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Preclinical neuroprotective actions of xenon and possible implications for human therapeutics: a narrative review

  • Mervyn Maze
Review Article/Brief Review

Abstract

Purpose

The purpose of this report is to facilitate an understanding of the possible application of xenon for neuroprotection in critical care settings. This narrative review appraises the literature assessing the efficacy and safety of xenon in preclinical models of acute ongoing neurologic injury.

Source

Databases of the published literature (MEDLINE® and EMBASE™) were appraised for peer-reviewed manuscripts addressing the use of xenon in both preclinical models and disease states of acute ongoing neurologic injury. For randomized clinical trials not yet reported, the investigators’ declarations in the National Institutes of Health clinical trials website were considered.

Principal findings

While not a primary focus of this review, to date, xenon cannot be distinguished as superior for surgical anesthesia over existing alternatives in adults. Nevertheless, studies in a variety of preclinical disease models from multiple laboratories have consistently shown xenon’s neuroprotective properties. These properties are enhanced in settings where xenon is combined with hypothermia. Small randomized clinical trials are underway to explore xenon’s efficacy and safety in clinical settings of acute neurologic injury where hypothermia is the current standard of care.

Conclusion

According to the evidence to date, the neuroprotective efficacy of xenon in preclinical models and its safety in clinical anesthesia set the stage for the launch of randomized clinical trials to determine whether these encouraging neuroprotective findings can be translated into clinical utility.

Keywords

Traumatic Brain Injury NMDA NMDA Receptor Xenon KATP Channel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Action neuroprotectrice préclinique du xénon et implications possibles pour la thérapeutique humaine: un compte rendu narratif

Résumé

Objectif

L’objectif de ce compte rendu est d’aider le lecteur à mieux saisir les applications possibles du xénon pour favoriser la neuroprotection dans les contextes de soins critiques. Ce compte rendu narratif examine la littérature évaluant l’efficacité et l’innocuité du xénon dans des modèles précliniques de lésion neurologique aiguë et en développement.

Source

Les bases de données de littérature publiée (MEDLINE® et EMBASE™) ont été passées en revue pour en extraire les manuscrits révisés par les pairs portant sur l’utilisation du xénon dans des modèles précliniques ou des états maladifs de lésion neurologique aiguë et en développement. Dans le cas d’études cliniques randomisées pas encore rapportées, nous nous sommes fondés sur les déclarations des chercheurs sur le site des études cliniques des Instituts nationaux de santé (National Institutes of Health).

Constatations principales

Bien que ce ne soit pas le sujet principal de ce compte rendu, à ce jour, on ne peut déterminer que le xénon est supérieur aux alternatives existantes pour l’anesthésie chirurgicale pratiquée chez l’adulte. Toutefois, les études traitant de divers modèles précliniques de maladies et provenant de plusieurs laboratoires reconnaissent, de façon constante, les propriétés neuroprotectrices du xénon. Ces propriétés sont encore rehaussées dans les contextes où le xénon est combiné à l’hypothermie. De petites études cliniques randomisées sont en cours afin d’explorer l’efficacité et l’innocuité du xénon dans les contextes cliniques de lésion neurologique aiguë, où l’hypothermie constitue la norme actuelle de soins.

Conclusion

Selon les données probantes à ce jour, l’efficacité neuroprotectrice du xénon dans les modèles précliniques et son innocuité en anesthésie clinique ouvrent la voie pour la réalisation d’études cliniques randomisées afin de déterminer si ces effets neuroprotecteurs encourageants peuvent se traduire en une utilité clinique.

Interest in the clinical applications of xenon, a monoatomic gas, has waxed and waned over the last 70 years. The advent of the market authorization of xenon for use as an anesthetic is an auspicious time to reflect on concerns and expectations of its future use in critical care settings. In particular, within the last decade, several findings have propelled xenon into the frame as a neuroprotective agent to guard the central nervous system against imminent and acute ongoing damage. This review provides a critical appraisal of reports of xenon in preclinical models retrieved in the MEDLINE® and EMBASE™ databases using the search terms (xenon) AND (neuroprotect*). Pertinent references from manuscripts were also reviewed. Where appropriate, attention is drawn to ongoing clinical trials identified through the National Institutes of Health website (https://clinicaltrials.gov/).

It is worth pointing out the vast number of casualties that litter the clinical trial pathway in the as yet unsuccessful pursuit of a safe and effective neuroprotectant.1 The focus of attention has been on the reasons why the U.S. Food and Drug Administration has yet to approve a single neuroprotective agent despite encouraging preclinical data. The veracity of preclinical findings is questioned in the absence of randomization, blinded assessment, and power analysis in the preclinical studies.2

History of xenon

Xenon derives its name from the Greek word for “stranger” because of its rarity,3 representing no more than 0.0875 ppm in the atmosphere.4 Xenon is a colourless, odourless, tasteless, and inert gas that was discovered by Ramsay and Travers in 1898. It is used commercially for lasers,5 high-intensity lamps,6 plasma screens,7 propellant in the aerospace industry,8 x-ray tubes, and medical applications, including imaging9 and anesthesia.

