Traumatic brain injury (TBI) and stroke continue to ravage the health of the young and old, respectively, worldwide, creating a significant public health burden that is devastating for survivors and families alike. Similarly, mild head injury continues to make headlines in the National Hockey League and National Football League as an initiator of long-term cognitive dysfunction, mental health disorders, and functional disability. There is no paucity of TBI or stroke research; it is just an extraordinarily complex task to treat the injured brain. Indeed, in close to 50 years of basic science research aimed at cellular protection of the brain, neuroscience has yet to advance to a therapeutic strategy for reducing neuronal injury during periods of ischemia or trauma. Most research is aimed at mitigating secondary (or delayed) injury that occurs in the hours to days after an acute insult, as the primary injury is more or less complete instantaneously. Neuroscientists and clinicians have come to understand that the difficulty in identifying a magic bullet for the treatment of stroke or diffuse brain injury lies in the complexity of the processes involved in perpetuating secondary cell death1—and it is unlikely, if not impossible, to design a compound capable of mitigating each of these processes. When considering protection of the brain during its most vulnerable time, an abbreviated list of the neurotoxic sequelae that need to be addressed include excitotoxicity and calcium deregulation, neuroinflammation, microthrombosis, reactive oxygen species (ROS) generation, cytoskeletal proteolysis, and apoptosis.1
There may be utility in protection of the brain with one of the most commonly used drug in anesthesia, and its mechanisms of action address a number of these prodeath processes. Ketamine, a cheap, lipid-soluble, enantiomeric phencyclidine derivative, is most often used for induction of dissociative general anesthesia in hemodynamic instability, at lower doses for analgesia or sedation as a bolus or infusion, and it has utility for bronchospasm, anesthesia for congenital cardiac disease with right to left shunting, and, recently, for treatment of refractory depression. In addition, because of its cost, ketamine is the only anesthetic available in many parts of the developing world and is used in a multitude of clinical scenarios. Notably, TBI incidence in the developing world exceeds that of developed countries,2 as population growth outpaces infrastructure development and primary prevention initiatives, emphasizing the potential of a cheap therapy to dramatically change neurologic outcomes in these countries.
There is a plethora of other situations in which ketamine provides an excellent choice of anesthetic that is beyond the scope of this article. However, the use of ketamine in the neurosurgical population and indeed in the acute brain injury population was, until recently, contraindicated because of concerns over drug-induced increases in intracranial pressure. However, recent reevaluation of the drug has shown this to be untrue,3–8 particularly in mechanically ventilated patients in which normocarbia is maintained. Thus, in some circles of care, it has reemerged as a potential neuroprotective agent because of its pharmacodynamics at the cellular level. Here, the evidence for ketamine as a potential neuroprotective anesthetic is highlighted. A search of the relevant literature using MEDLINE and Cochrane databases between 1980 and 2016 was performed using ketamine as a key word in combination with one or more of the following terms “traumatic brain injury,” “intracranial pressure,” “subarachnoid hemorrhage,” “status epilepticus,” “neuroinflammation,” “inflammation,” “excitotoxicity,” “ischemia,” “apoptosis,” and “thrombosis.” Relevant original articles including randomized control trials, retrospective trials, and case reports are included, as are preclinical investigations including both in vivo animal modeling and in vitro cell culture data.
KETAMINE AND EXCITOTOXICITY
There are numerous preclinical studies highlighting that ketamine can save injured neurons. Ketamine was shown to reduce cell injury in axotomized cell cultures as far back as 1996,9 and has subsequently been shown to improve neuronal survival using animal models of stroke and brain trauma and to reduce neuronal discharge and damage in status epilepticus.10–15 Among these investigations, ketamine was shown in multiple studies to reduce infarct volume in focal ischemia and to reduce the volume of hemorrhagic necrosis in experimental head injury.10–13 These investigations, while preclinical, demonstrated that ketamine affords functional and histopathologic neuroprotection across a wide array of neuroinjury models. Subsequently, a number of mechanisms have been proposed for how ketamine might protect the brain.
