticity via ity, TBARS formation, carbonyl protein formation, and the mTOR multieffector /threonine protein kinase nitrite/nitrate concentration are surrogates for increased pathway described above,22 different subanesthetic doses oxidative stress, whereas superoxide dismutase activity of ketamine have been shown to increase oxidative stress and catalase activity are surrogates for protection against in the brain of rats.23 Therefore, the beneficial effects oxidative stress. of increased synaptogenesis may be counteracted by The results of the study by Abelaira et al were nu- increased oxidative stress and inflammatory cytokines merous. They found that ketamine at a dose of 15 mg/ when ketamine is administered to patients. kg reduced the immobility time in rats. Although these The goals of this review are to discuss (1) the litera- findings have not been validated in human studies, ture further elucidating the neurophysiologic effects of these findings propose that ketamine use may actually ketamine after mTOR inhibition as an avenue to decrease help with early postoperative mobilization. Also, TBARS the oxidative stress and inflammatory response associ- levels were increased in the PFC, hippocampus, and ated with ketamine administration, (2) ketamine’s physi- amygdala after ketamine administration, and nitrite/ ologic effects at the spinal cord level, and (3) the effects nitrate concentration was increased in all 4 brain regions of ketamine on “feedback” connectivity. Reviewing these of interest. Protein carbonyl content was increased in neurophysiologic mechanisms of ketamine will allow an- the PFC, amygdala, and nucleus accumbens after ket- esthesia providers to better understand the downstream amine administration, and myeloperoxidase activity was effects of this medication based on the current literature, increased in the hippocampus and nucleus accumbens. which can potentially lead to better administration and These findings suggest that perioperative ketamine use fewer adverse effects. may increase oxidative stress in the brain. In attempts to help curb this inflammatory reaction, the authors Methods administered the mTOR inhibitor rapamycin before The literature presented in this review was selected ketamine injection and recorded the results. They found from a comprehensive electronic search in the PubMed, a statistically significant decrease in TBAR levels and MEDLINE, and Google Scholar databases through Albany nitrite/nitrate concentration in the hippocampus; de- Medical College’s Schaeffer Library. Key terms used for crease in nitrite/nitrate concentration, protein carbonyl the search included ketamine and brain biology, molecular content, and myeloperoxidase activity in the nucleus effects of ketamine anesthesia, effects of ketamine on the accumbens; and decrease in protein carbonyl content

490 AANA Journal  December 2019  Vol. 87, No. 6 www.aana.com/aanajournalonline in the PFC. Both superoxide dismutase activity and study was conducted in 15 men and 15 women aged catalase are enzymes that help protect against oxidative 22 to 64 years old, with ASA physical status class 1 or damage caused by reactive oxygen species, and ketamine 2, who were scheduled for elective stomach, colorectal, was found to decrease the levels of both these protec- thyroid, or breast surgery. Exclusion criteria included tive enzymes in all 4 brain regions. Finally, there was previous cardiovascular disease (including hypertension), a statistically significant increase in the tumor necrosis a previous brain surgery, a history of drug or de- factor, an inflammatory cytokine involved in systemic in- pendence, known neurologic or psychiatric disorders, and flammation, after administration of ketamine. Therefore, current use of psychotropic medications. Ketamine (2 mg/ results of this study indicate that ketamine may cause kg diluted in 10 mL of 0.9% normal saline) was infused an increase in both brain and systemic inflammation via over 2 minutes, and EEG and electromyography data were 2 mechanisms: (1) increasing the amount of oxidative acquired until 5 minutes after loss of consciousness. The stress and (2) decreasing the brain’s ability to protect propofol and data were originally gathered against oxidative stress. for a previous study of the frontoparietal system by Ku et Schnoebel et al25 conducted a quantitative study to al.28 In their study, 8 men and 10 women aged 29 to 66 investigate the effects of the local-anesthetic-like actions years old, with an ASA physical status 1 and 2, who were of ketamine and its enantiomers on Na+ and K+ chan- scheduled for elective abdominal or breast surgery were nels and their functional importance in intact rat dorsal enrolled to receive either propofol (n = 9) or sevoflurane horn neurons of laminae 1 through 3. The study found (n = 9) for general anesthesia induction while 8-channel dose-dependent inhibition of Na+ current by ketamine electroencephalography data were recorded. Propofol was in dorsal horn neuronal somata. Blockade was rapid in initially administered with a target-controlled infusion onset and readily reversible on washout. The S(+) ket- of 2.0 μg/mL and was increased at a rate 1.0 μg/mL per amine enantiomer was significantly more potent than the 20 seconds until loss of consciousness; sevoflurane was R(−) enantiomer; illustrating stereoselective blockade of initially administered as 2 vol% and increased at a rate of Na+ current. K+ currents were also recorded and studied. 