Use of xenon in anesthesia

Nearly 70 years ago, a group of physiologists at the University of California reported xenon’s anesthetic properties in animals.10 Within five years, this preclinical finding was advanced to patients in what was the first report in the English literature of its clinical use for general anesthesia.11 It took a further five decades, however, before marketing authorization was granted for the use of xenon as a general anesthetic. The Russian Federation was first to approve its use, possibly because of its notoriety as the purported anesthetic for the Russian President’s heart surgery in 1996.1 Since then, western Europe has approved its use, but xenon remains without marketing authorization for use as an anesthetic in North America. Certain factors have driven up the price of xenon to a point where its value is difficult to justify for general anesthesia, including its scarcity, the high cost of xenon purification from the atmosphere by fractional distillation, as well as competition posed by high-spend industries, such as aerospace, for its anesthetic indication. To date, studies have not shown a compelling advantage for the use of xenon over lower cost alternatives as the general anesthetic of choice in adults. Xenon has yet to be tested for pediatric anesthesia where its potential in preventing anesthetic-induced developmental toxicity may direct its use as an anesthetic for this vulnerable patient population.12-14

Mechanisms for the biological properties of xenon

Xenon’s physicochemical properties prevent covalent bonding with other molecules under biologic conditions. Despite this chemical inertness, biological interactions can occur through non-covalent van der Waals intermolecular forces. Xenon’s outer electron shell is full, which prevents covalent binding under biological conditions, but xenon is highly polarizable, which enables its attraction to surrounding molecules. Franks et al.15 were the first to show that xenon can interact with the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, a plausible site for its anesthetic properties, by competing for binding at the glycine coactivation site16 through an interaction with a phenylalanine residue.17 While other targets may also contribute to xenon’s anesthetic properties, including other glutamate receptor subtypes18 and molecular species inducing potassium leak currents,19 the importance of the NMDA subtype of the glutamate receptor in the excitotoxic phase of acute neurologic injury spurred a series of studies exploring xenon’s neuroprotective properties.

Cellular and molecular candidate mechanisms for neuroprotective properties of xenon

Excitotoxicity

Overactivation of glutamate receptors is involved in a number of pathological processes. Excessive entry of calcium, mediated by NMDA receptors, triggers biochemical cascades that ultimately lead to neuronal cell death. This neurotoxicity due to overactivation of NMDA receptors, termed excitotoxicity by Olney,20 is considered to underlie the acute neuronal injury observed following insults such as stroke, cardiac arrest, and traumatic brain injury (TBI). N-methyl-D-aspartate receptor antagonists are neuroprotective in in vitro and in vivo brain injury models.21

Following the discovery that xenon inhibits NMDA receptors,15 it was shown that xenon could protect neuronal cell cultures against injury induced by NMDA, glutamate, or oxygen-glucose deprivation.22 The same study showed xenon to be neuroprotective in vivo against neuronal injury caused by subcutaneous injection of N-methyl-D,L-aspartate in rats. Subsequently, Petzelt et al. corroborated this finding in an in vitro model of hypoxia23 and in an in vivo model of stroke.24 Several NMDA antagonists have been clinically evaluated for their putative neuroprotective properties. Gavestinel (with activity at the glycine co-agonist site) and magnesium sulfate (an open pore blocker) were among the more recent, but neither had sufficient efficacy, possibly on the basis of poor central nervous system (CNS) penetrability.25,26

Other NMDA receptor antagonists, such as nitrous oxide, ketamine, and dizocilpine (MK-801) have intrinsic neurotoxicity,27 but xenon not only appears to be devoid of these neurotoxic effects but also ameliorates the injury produced by other NMDA antagonists.28 Reasons for xenon’s relative lack of neurotoxicity may relate to both the site of its action on the NMDA receptor as well its neutral effect on spontaneous dopamine release that the other NMDA antagonists enhance.29

Existing data distinguish the actions of xenon as a competitive inhibitor of NMDA receptors from well-established open-channel blockers of NMDA receptors, such as ketamine and MK-801. Open-channel blockers of NMDA receptors invariably show changed kinetics following the application of the agonist in the presence of the inhibitor. For example, when NMDA is applied to NMDA receptors, the rate of closure of the channel is always much faster when an open-channel blocker, such as ketamine or MK-801, is present.30 In the presence of xenon, there is no increase in the rate of closure of the NMDA response.15,16 Also, open-channel blockers, such as ketamine, invariably increase the decay of excitatory postsynaptic currents,31 but this is not observed with xenon.32 Thus, with both heterologous expression systems and intact synapses, xenon does not behave as an open-channel blocker, which may be an additional reason why it lacks the neurotoxicity seen with other NMDA antagonists.

Further reasons for the lack of neurotoxicity are provided below in the description of xenon’s other mechanisms of neuroprotective action.