The first and most obvious neurotoxic process that ketamine attenuates is excitotoxicity, a profound state of deregulation of neuronal calcium homeostasis resulting from excessive binding of glutamate to postsynaptic N-methyl-d-aspartate (NMDA) receptors. Glutamate spillage occurs in the ischemic or traumatic brain because of decreases in regional blood flow that lead to dysfunction of the sodium-potassium exchanger (the ATP-dependent membrane-bound ion pump responsible for maintaining neuronal resting membrane potential). When oxygen and glucose delivery is impaired, ATP delivery is compromised, the sodium-potassium exchanger fails, and intracellular sodium accumulates. The sodium-calcium exchanger operates on an electrogenic sodium gradient, such that when intracellular sodium is increased, operation of the pump ceases (failing to extrude calcium) and, in some cases, it will reverse, pumping calcium into the cell. Calcium will also enter the cell through the activation of voltage-gated calcium channels. This elevation of presynaptic calcium in turn triggers the uncontrolled fusion of glutamatergic vesicles with the presynaptic membrane, exocytosis of glutamate, spillage into the synapse, and profound increases in postsynaptic calcium.
Deregulated postsynaptic calcium leads to increased generation of ROS including superoxide and peroxynitrite, increased DNA fragmentation, activated proteolytic calpains that degrade the neuronal cytoskeleton, and induces apoptosis.16–18 These processes have been known mediators of secondary neuron injury in stroke and trauma for decades. It is important to make the distinction, however, that we now know that NMDA receptor-mediated cell death is mediated primarily by extrasynaptic receptors, that is, those that exist outside the normal synapse and contain the NR2B (rather than NR2A) subunit. These receptors are particularly dangerous, because they couple directly to cell death effector proteins like neuronal nitric oxide synthase.16 Our laboratory has also shown that these extrasynaptic receptors couple to the trafficking of other glutamate receptors to the cell surface (eg, calcium permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors), leading to posttraumatic hyperexcitability and vulnerability to secondary injury in experimental TBI.19 These extrasynaptic receptors are less active under physiologic conditions where neurotransmission is synaptic, but they are markedly stimulated during excitotoxicity due to the spillover of glutamate to extrasynaptic sites.
Laboratory evidence suggests that ketamine can mitigate excitotoxicity by slowing the perpetuation of these processes. First, ketamine exhibits noncompetitive antagonism of the NMDA receptor, reducing calcium influx through the channel pore by both an open and closed block—the former characterized by a reduction of current amplitude upon glutamate binding and the latter as a reduced frequency of channel opening in the closed state.20 Notably, ketamine also attenuates glutamate release by reducing presynaptic soluble NSF attachment protein receptors complex formation, thereby interfering with the ability of glutamate-containing vesicles to fuse with the presynaptic membrane.21 This combination of inhibitory mechanisms has the net effect of slowing excitatory neurotransmission and antagonizing excessive glutamate release. Indeed, the potential of ketamine to reduce spreading depolarization in TBI patients was recently highlighted,22 and evidence is emerging that ketamine is a safe and effective treatment for refractory status epilepticus (see below).23 More importantly recent work, however, has shown that ketamine has a profound extrasynaptic antagonistic effect, markedly inhibiting activation of the selectively neurotoxic NR2B-containing NMDA receptors.24 In these experiments, prosurvival benefits of ketamine were deleted with knockout of the NR2B subunit. Taken together, these data suggest that antiexcitotoxic effects of ketamine are multipronged—through reduction of presynaptic glutamate release and through antagonism of particularly neurotoxic extrasynaptic receptors. Ketamine also addresses the root cause of excitotoxicity that is decreased cerebral perfusion. A recent systematic review based on 38 animal and 20 human studies concluded that ketamine increases both global and regional cerebral blood flow25 and reduces cerebrovascular resistance26,27 even at subanesthetic doses. Finally, with respect to neuronal regeneration following injury, the anti-NR2B effects of ketamine have been shown to markedly upregulate dendritic spine density,24 a potentially attractive phenomenon in the injured brain that attempts to repair itself in the chronic phase after TBI or stroke.
