Neuroprotective Properties of Xenon in Traumatic Brain Injury* Yun Kyoung Ryu, PhD C. David Mintz, MD, PhD Department of Anesthesiology and Critical Care Medicine Johns Hopkins Medical Institutes Baltimore, MD enon is a colorless, odorless noble gas originally introduced into medical practice as an anesthetic (1) that has recently been the subject of much study in the field of neural injury and repair (2). Xenon occurs in only trace amounts in the atmosphere, and medical xenon is obtained by a complex air separation process involving multiple distillation steps. Although the cost of xenon pro duction may limit its practical availability for medical usage, in the absence of other effective therapies, xenon’s neuro protective properties have garnered considerable attention in the scientific literature. To date, the evidence for a role for xenon in neuroprotection comes primarily from animal models, although several clinical trials are under way. Preclinical studies have shown improved histopathological and behavioral outcomes in animal models of adult stroke (3), cerebral ischemia after cardiac arrest (4), neonatal hypoxicischemic injury (5), and ischemic spinal cord injury (6). The mechanisms underlying xenon neuroprotection have not been extensively studied. The available evidence suggests that xenon acts as an antagonist at the glycine binding site on iV-methyl-D-aspartate (NMDA) receptors (7, 8), which may provide neuroprotection by reducing excitotoxic cell death. The potential role for xenon as a neuroprotectant has been studied primarily in ischemic models, and it is of great inter est to determine whether it may have benefits in other modes of brain injury. In this issue of Critical Care Medicine, Campos-Pires et al (9) have investigated the effects of xenon treatment on his tological and behavioral tests of neurological function in a mouse model of traumatic brain injury (TBI). Previous work from the same group demonstrated a neuroprotective effect of xenon in an organotypic brain slice culture model of TBI that was likely mediated through NMDA receptors (10), and the current study represents the first in vivo assessment of xenon in TBI. Mice were subjected to controlled cortical impact, a standard model for TBI (11), and then treated with xenon and
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*See also p. 149. Key Words: neuroprotection; A/-methy!-D-aspartate; trauma; traumatic brain injury; xenon The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0000000000000662 250
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oxygen in a closed circuit chamber. The authors used a range of xenon doses between 30% and 75%, which is quite helpful both because concentration-dependent pharmacologic phe nomenon have additional credibility over single-dose studies and because clinically relevant doses of xenon for this applica tion have yet to be established. Furthermore, in recognition of the practical reality that TBI victims are likely to experience a delay of minutes to hours before treatment can be initiated, therapy was begun at time points ranging from 15 minutes to 6 hours after injury. Outcomes were assessed histologically by measuring contusion volume at 24 hours after injury. Neuro logic outcome was assessed acutely after injury using a scoring system focused on motor function, balance, and behavior, and chronically at 1 month using an evaluation of gait and also the CatWalk paradigms, which tests for balance and coordination. Xenon treatment was effective in improving short-term neuro logic outcomes if it was administered within 1 hour of injury, and it was effective even after a 3-hour delay in reducing con tusion volume, which suggests an effect on secondary injury. Xenon concentrations as low as 30% were effective in improv ing short-term neurologic scores and reducing contusion size, although most of the study results were obtained using 75%, a concentration which may be impractically high. Of great inter est, this study also demonstrated that xenon treatment resulted in long-term improvements in neurologic function measured at 1 month, albeit with a high dose of 70% xenon delivered 15 minutes after injury. Taken together, these data suggest that xenon administration holds promise as a therapy for TBI, a devastating and prevalent disorder for which no effective dis ease-modifying therapy currently exists. The adoption of xenon as a treatment for TBI in human patients will require considerable further research. Validation in large animal models is critical and could best be accom plished in a porcine or nonhuman primate model. The key questions to be