Modulation of background (“leak”) potassium conductance

Activation of the two-pore potassium channels (K2p channels) tends to hyperpolarize the membrane potential, taking it farther from an activation threshold. Xenon was shown to activate a species of these channels (TREK-1),2 with the activation being critically dependent on a specific amino acid residue (Glu306). These TREK-1 channels are the mediating mechanism whereby intracellular acidification as well as polyunsaturated fatty acids produce neuroprotection.33 Genetically modified mice that lack TREK-1 channels fare poorly in models of cerebral ischemia, highlighting the importance of this molecular species in the organism’s defence against acute neuronal injury.34 It is notable that other NMDA antagonists, including nitrous oxide and cyclopropane, also activate TREK-1.19

Modulation of neuroapoptosis

Acute neuronal ischemic injury provokes sequential waves of signalling mechanisms, which successively results in neuronal death at different times. While excitotoxicity features early in the processes, resulting in neuronal death, apoptosis (i.e., programmed cell death) follows later through signalling mechanisms that are well defined.35 Xenon reduces the expression of pro-apoptotic genes, such as BAX,36 and increases anti-apoptotic proteins, such as Bcl-xL 36 and Bcl-2,36 , 37 resulting in a significant decline in neuroapoptosis.36

Modulation of neuroinflammation

Several investigators have reported that circulating immune cells traverse the blood-brain barrier following acute injury;38 furthermore, the ischemic brain activates the resident microglia cells. These activated macrophages propagate the ongoing neuronal damage through several pathways, including through the elaboration of pro-inflammatory cytokines that further injures the penumbra around an infarcted core.39 This process selectively prevents neuroinflammation and attenuates brain ischemic injury.40-42 In several types of organ injury models, xenon has been shown to exert anti-inflammatory effects43,44 and decrease neuronal dysfunction associated with neuroinflammation.45,46

Induction of hypoxia-inducible factor 1alpha (HIF-1α)

Xenon potently increases the translational efficiency and upregulation of the oxygen sensor, HIF-1α, under normoxic conditions.47 Downstream effectors of HIF-1α, including erythropoietin (EPO), have been shown to exert important neuroprotective properties.48 Nevertheless, it should be emphasized that, when EPO was administered to patients with anemia due to diabetes-induced renal failure, there was a twofold increase in stroke.49 In the setting of organ injury, xenon-induced upregulation of HIF-1α has been shown to be cytoprotective in the kidney,47,50 lung,43 heart,51 and brain.52 The Russian Federation’s Biomedical Agency exploited xenon’s ability to induce EPO by pretreating its endurance athletes. Some have speculated that this may have contributed to the athletes’ superior performance at the Sochi 2014 Winter Olympics. Since September 1, 2014, xenon has been banned for use in competitive athletics.3

Modulation of adenosine triphosphate (ATP)-sensitive potassium channels (KATP channels)

Hypoxic-ischemic neuronal injury can be preempted by activation of KATP channels,53,54 and its absence exacerbates cerebral ischemic injury.55 Pretreatment with xenon prevents glucose- and oxygen-deprived neuronal cells from dying in primary cultures. A key mechanism involves xenon’s activation of the KATP channels.56,57

Neuroprotective efficacy of xenon in preclinical models

Tables 1, 2, 3, 4 and 5 summarize the preclinical studies assessing the effects of xenon in models of acute neurological injury. The studies are arranged to address each of the putative indications for which xenon may be beneficial, including neonatal hypoxic ischemic encephalopathy (HIE) from intrapartum asphyxia (Table 1), stroke (Table 2), TBI (Table 3), anesthetic-induced developmental toxicity (Table 4), and cardiac arrest (Table 5).
Table 1

Xenon in hypoxic-ischemic encephalopathy models

Author/Journal/Year of publication

Species

Injury

Results/Conclusions

Wilhelm et al., Anesthesiology 200222

Mouse

cell culture

Rat

Injury provoked by oxygen-glucose deprivation and assessed by the release of lactate dehydrogenase into the culture medium;

N-methyl-D,L-Aspartate

Xenon, when co-administered with the injurious agent, exerts a concentration-dependent neuroprotective effect at concentrations below which anesthesia is produced

Ma et al., J Cereb Blood Flow Metab 2006107

Rat

Hypoxia-ischemia

Protective in preconditioning

Dingley et al., Stroke 2006108

Rat

Hypoxia-ischemia

Neuroprotective post injury

Rajakumaraswamy et al., Neurosci Lett 2006109

Mouse cell culture

Rat

Oxygen-glucose deprivation;

Hypoxia-ischemia

Synergistic neuroprotection between xenon and dexmedetomidine

Dingley et al., Anesth Analg 2008110

Rat

Hypoxia-ischemia

Effect of xenon and hypothermia on respiration

Cattano et al., Neurosci Lett 2008111

Rat

No injury

Xenon induces ADNP

Valleggi et al., J Neurosurg Anesthesiol 2008112

Rat

No injury

Xenon induces 6 genes involved in preconditioning pathways

Luo et al., Anesthesiology 2008113

Cell culture

Rat

Oxygen-glucose deprivation;

Hypoxia-ischemia

Xenon preconditions through phospho-CREB

Bantel et al., Anesthesiology 201056

Cell culture

Oxygen-glucose deprivation

Preconditioning via KATP plasmalemmal channels

Chakkarapani et al., Anesth Analg 2009114

Pig

Hypoxia-ischemia

Effectiveness of xenon delivery device

Jawad et al., Neurosci Lett 2009115

Fetal neuronal culture

Oxygen-glucose deprivation

Xenon most efficacious noble gas for neuroprotection

Faulkner et al., Ann Neurol 201162

Pig

Hypoxia-ischemia

Decrease Lac/NAA by xenon and hypothermia

Yang et al., PLoS One 2012116

Rat

Hypoxia-ischemia

Maternal exposure provides neuroprotective preconditioning for fetus

Chakkarapani et al., Intensive Care Med 2012117

Pig

Hypoxia-ischemia

Neuroprotection and hemodynamic stability from xenon and hypothermia

Chakkarapani et al., J Cereb Blood Flow Metab 2012118

Pig

Hypoxia-ischemia

Cerebrovascular reactivity maintained during xenon and hypothermia

ADNP = activity-dependent neuroprotective protein; CREB = cyclic adenosine monophosphate response element binding protein; KATP = adenosine triphosphate potassium; Lac/NAA = lactate to N-acetylaspartate ratio