Further evidence exists that the antiglutamatergic effects of ketamine might have a role in the treatment of delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) and vasospasm. Indeed both are associated with a marked rise in extracellular glutamate28–30 as detected via human studies of microdialysis of cerebrospinal fluid samples. These rises in extracellular glutamate correlate with the clinical course and neurologic symptoms of patients post-SAH, as well as incidences of DCI.28–30 Supporting this further, extensive animal data demonstrate marked electrophysiologic dysfunction of glutamatergic synaptic circuits following experimental SAH—including those heavily involved in cognition and memory formation.31–33 Thus, ketamine could play a profound role in the mitigation of glutamate-induced cell death in this context as well.
KETAMINE AND APOPTOSIS
Beyond inhibition of excitotoxicity, other mechanisms have been proposed for how ketamine acts as a neuroprotectant. In a model of focal ischemia, it was proposed that ketamine regulates the phosphorylation of cyclic adenosine monophosphate response element binding protein (CREB), a transcription factor that binds to its partner DNA sequence to regulate the expression of various downstream proteins. One of these proteins, B-cell lymphoma 2, is antiapoptotic and promotes cell survival. In a model of ischemia, it was shown that ketamine upregulates B-cell lymphoma 2 expression by inhibiting ischemia-mediated CREB dephosphorylation, thereby reducing apoptosis and cell death.14 These data are further supported by a recent investigation demonstrating ketamine prevents neuronal and glial apoptosis in chronic stress modeling, evidenced by decreased cleaved caspase-3, preserved CREB phosphorylation, and upregulation of brain-derived neurotrophic factor.34 Notably, the antiapoptotic effects in central nervous system (CNS) injury are different from the proapoptotic effects in the developing brain (see Conclusions). Another team suggested in the early 1990s that the neuroprotective effects of ketamine are due to, paradoxically, inhibition of catecholamines including adrenaline, noradrenaline, and dopamine.15 The mechanism of inhibition was unclear, but an increased catecholamine response has been identified as a risk factor for poor outcome in cerebral ischemia and trauma, due in part to the direct neurotoxic effects of catecholamine metabolites.35 Moreover, catecholamines induce neuronal apoptosis,36–38 leaving open the possibility that catecholamine inhibition afforded survival by mitigating apoptotic pathways.
KETAMINE AND NEUROINFLAMMATION
A further attractive property that bridges across both the analgesic and neuroprotective actions of ketamine is its anti-inflammatory effects. Ketamine mediates inhibition of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 8 (IL-8) production, and proinflammatory cytokine activity in both peripheral immune cells and CNS glial cells and microglia.39–45 It was also recently shown to mitigate the neuroinflammatory response to hypoxia.46,47 The initial protective inflammatory response in the CNS in defense of injured parenchyma is often rapidly deregulated in TBI and stroke, resulting in excessive microglial activation, release of TNF-α (which leads to activation of the extrinsic apoptotic pathway), IL-1β, IL-8, and IL-6, which in turn increase blood-brain barrier permeability. This allows neutrophils, monocytes, and lymphocytes to cross the blood-brain barrier into the CNS, leading to further prostaglandin, cytokine, and ROS generation.48 Another recently identified and novel anti-inflammatory mechanism of ketamine is inhibition of high-mobility group box 1 (HMGB1)-induced activation of endothelial cells. HMGB1 is a main prototype of the emerging damage-associated molecular proteins and signals to the host that there is tissue damage. As such, it initiates proinflammatory cytokine release in endothelial cells, as well as leukocyte adhesion/transmigration. Elevated HMGB1 levels predict nonsurvivors in SAH and enhance neuroinflammation in SAH models.49–51 Ketamine was recently shown to have a marked inhibitory effect of HMGB1-induced endothelial cell activation, in a mechanism involving nuclear factor κB and toll-like receptor 2/4.52 Taken together with direct inhibition of cytokine release as highlighted, ketamine may prove an effective CNS therapeutic solely due to its anti-inflammatory effects. A complete review of the anti-inflammatory effects of ketamine can be found elsewhere,53 but it is highly likely that this not only contributes to the profound analgesic effects of ketamine in chronic pain, but also attenuates neuroinflammation in the acute injury process.