asked in the large animal model mirror those approached in the accompanying study. If xenon therapy is to be effective, it is likely that it must be successful at dose ranges lower than 75%, if only because many patients with TBI require supplemental oxygen. Furthermore, practical considerations would require that xenon treatment be effec tive even with some delay in administration after trauma, which the study by Campos-Pires et al (9) shows is possible in principle. Lastly, widespread use of xenon for a disorder as prevalent as TBI may require advances either in the form of less costly production or more efficient delivery and scaveng ing systems that allow for treatment with very small quan tities of the gas (12). Although these issues pose challenges, xenon has already been used safely in humans, which elimi nates a major barrier to its use. The era of xenon as a therapy for neuroprotection in TBI and other forms of CNS injury has not yet arrived, but it may be close at hand. January 2 0 1 5 * Volume 43 • Number 1
Editorials REFERENCES 1. Cullen SC, Gross EG: The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 1 1 3 :5 8 0 -5 8 2 2. Dickinson R, Franks NP: Bench-to-bedside review: Molecular phar macology and clinical use of inert gases in anesthesia and neuropro tection. Crit Care 2010; 14:229 3. Homi HM, Yokoo N, Ma D, et al: The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice. Anesthesiology 2003; 99 :876-881 4. Schmidt M, Marx T, Gloggl E, et al; Xenon attenuates cerebral dam age after ischemia in pigs. Anesthesiology 2005; 1 0 2 :9 2 9 -9 3 6 5. Ma D, Hossain M, Chow A, et al: Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005; 5 8 :1 8 2 -1 9 3 6. Yang YW, Cheng WP, Lu JK, et al: Timing of xenon-induced delayed postconditioning to protect against spinal cord ischaemia-reperfusion injury in rats. Br J Anaesth 2014; 1 1 3 :1 6 8 -1 7 6 7. Banks P, Franks NP, Dickinson R: Competitive inhibition at the gly cine site of the A/-methyl-o-aspartate receptor mediates xenon
neuroproteotion against hypoxia-ischemia. Anesthesiology 2010; 1 1 2 :61 4-6 22 8. Natale G, Cattano D, Abramo A, et al: Morphological evidence that xenon neuroprotects against /V-methyl-DL-aspartic acid-induced dam age in the rat arcuate nucleus: A time-dependent study. Ann N Y Acad Sci 2006; 1 0 7 4 :6 50 -658 9. Campos-Pires R, Armstrong SP, Sebastiani A, et al: Xenon Improves Neurologic Outcome and Reduces Secondary Injury Following Trauma in an In Vivo Model of Traumatic Brain Injury. Crit Care Med 2 0 1 5 ;4 3 :1 4 9 -1 5 8 10. Harris K, Armstrong SP, Campos-Pires R, et al: Neuroprotection against traumatic brain injury by xenon, but not argon, is medi ated by inhibition at the A/-methyl-D-aspartate receptor glycine site. Anesthesiology 2013; 1 1 9 :1 1 3 7 -1 1 4 8 11. Marklund N, Hillered L: Animal modelling of traumatic brain injury in preclinical drug development: Where do we go from here? Br J Pharmacol 2011; 1 6 4 :1 2 0 7 -1 2 2 9 12. Esencan E, Yuksel S, Tosun YB, et al: XENON in medical area: Emphasis on neuroprotection in hypoxia and anesthesia. Med Gas Res 2013; 3:4
Strength by Sheer Numbers: Electroencephalogram Gathers Momentum as a Positive Predictor* Tommaso Pellis, M D Anesthesia, Intensive Care and Emergency Medical Service Santa Maria Degli Angeli Hospital Pordenone, Italy
he introduction of therapeutic hypothermia, and then of the broader concept of temperature management, has profoundly changed the gameplay of prognostica tion after resuscitation. Physicians must now rely on a limodal approach and should refrain from the temptation of establishing prognosis earlier than 72 hours (1). Most recently, practical recommendations and a large postresuscitation trial on temperature management further delayed prognostication to 72 hours after reestablishing normothermia (2,3). As a con sequence, treating physicians, and families alike, face a painful stall in a possible end-of-life decision-making process. Recently, electroencephalogram has been investigated with growing interest for its potential role in providing clues to positive prognostication. In the contrary, in the multimodal approach to patients who do not regain consciousness, clinical
T
*See also p. 159. Key Words: cardiac arrest; neurologic outcome; postresuscitation care; prognostication; target temperature management Dr. Pellis lectured for Bard Medical. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM .0000000000000661
Critical Care Medicine