Table 2

Xenon in stroke models

Author/Journal/Year of publication

Species

Injury

Results/Conclusions

Homi et al., Anesthesiology 2003119

Mouse

Xenon vs N2O in middle cerebral artery occlusion (MCAO)

Xenon neuroprotective in morphological and functional assay at 24 hr

David et al., J Cereb Blood Flow Metab 200324

Cortical neuronal-glial culture

Rat

NMDA-induced Calcium (Ca++) influx;

Xenon vs N2O in MCAO

Xenon decreases Ca++ influx;

Xenon but not N2O decreases ischemic brain damage in resistant region

Limatola et al., Neuroscience 201052

Mouse

MCAO

Xenon preconditions through HIF-1α

David et al., J Cereb Blood Flow Metab 2010120

Rat

MCAO

Xenon protective after MCAO and against hemorrhagic properties of tPA*;

Xenon blocks tPA* activity

Sheng et al.,

Anesthesiology 2012105

Rat

Temporary focal ischemia

Concentration- and time-dependent synergistic neuroprotection with hypothermia

* tPA = tissue plasminogen activator. HIF-1α = hypoxia-inducible factor-1-alpha

Table 3

Xenon in traumatic brain injury models

Author/Journal/Year of publication

Species

Injury

Results/Conclusions

Coburn et al., Crit Care Med 2008103

Mouse in vitro

Trauma to hippocampal slice

Xenon mitigates injury

Harris et al., Anesthesiology 2013121

Mouse in vitro

Trauma to hippocampal slice

Xenon is best noble gas against injury

Campos-Pires et al., Crit Care Med 2015104

Mouse in vivo

Controlled cortical impact trauma

Xenon improves functional and histological outcomes

Table 4

Xenon in anesthetic-induced developmental neurotoxicity models

Author/Journal/Year of publication

Species

Injury

Results/Conclusions

Ma et al., Anesthesiology 200712

Neonatal rat

Hippocampal slice preparation

Effect of xenon vs N2O on isoflurane-induced neurotoxicity

Xenon prevents, while N2O enhances, isoflurane-induced neurotoxicity;

Xenon alone does not produce neurotoxicity

Cattano et al., Can J Anesth 200813

Neonatal mouse

Effect of xenon on isoflurane-induced neurotoxicity

Xenon prevents isoflurane-induced neurotoxicity;

Xenon alone produces modest neurotoxicity

Cattano et al., Neurosci Lett 2008111

Neonatal rat

None

Xenon upregulates brain ADNP

Shu et al., Anesthesiology 2010101

Neonatal rat

Exposure to xenon vs N2O or hypoxia on isoflurane neurotoxicity

Xenon prevents while N2O and hypoxia exacerbate isoflurane-induced neurotoxicity; anti-apoptotic factors induced by xenon

Cattano et al., Minerva Anestesiol 2011122

Neonatal rat

None

Xenon upregulates anti-apoptotic genes

Brosnan et al., Anesthesiology 2013102

Hippocampal slice preparation

Xenon vs isoflurane vs sevoflurane

At 1 MAC, each produced apoptosis; less with 1 MAC xenon; at 0.75 MAC xenon produced no apoptosis

Sabir et al., Anesthesiology 201314

Piglet

Xenon vs isoflurane on neurotoxicity

Xenon does not produce neuroapoptosis

ADNP = activity-dependent neuroprotective protein; MAC = minimum alveolar concentration

Table 5

Xenon in cardiac arrest models

Author/Journal/Year of publication

Species

Injury

Results/Conclusions

Schmidt et al., Anesthesiology 2005123

Pig

Effect of xenon vs total intravenous anesthesia exposure before 4 min of cardiac arrest

Xenon preconditions against brain injury

Fries et al., Crit Care Med 2008124

Pig

Xenon after 8 min cardiac arrest + 4 min resuscitation

Xenon improves functional and histopathological outcome

Fries et al., Crit Care Med 201264

Pig

Xenon combined with hypothermia after 10 min cardiac arrest

Xenon improved neurological and cardiac functional outcome

Synergistic interaction between xenon and therapeutic hypothermia

There are convincing scientific data to extend the potential neuroprotective properties of xenon to settings in which hypothermia (i.e., therapeutic hypothermia/targeted temperature management [TH/TTM]) is provided. Data - published in eight peer-reviewed manuscripts from four different laboratories involving four preclinical injury models - show that xenon’s neuroprotective action is most effective when body temperature is reduced (Table 1). Unlike other neuroprotective strategies, including a different NMDA antagonist (gavestinel), xenon alone exhibits this enhanced efficacy when temperature is reduced. In order to determine the possible mechanism for the superior neuroprotection that xenon provides in the presence of hypothermia, further studies were performed in vitro using an oxygen-glucose deprivation model to induce ischemic damage (lactate dehydrogenase release) in cultured neurons (Figure).36 Using the slope of a van’t Hoff plot to quantify the overall heat transfer (increase in enthalpy) that occurs during ischemic damage, the addition of xenon (12.5%) significantly altered the mean (SD) slope from 34.8 (4.5) to 177 (12) kJ·mol−1. This was not noted with another neuroprotectant (gavestinel) that does not have a synergistic interaction with hypothermia.36 The precise mechanism for the increase in enthalpy has not been determined.
FIGURE