KETAMINE AND MICROTHROMBOSIS
Microthrombosis is a further deleterious process that contributes to neuronal injury following TBI and SAH. Composed primarily of platelet aggregates that form in cerebral microvessels, some advocate that these microclots disrupt oxygen and glucose delivery to surrounding neurons, creating local hypoxia, and surrounding neuron injury.54 However, we have also shown evidence of marked glutamate release from platelets themselves during aggregation, and downregulation of surrounding glutamate receptors in the neuronal parenchyma, suggesting microthrombi might be a novel source of excitotoxicity as well.55 Either way, it is now generally accepted that microthrombosis is a mediator of DCI following SAH, in addition to cerebral vasospasm. Ketamine may play an additional role in mitigating this process, because it exhibits antiplatelet effects, mediated through reduced intracellular calcium mobilization and thromboxane A2 formation.56 Other studies have shown ketamine suppresses platelet-derived inositol triphosphate formation,57 which also reduces intracellular calcium accumulation, and would reduce aggregation and microthrombi formation. Interestingly, ketamine induction for cardiopulmonary bypass in primates caused a significant reduction in platelet activation as well, measured by CD62 (P-selectin) expression.58 The role of clinically significant antiplatelet activity of ketamine is unclear, but, in the context of microthrombosis or ischemia, this additional effect would be beneficial.
KETAMINE AND CLINICAL NEUROPROTECTION
Clinical data are sparse regarding the use of ketamine for neuroprotection (either intraoperatively, at induction for neurosurgical cases, or in the intensive care unit setting) with adequate neurocognitive or neuroradiologic follow-up, but a few patient studies do exist that support the hypothesis that ketamine may protect the brain. One group has been particularly interested in the potential of ketamine to mitigate postoperative cognitive dysfunction (POCD) in non–head-injured patients via the aforementioned mechanisms. In particular, they examined the utility of dosing ketamine at induction of anesthesia on POCD following cardiopulmonary bypass, in which a significant degree of cerebral hypoperfusion/neuroinflammation is thought to occur. These investigators have demonstrated in multiple investigations that a single dose of ketamine at induction (0.5 mg/kg) attenuated POCD in cardiac surgery patients.59,60 They demonstrated that ketamine on induction reduced the incidence of postoperative delirium from 31% to 3%.59,60 Mechanistically, the beneficial effects of ketamine have mostly been attributed to attenuation of the systemic inflammatory response postoperatively. One investigation demonstrated that 0.25 mg/kg ketamine on induction reduced systemic neutrophil activation and superoxide production, whereas others have shown postoperative inhibition of C-reactive protein, IL-6, and IL-10,60–63 although not necessarily in the brain. Given the marked morbidity of POCD and ease of implementation of this protocol, further study seems warranted on the utility of ketamine in this context.
Another compelling clinical study looked retrospectively at the effect of ketamine on the incidence of spreading depolarization in a continuum of neurologic disease including TBI, SAH, and malignant stroke and found a consistent inhibitory effect on neuronal discharges across all injury modalities.22 This seems compelling in the context of neuroprotection, given the propensity of spreading depolarization to worsen flow-metabolism coupling and excitotoxicity. Indeed spreading depolarizations are thought to be a significant contributor to DCI following SAH.