2 vol% per 20 seconds (up to 8%) until loss of conscious- The total voltage-gated K+ current consists of inactivat- ness. The data were aggregated and presented alongside ing A (KA) and delayed-rectifier (KDR) components. The the ketamine data for comparison. study found that ketamine inhibited delayed-rectifier The authors were interested in feedback and feed- K+ current in a dose-dependent manner and that ket- forward connectivity. Information feedback from the amine blocked delayed-rectifier K+ current to a greater frontal cortex to other cortical regions is thought to degree than inactivating A K+ current. Lastly, the effects mediate consciousness,29,30 whereas feedforward infor- of ketamine on action potentials were seen with using mation flowing in the posterior-to-anterior direction is concentrations as low as 30 µM of ketamine, with more thought to mediate sensory processing, which can occur profound effects with dose escalation. Ketamine was outside of consciousness.31,32 The authors found that found to decrease all properties of single-action poten- the relative power of delta, theta, and gamma EEG fre- tials, including action potential overshoot, maximum quency bands increased, but the relative powers of alpha positive slope, maximum negative slope, and duration at and beta EEG frequency bands decreased after ketamine 100-µM concentrations. The findings of this study help administration. The simultaneous increase of the relative us understand the physiologic effects of ketamine ad- powers for both slow waves (delta and theta) and fast ministration in spinal blockade and help further explain waves (gamma) was unique to the ketamine administra- the results of a prior study by Togal et al.26 In that prior tion. Propofol and sevoflurane varied from ketamine in study, S(+) ketamine, 0.1 mg/kg, with 7.5 mg of bupiva- that delta, theta, and alpha frequency bands increased, caine for spinal anesthesia provided adequate intraopera- whereas beta and gamma frequency bands decreased. tive effects, with shortened time-of-onset of motor and The key finding was that ketamine reduced alpha power sensory block and decreased duration of analgesia. The and increased gamma power compared with the opposite authors found S(+) ketamine to be an effective spinal activity produced by propofol and sevoflurane. During blockade adjunct with particular local anesthetic effect administration of ketamine, feedback connectivity was when used with , as evidenced by decreased gradually reduced and significantly inhibited after loss onset time, equivalent analgesic consumption and patient of consciousness, but feedforward connectivity was pre- satisfaction, and no adverse hemodynamic effects.26 served. The asymmetry of information flowing in the Lee et al27 conducted a prospective nonrandomized frontal to parietal direction was also significantly reduced cohort study using electroencephalography (EEG) and during ketamine injection and led to balanced informa- normalized symbolic transfer entropy to assess directional tion flow during the first minute after loss of conscious- connectivity across the frontal, parietal, and temporal ness. Although the asymmetry of information flowing regions of human surgical patients receiving ketamine, in the frontal to temporal direction was also reduced, propofol, or sevoflurane. The ketamine portion of the there still remained greater feedback connectivity in this

www.aana.com/aanajournalonline AANA Journal  December 2019  Vol. 87, No. 6 491 pathway. Therefore, inhibition of feedback connectivity improve patients’ outcomes by decreasing inflammation, in the frontotemporal network was not as robust as that the importance of the mTOR pathway in other areas of of the frontoparietal network.27 In the comparison of human biology may not allow for its inhibition in human ketamine, propofol, and sevoflurane, dominant feedback patients. Activation of the mTOR pathway is involved in connectivity in the baseline state and the selective inhibi- proliferation and clonal expansion of antigen-specific T tion of feedback connectivity after induction was demon- cells, and inactivation of the pathway leads to detrimental strated among all 3 agents, yet feedforward connectivity immunosuppression.24 However, perhaps future studies was preserved. Therefore, the authors concluded that can investigate administration of dexamethasone, a well- the reduction of feedback dominance and reduction of tolerated, clinically used anti-inflammatory agent, to pa- feedback/feedforward asymmetry in the frontoparietal tients receiving perioperative ketamine in an attempt to network was a common neural correlate of anesthetic- mitigate the oxidative stress and inflammation associated induced unconsciousness across ketamine, propofol, and with ketamine administration. sevoflurane despite different mechanisms of actions and The research by Schnoebel et al25 showed that ket- pharmacologic profiles. This is the first study showing a amine blocks voltage-dependent sodium and delayed common biological mechanism for the loss of conscious- rectifying potassium channels in superficial dorsal horn ness among all 3 anesthetic agents. lumbar neurons and somata at clinically relevant concen- trations.25 Although the findings of this study are certain- Discussion