Neuroprotective effects of xenon and hypothermia in vitro. (A) Photomicrographs of normal Nissl-stained neurons, (B) after oxygen-glucose deprivation (OGD), (C) after OGD in the presence of xenon (75%), and (D) after OGD in the presence of hypothermia at 20°C. (E) Lactate dehydrogenase (LDH) release from OGD-injured cultured neurons exposed to increasing concentrations of xenon at normothermia (37°C) and hypothermia (33°C). (F) LDH release from OGD-injured cultured neurons exposed to decreasing temperature with or without xenon (12.5%). (G) Isobologram illustrating the protective efficacy of combining xenon and temperature on injured cultured neurons. Protection from damage to OGD-injured neurons is synergistically enhanced when provided in combination as reflected by IC50 values for the interventions that were significantly to the left of the “line of additivity” joining the IC50 of the individual interventions. (H) van’t Hoff plot showing the temperature dependence of neuroprotection for hypothermia alone and hypothermia in the presence of xenon. The enthalpy change (H) is a measure of the overall heat flow during the process. (I) LDH release from OGD-injured cultured neurons exposed to increasing concentrations of gavestinel at normothermia (37°C) and hypothermia (33°C). (Reprinted with permission from: Ma D, Hossain M, Chow A, et al. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005; 58: 182-93).36

The following two preclinical models mimicking neonatal asphyxia and cardiac arrest are described in greater detail because of their relevance to subsequent clinical trials.

In a Rice-Vannucci rat model of neonatal asphyxia,36 neither xenon (20%) alone nor temperature reduction (35°C) alone was capable of preventing long-term neurological consequences; however, the combination of xenon (20%) and 35°C was highly effective. Even when initiated at different times, the combination of TH/TTM plus xenon was efficacious, whereas neither treatment alone was effective.58,59 In a Rice-Vannucci rat model of neonatal asphyxia, xenon (50%) at normothermia was ineffective; however, adding xenon (50%) to hypothermia (32°C) proved to be more effective than either intervention alone.60

In piglets with global cerebral ischemia for 45 min,61 the combination of xenon (50%) and hypothermia (33.5°C) produced superior protection than either intervention alone when assessed three days later. In piglets with global cerebral ischemia produced by bilateral vertebral artery occlusion and hypoxia,62 neither xenon (50%) nor hypothermia to 33.5°C was effective at preventing evidence of cerebral energy failure by nuclear magnetic resonance (NMR) spectroscopy; however, the combination of both xenon and hypothermia for 24 hr prevented post-global ischemia energy failure (Table 6).
Table 6