The use of ketamine in other hyperexcitable neuronal states, including refractory status epilepticus (RSE) has also been investigated and is an emergent paradigm in the neurointensive care unit. A retrospective analysis over 13 years identified 58 patients with RSE, of which one-third of the cases resolved completely with the initiation of ketamine therapy.64 Another systematic review analyzing 23 studies and 110 patients identified a 56.5% response rate of RSE to ketamine, with duration of treatment ranging from hours to 27 days.65 Numerous case reports also exist highlighting anecdotal resolution of epileptiform discharges in response to ketamine in adult and pediatric populations.23,64,66,67 Pathophysiologically, ketamine appears to attenuate RSE due to the fact that prolonged seizure activity downregulates GABA receptor activity, while simultaneously upregulating the number of postsynaptic NMDA receptors.68 Thus, ketamine has demonstrated efficacy in RSE where traditional GABAergic anticonvulsants have failed, due to an apparent molecular switch from reduced GABAergic activity to increased glutamatergic activity in prolonged seizures. Interestingly, the etiology of RSE does not appear to influence the efficacy of ketamine in attenuating neuronal discharges, and preclinical models confirm histopathologically that ketamine affords substantive and widespread neuroprotection from cell death following status epilepticus.10 The literature and clinical opinion appear to be leaning toward early implementation of NMDA receptor antagonists in RSE, and a number of excellent reviews are now being written exclusively on this topic.68–70 A recent recommendation is to implement ketamine within 24 to 48 hours of status epilepticus onset, or after failure with one of the first-line antiepileptic drugs such as midazolam, propofol, or barbiturates.69,70 Dosing is recommended to include a bolus of 3 mg/kg, followed by infusion of up to 10 mg/kg/h, for a duration of up to 7 days.69
Although no drug currently exists to address all the pathophysiologic mechanisms of secondary neuronal injury during stroke or trauma, ketamine, on paper, appears to come pretty close. It exhibits multipronged effects that address a number of important processes contributing to cell death in the injured brain, including excitotoxicity, neuroinflammation, and microthrombosis, and it has shown promise in attenuating neuronal hyperexcitability and postoperative cognitive dysfunction in clinical populations (Figure 1). Likely, the administration of the drug in the setting of an acute CNS insult would need to come in a timely fashion in a monitored setting. It should also be noted that the neuroprotective effects of ketamine likely do not extend to children with neurologic injury. This is because interference with physiologic glutamate receptor activity in the developing brain has consistently demonstrated proapoptotic sequelae and neurotoxicity.71–73 Indeed, the NR2A subunit of the NDMA receptor couples to many important proteins necessary for neurodevelopment and neuroplasticity,74,75 including CREB activation, the phosphatidylinositol 3-kinase–Akt pathway, and transcription of brain-derived neurotrophic factor. Interference with these mechanisms has been shown to cause, rather than improve, neuronal damage.76,77 In addition, the best evaluation of the drug in terms of its efficacy in adults would likely be long-term follow-up, rather than acute resolution of neurologic symptoms, because the drug itself can cause profound sedation and make the evaluation of its efficacy in an acute neurologic injury difficult. It is for this reason that we have embarked on the KIND trial, which stands for ketamine infusion for neurologic deficit, a randomized feasibility study examining the ability of subanesthetic doses of ketamine to improve outcome and mitigate neuronal injury (assessed with 3 tesla MR imaging and analysis of plasma and cerebrospinal fluid neuroinjury biomarkers) from DCI in World Federation of Neurological Surgeons (WFNS) grade I–IV SAH patients (Clinical Trials number NCT02636218).
In recent years, ketamine has become in vogue with almost daily media reports of its efficacy in treating refractory depression and chronic pain. Neurologic injury may be the next paradigm in which this old, inexpensive drug finds new meaning, and addresses a long-standing problem for which we have no other effective treatments. As John Coltrane once said “I’ve found you’ve got to look back at the old things and see them in a new light.”
Name: Josh D. Bell, MD, PhD.
Contribution: This author analyzed the data and wrote the manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
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