ly interesting and present an explanation for the mecha- Ketamine has been used clinically for more than 50 years. nism of action of ketamine when used as spinal blockade, Its ability to act on glutamate receptors, nicotinic and we must remain wary of in vitro studies because the muscarinic cholinergic receptors, monoaminergic and findings may not persist in vivo. Furthermore, ketamine opioid receptors, and voltage-dependent ion channels is often combined with opioids when administered as a such as Na+ and L-type Ca2+ channels has led to a con- spinal blockade, and, therefore, the generalizability of tinued evolution of our knowledge regarding its mecha- these findings is limited when clinical practice patterns nisms of action and the downstream physiologic effects are taken into consideration. of its use. The 3 articles herein discussed help to further The study by Lee et al27 is the first study to provide ev- our understanding of ketamine physiology in the central idence for a common correlate between non-GABAergic nervous system. (ketamine) and GABAergic (propofol and sevoflurane) A major limitation is that all 3 studies have small anesthetics: the inhibition of frontal to parietal feedback sample sizes. The study by Abelaira et al was conducted connectivity with preserved feedforward connectivity. in 39 rats, the study by Schnoebel et al in 39 rat neurons In addition to the study limitations already noted, the and 52 rat somata, and the study by Lee et al in 30 human study assessed only external consciousness mediated by patients. The small numbers of these studies cannot allow lateral frontoparietal networks and did not assess inter- readers to draw any definitive conclusions; rather they nal consciousness mediated by more medial networks. serve as investigational reports that can potentially lead This is a limitation of the spatial resolution provided by to larger more highly powered studies. Furthermore, the 8-channel EEG and could be improved upon by future physiologic data obtained from the studies by Abelaira et al study designs using higher-resolution EEG recordings. and Schnoebel et al were from rats. Although this is a sci- Furthermore, the results of this study are limited to use entifically acceptable first step in the investigation of this of ketamine for induction, whereas many providers use physiology, the results should be validated in mammalian ketamine as an adjunctive anesthetic agent. The effects animal models to make the results more generalizable to of ketamine as an adjunctive agent in brain connectiv- human patients. It would be unethical to obtain human ity remain to be investigated and could differ from the brain tissue, neurons, and somata simply to study an an- results of this study. Finally, this study used normal- esthetic’s mechanism of action, and therefore mammalian ized symbolic transfer entropy, a computational method studies may be the next-best surrogate. Another limitation based on information theory, to measure directional con- of these findings is the nonblinded, nonrandomized nature nectivity, which limits the ability to declare a true, causal of all 3 studies. This could have led the findings to be in- interaction between brain regions.27 fluenced by measurement bias because the experimental groups were known to the researchers. Conclusion The work by Abelaira et al24 highlighted ketamine’s The studies by Abelaira et al, Schnoebel et al, and Lee et role in inflammation and oxidative stress and showed al, although inherent with their respective limitations, that the use of rapamycin, an mTOR inhibitor, could contribute greatly to our understanding of ketamine decrease the inflammatory and oxidative effects in some physiology as a general anesthetic and local blockade brain areas. However, although coadministration of agent. Abelaira et al found that ketamine increased myelo- rapamycin with ketamine may appear enticing to help peroxidase activity, thiobarbituric acid-reactive species

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www.aana.com/aanajournalonline AANA Journal  December 2019  Vol. 87, No. 6 493 29. Dehaene S, Changeux JP. Experimental and theoretical approaches AUTHORS to conscious processing. Neuron. 2011;70(2):200-227. doi:10.1016/j. Chelsea Ann Ragule, RN, BSN, CCRN, is a graduate student at the Center neuron.2011.03.018 for Nurse Anesthesiology, Albany Medical College, New York, New York. 30. Changeux JP. Conscious processing: implications for general anes- Email: [email protected]. thesia. Curr Opin Anaesthesiol. 2012;25(4):397-404. doi:10.1097/ Kristie Lee Wade, DNAP, CRNA, is practicing at Berkshire Medical ACO.0b013e32835561de Center in Pittsfield, Massachusetts.. 31. Lamme VA, Super H, Spekreijse H. Feedforward, horizontal, and Sebastian Rubino, MD, is in the Department of Neurological Surgery feedback processing in the visual cortex. Curr Opin Neurobiol. at Albany Medical Center. 1998;8(4):529-535. doi:10.1016/s0959-4388(98)80042-1 32. Lamme VA, Roelfsema PR. The distinct modes of vision offered by feed- forward and recurrent processing. Trends Neurosci. 2000;23(11):571- DISCLOSURES 579. doi:10.1016/s0166-2236(00)01657-x The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did discuss off- label use within the article. Disclosure statements are available for viewing upon request.

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