Neuroprotection through a combination of xenon and hypothermia

Author/Journal/Year of publication

Species

Injury

Results/Conclusions

Ma et al., Ann Neurol 200536

Rat pup

Rice-Vannucci model of neonatal asphyxia

Synergistic interaction between Xe and TH

Martin et al., Br J Anaesth 200758

Rat pup

Rice-Vannucci model of neonatal asphyxia

Synergy even when Xe + TH delivered asynchronously

Hobbs et al., Stroke 2008125

Rat pup

Rice-Vannucci model of neonatal asphyxia

Synergistic interaction between Xe and TH

Thoresen et al., J Cereb Blood Flow Metab 200959

Rat pup

Rice-Vannucci model of neonatal asphyxia

Additivity even when Xe + TH delivered asynchronously

Chakkarapani et al., Ann Neurol 201061

Piglet

Global ischemia for 45 min

Superior protection with Xe +TH

Faulkner et al., Ann Neurol 201162

Piglet

Global ischemia until energy loss

Synergistic interaction between Xe and TH

Fries et al., Crit Care Med 201264

Pig

Xenon combined with hypothermia after 10 min cardiac arrest

Xenon improved neurological and cardiac functional outcome

Sabir et al., PLoS One 201460

Rat Pup

Rice-Vannucci model of neonatal asphyxia

Superior protection with Xe +TH

TH = therapeutic hypothermia; Xe = xenon

In an adult pig model of cardiac arrest followed by cardiopulmonary resuscitation,63 xenon (70%) did not improve either neurocognitive outcomes or histopathological evidence of global ischemia. Nevertheless, one hour of xenon (70%) with 16 hr of hypothermia (33°C) was significantly more effective than either alone.64 Fries et al.’s study64 merits further detailed consideration because of its relative importance for the conduct of the recently concluded Xe-hypotheca trial (https://clinicaltrials.gov/ct2/results?term=Xe-Hypotheca&Search=Search). After a ten-minute ventricular fibrillation-induced cardiac arrest and respiratory arrest (through termination of mechanical ventilation during general anesthesia in the presence of muscle relaxation), the pigs were resuscitated with compression and mechanical ventilation (F i O2 = 1.0; tidal volume of 15 mL·kg−1) at a ratio of 30:2. After six minutes of resuscitation, spontaneous circulation was restored by injecting epinephrine directly into the right atrium through a pulmonary artery catheter. It is notable that the arrest, time to resuscitation, and methods of resuscitation are quite similar to those performed clinically. Thereafter, the 15 resuscitated pigs with return of spontaneous circulation (ROSC) were randomized into one of three groups (n = 5), namely, Control group (in which the pigs received fluid therapy and maintenance of normothermia), mild therapeutic hypothermia group (MTH group, in which pigs received fluid therapy with surface cooling to achieve a core temperature of 33°C), and mild therapeutic hypothermia with xenon group (Xe+MTH group, in which pigs also received one hour of xenon at 70% through a closed-system ventilator). In the animals that received MTH, surface cooling lasted 16 hr and then rewarming occurred at a rate of 1°C·hr−1. The pigs were weaned off the ventilator and returned to their housing pen. Post-arrest, the neurologic status was scored with a validated neurologic deficit score in which four items (level of consciousness, respiration, posture, and feeding behaviour) were evaluated to yield a score that varies from 0 = no neurologic impairment to 100 = brain death. Apart from the specific evaluation of the CNS, an overall performance score was used. Five days after resuscitation, the pigs were sacrificed during general anesthesia and neurohistopathology was performed, including an assessment of neuroinflammation. Both hypothermia groups (MTH and Xe+MTH) showed better overall performance scores. Interestingly, there was a premature death in each of the Control and MTH groups but not in the Xe+MTH group. While both hypothermia groups had less histopathological damage than the normothermic group, the Xe+MTH group was distinctive in exhibiting reduced astrogliosis and microgliosis. Overall, the authors concluded that the addition of xenon to hypothermia resulted in a significant improvement in functional outcome (no deaths and fewer neurologic deficits over time) and ameliorated myocardial dysfunction.

In the above-mentioned preclinical studies, dose-concentrations are limited to < 70% by the need to provide sufficient oxygen for adequate saturation. Unless accompanied by therapeutic hypothermia, concentrations of xenon < 20% appear to be ineffective. Therefore, the clinical effective range is likely to reside in a relatively narrow range of 20-70%.

Clinical studies of neurological injury treated with a combination of Xe+TH

For patients undergoing coronary artery bypass grafting while on cardiopulmonary bypass

There is an increased incidence of postoperative neurocognitive deficit (POCD) following cardiac surgery with cardiopulmonary bypass (CPB).65 Moreover, the pathogenic mechanisms involved in the development of POCD may be similar to those involved in the propagation of acute neuronal injury from other causes.66 Hence, xenon has been investigated as a potential prophylactic pharmacological intervention.67 To test the feasibility and safety of delivering xenon to patients undergoing coronary artery bypass graft surgery while on CPB, xenon was administered to patients in an open-label dose-escalation study (0, 20, 35, 50% xenon in oxygen and air; n = 4 per group). Xenon was delivered throughout the surgical portion of the procedure, including prior to, during, and after CPB. Xenon concentration (partial pressures) was measured at five defined points before, during, and after CPB using gas chromatography. Because of a theoretical concern regarding gas bubble emboli, middle cerebral artery Doppler was used to assess embolic load. Blood markers, S100-β and troponin I, were also used to assess adverse effects of emboli on major organ system function.

Xenon was delivered at the chosen partial pressures using a closed-circle breathing system that recirculated the gas after scrubbing out the carbon dioxide and supplementing oxygen to ensure adequate oxygenation.

Neither the duration of tracheal intubation nor length of stay in the intensive care unit (ICU) and hospital was different between the control (no xenon) and any of the xenon concentration groups. Patients administered xenon had no major organ dysfunction, and concerns about possible damage created by theoretical expansion of air bubbles did not materialize. This finding is consistent with a previous report in which diffusion of gas into a closed space, and hence its expansion, was considered in a preclinical model of ileus. While xenon increased gas diffusion, this was considerably less than was seen with nitrous oxide.68 This small open-label trial showed the tolerability of xenon in patients with cardiac disease and was an important precursor for the subsequent Xe-hypotheca study in which patients were randomized.

Xenon and therapeutic hypothermia for out-of-hospital cardiac arrest (OHCA)

The Xe-hypotheca study was a Phase II drug clinical trial in adult victims of OHCA with an initial cardiac rhythm that was “shockable”, i.e., either ventricular fibrillation or pulseless ventricular tachycardia. One hundred ten patients were randomized in a 1:1 ratio to receive either mild therapeutic hypothermia treatment alone for 24 hr (MTH group) or in combination with inhaled xenon. A report of the feasibility and safety of the first 36 patients enrolled in the trial has been published.69

After assessment and emergent treatment (i.e., mechanical ventilation and correction of cardiovascular instability) in the emergency department, patients underwent a brain computerized tomography scan and transthoracic echocardiography to exclude a possible cerebral origin of the cardiac arrest and to assess myocardial function. If an ST-elevation myocardial infarction was established, primary percutaneous coronary intervention was performed before ICU admission. Subsequent care was performed according to the Utstein style, and the recommendations of the International Liaison Committee on Resuscitation were followed.70,71

Cooling of patients was conducted with the use of an Alsius CoolGard™ 3000 thermal regulation system (Zoll Medical Corporation, Chelmsford, MA, USA), an invasive intravascular temperature management device, to achieve a target core temperature of 33°C and then to maintain the core temperature for 24 hr. Subsequent rewarming was performed at a maximum rate of 0.5°C·hr−1. Sedation was accomplished with a continuous infusion of propofol (1-5 mg·kg−1·hr−1) and fentanyl (50-100 μg·hr−1), and shivering was terminated with cisatracurium. Exposure to xenon was accomplished through a PhysioFlex™ closed-system ventilator (Dräger, Lübeck, Germany) to achieve an end-tidal xenon concentration of at least 40%. This was delivered continuously until completion of rewarming.

At the time of the first report, no adverse reactions attributable to xenon were identified.69 In the 28 patients with coronary artery disease, the median (interquartile range [IQR]) delta troponin T value at 72 hr was 0.62 [0.18-2.39] μg·L−1 in the control group and 0.08 [0.0-0.67] μg·L−1 in the xenon-treated group.

These favourable cardiovascular features, together with the use of xenon at higher concentrations in surgical settings (albeit for shorter durations), portend safe use of xenon when combined with mild therapeutic hypothermia in patients with cardiovascular disease.

Hypoxic ischemic encephalopathy

The 2010 International Liaison Committee on Resuscitation guidelines state that infants born at (or near) term with moderate to severe HIE should be offered therapeutic hypothermia. Treatment should be initiated and conducted under clearly defined protocols at neonatal intensive care facilities that provide multidisciplinary care and follow-up.72 A meta-analysis that included 767 neonates concluded that therapeutic hypothermia significantly reduced the risk of death or disability at 18 months vs standard care (relative risk, 0.81; 95% CI, 0.71 to 0.93). The number needed to treat of neonates for one newborn to be free of death or disability was 9 (95% CI, 5 to 25).73 Thus, the therapeutic benefit of hypothermia is modest and further neuroprotective interventions are urgently needed. This was recognized by the National Institute of Child Health and Human Development who arranged two workshops to discuss the next steps.74,75 From this initiative, studies have evolved to identify adjunctive agents that have focused around the use of EPO and xenon. While early studies had shown the safety and possible additional benefit of EPO treatment,76,77 randomized trials need to be undertaken with this adjuvant. The current evidence is insufficient to recommend adjunctive EPO therapy for newborns with HIE who are undergoing hypothermia.

For the use of xenon as an adjunctive to therapeutic hypothermia, two groups have independently pursued clinical studies to ascertain the dose range, duration, feasibility, and safety (i.e., the CoolXenon Study; ISRCTN75602528, www.isrctn.com/ISRCTN75602528) and to compare xenon and therapeutic hypothermia vs therapeutic hypothermia alone (i.e., the TOBY Xe Trial; NCT00934700, https://clinicaltrials.gov/ct2/show/NCT00934700).

The TOBY Xe Trial (NCT00934700)

This randomized proof-of-concept clinical trial was approved by the National Research Ethics Board in the UK (June 2010), and according to its website (see www.npeu.ox.ac.uk/toby-xe for a detailed description of the trial protocol), it has recruited 89 patients at four sites: Hammersmith Hospital (Imperial College Hospital Trust), St. Thomas Hospital (King’s College Hospital Trust), University College London Hospital, and Liverpool Women’s Hospital.

The investigators have reported preliminary findings regarding the potentially beneficial effect of xenon on seizure activity.78 These data are very encouraging because the severity of seizures in asphyxiated encephalopathic neonates is strongly associated with more extensive brain injury79 and worse clinical outcome.80

The CoolXenon Study (ISRCTN75602528)

In this single-arm dose-escalation study led by Prof. Marianne Thoresen and Dr. John Dingley, xenon was administered to 14 infants who received therapeutic hypothermia for HIE.81 The primary outcomes (i.e., cardiorespiratory stability, electroencephalogram (EEG) parameters, and feasibility) were compared with 42 case-matched neonates who received therapeutic hypothermia alone. For the secondary outcome of safety, the Bayley Scales of Infant Development II was used to assess infants aged 18-20 months. It is noteworthy that most of the xenon-treated patients (13/14) received 50% xenon for 18 hr during the 72 hr of therapeutic hypothermia. As with the TOBY Xe study, an anticonvulsant effect of xenon was noted. Prior to starting xenon, 8/14 patients had seizure activity clinically or by EEG, while only 1/14 had seizure activity during xenon administration. There was cardiorespiratory stability throughout the period that xenon was administered. At 18 months, seven of 14 patients survived with a good clinical outcome; three died while in the hospital, and four survivors incurred disability. Therefore, death and disability occurred in 50% of patients. Historically, this number is 75%. Based on these encouraging data, the investigators have proposed randomized trials comparing xenon and therapeutic hypothermia vs therapeutic hypothermia alone (Thoresen M, CoolXenon2, NCT01545271, 2012, https://clinicaltrials.gov/ct2/show/NCT01545271; and Thoresen M, CoolXenon3, NCT02071394, 2014, https://clinicaltrials.gov/ct2/show/NCT02071394).

Future applications of xenon’s neuroprotective properties

Anesthetic-induced developmental neurotoxicity

Despite the reversible nature of general anesthesia, when immature organisms are exposed to compounds that produce the anesthetized state, brain injury can occur and result in long-term neurobehavioural deficits.82 This anesthetic-induced developmental neurotoxicity (AIDN) is unlikely due to physiological derangements that may accompany the anesthetized state because blood gas tensions were normal,83 and anesthetic-induced toxicity can be reproduced in in vitro neuronal cell cultures84 as well as in ex vivo brain slices (Table 4).12,85,86 Indeed, this AIDN has been noted with structurally unrelated compounds spanning the entire panoply of general anesthetic agents approved for pediatric use.82,87-90 It is also evident across species - from nematodes91 to rodents,82 to piglets,92 as well as to non-human primates.93-97

In contrast to the preponderance of preclinical studies establishing AIDN, this has yet to be confirmed in well-controlled prospective randomized clinical trials. In fact, observational data obtained from databases collected for other reasons98,99 represent the most compelling support for an association between exposure to general anesthesia and subsequent cognitive and behavioural problems later in human life. This association is strongest for multiple anesthetics administered to children younger than three years.100

Based on the known neuroprotective effects of xenon, we and others have investigated whether xenon itself produces AIDN and whether it can prevent AIDN.12-14,101,102 Apart from the in vitro preparation in which concentrations of xenon above 1 MAC produced injury, each of the studies in neonatal rats, neonatal mice, and piglets showed attenuation of anesthetic-induced neurotoxicity and/or lack of AIDN when exposure to xenon was included.12-14,101 Nevertheless, it is noteworthy that xenon alone did produce significant, albeit modest, neuroapoptosis (though less than isoflurane) when administered alone to mice.13 Nevertheless, xenon attenuated the injury produced by isoflurane in this species, as well as in other species.13

Traumatic brain injury

Approximately 1.7 million patients per year require medical care in the United States for TBI, incurring an annual medical cost burden of over $70 billion.4 The severity of the condition is highlighted by the fact that 1/3 of injury-related deaths are caused by TBI. The next imperative, following effective strategies to prevent TBI from concussive and blast assaults, is to acquire effective neuroprotective measures to salvage potentially surviving neurons from progressive damage and cell death. Earlier in vitro work on brain slice preparations showed significant neuroprotection with administered xenon (Table 3).103 A recent in vivo study of a TBI model in rats104 showed significant reduction in contusion volume, improved neurological outcome scores, and enhanced long-term locomotor function.

Stroke (Table 2)

Following the demonstration that intervention for a pre-hospital stroke can be delivered in the field,26 the stage is set for extending xenon’s use to a “field setting”. Members of emergency medical services are quite skilled at securing the necessary airway to administer inhalation therapy at the site where the patient is first encountered, long before admission to the emergency department. It would not be necessary to rule out intracranial hemorrhage as a cause for the stroke. According to the best available evidence to date, xenon appears to be equally effective and non-toxic for both hemorrhagic and non-hemorrhagic causes of stroke.105

Cost

In studies using efficient closed systems to recirculate the non-biotransformable xenon, no more than 2 L·hr−1 is required. While the production costs of xenon may be below $50·L−1, the price for xenon produced under current Good Manufacturing Practices (cGMP) is likely to be considerably higher. Pricing a new therapy may be subject to strict cost-benefit analysis as performed by regulatory entities such as the National Institute for Health and Care Excellence in the UK. In other healthcare environments, incremental cost-effectiveness ratios are used to indicate whether the health benefits in quality-adjusted life years exceeds the overall costs (price of the product as well as the additional care costs). The estimated healthcare costs to provide one additional quality-adjusted year of life to a neurologically injured patient has been estimated to be > $850,000.106 The cost of a 24-hr treatment with xenon could be compared with the use of nitric oxide over the same time period. Therefore, under the above circumstances, efficacious neuroprotection with xenon could be considered cost-effective.

Conclusion

Many preclinical neuroprotectants have failed to materialize into clinically effective treatments.1 While there may be “many a slip twixt cup and lip”,5 the wealth of positive preclinical studies appears to be translating into clinical utility. When the dust settles, we will know whether we are riding a horse or a donkey.

Footnotes

  1. 1.

    The New York Times. Yeltsin Has 7-Hour Heart Surgery And Doctors Say It Was a Success. Available from URL: www.nytimes.com/1996/11/06/world/yeltsin-has-7-hour-heart-surgery-and-doctors-say-it-was-a-success.html (accessed August 2015).

  2. 2.

    TREK-1 (also called KCNK2) is part of the subfamily of mechano-gated potassium channels that are present in mammalian neurons.

  3. 3.

    The Economist. An Obscure Gas Improves Athletes’ Performance. Available from URL: http://www.economist.com/news/science-and-technology/21595890-obscure-gas-improves-athletes-performance-breathe-it (accessed August 2015).

  4. 4.

    Centers for Disease Control and Prevention. Injury Prevention & Control. Traumatic Brain Injury. Available from URL: http://www.cdc.gov/TraumaticBrainInjury/ (accessed August 2015).

  5. 5.

    The Free Dictionary by Farlex. There's many a slip twixt cup and lip. https://idioms.thefreedictionary.com/There%27s+many+a+slip+twixt+cup+and+lip (accessed August 2015).

Notes

Funding

None.

Conflict of interest

Mervyn Maze is a founder, director, and owner of equity in NeuroproteXeon, a company whose mission is to develop and market xenon-based products for use against acute ongoing neurologic injury.

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Copyright information

© Canadian Anesthesiologists' Society 2015

Authors and Affiliations

  1. 1.Department of Anesthesia and Perioperative CareUniversity of California, San FranciscoSan FranciscoUSA

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