evaluation, somatosensory evoked potentials, biomarkers, and neuroimaging are all more reliable as negative than positive predictors (2,4). Another element that contributes to make extremely attrac tive the use of electroencephalogram is the timing with which it becomes informative. Despite hypothermia and ongoing sedation, several studies have highlighted early patterns of electroencephalogram activity associated with good outcome (5-7). In particular, a continuous background, even if slow, and reactivity should strongly reinforce motivation in con muttinuing aggressive postresuscitation care. The ramifications of the contribution of electroencephalogram as an early positive predictor should not be underestimated because in the first days the prevailing causes of death are postresuscitation myo cardial dysfunction and multiorgan failure (8). In this context, for example, electroencephalogram could positively contribute to the discussion on escalation of care such as with mechanical support. On the other hand, a perceived poor expectation may lead to early limitation of care, thus contributing to the main cause of death after resuscitation, which is neurological injury. Early positive indicators may counterbalance lurking skepti cism toward resuscitated patients. Yet, the available data so far suffered from the limitations deriving from low numbers and the retrospective nature of some studies (5-7, 9). In this scenario, Tjepkema-Cloostermans et al (10) should be complimented for presenting the largest prospective study so far on electroencephalogram for early prognostication. The authors analyzed a 5-minute section of a continuous electroencephalogram recording at 12 and 24 hours after cardiac arrest in 142 patients. A positive prediction w w w .c c m jo u r n a l.o r g
251
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
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*See also p. 149. Key Words: neuroprotection; A/-methy!-D-aspartate; trauma; traumatic brain injury; xenon The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0000000000000662 250
w w w .c c m jo u r n a l.o r g
oxygen in a closed circuit chamber. The authors used a range of xenon doses between 30% and 75%, which is quite helpful both because concentration-dependent pharmacologic phe nomenon have additional credibility over single-dose studies and because clinically relevant doses of xenon for this applica tion have yet to be established. Furthermore, in recognition of the practical reality that TBI victims are likely to experience a delay of minutes to hours before treatment can be initiated, therapy was begun at time points ranging from 15 minutes to 6 hours after injury. Outcomes were assessed histologically by measuring contusion volume at 24 hours after injury. Neuro logic outcome was assessed acutely after injury using a scoring system focused on motor function, balance, and behavior, and chronically at 1 month using an evaluation of gait and also the CatWalk paradigms, which tests for balance and coordination. Xenon treatment was effective in improving short-term neuro logic outcomes if it was administered within 1 hour of injury, and it was effective even after a 3-hour delay in reducing con tusion volume, which suggests an effect on secondary injury. Xenon concentrations as low as 30% were effective in improv ing short-term neurologic scores and reducing contusion size, although most of the study results were obtained using 75%, a concentration which may be impractically high. Of great inter est, this study also demonstrated that xenon treatment resulted in long-term improvements in neurologic function measured at 1 month, albeit with a high dose of 70% xenon delivered 15 minutes after injury. Taken together, these data suggest that xenon administration holds promise as a therapy for TBI, a devastating and prevalent disorder for which no effective dis ease-modifying therapy currently exists. The adoption of xenon as a treatment for TBI in human patients will require considerable further research. Validation in large animal models is critical and could best be accom plished in a porcine or nonhuman primate model. The key questions to be asked in the large animal model mirror those approached in the accompanying study. If xenon therapy is to be effective, it is likely that it must be successful at dose ranges lower than 75%, if only because many patients with TBI require supplemental oxygen. Furthermore, practical considerations would require that xenon treatment be effec tive even with some delay in administration after trauma, which the study by Campos-Pires et al (9) shows is possible in principle. Lastly, widespread use of xenon for a disorder as prevalent as TBI may require advances either in the form of less costly production or more efficient delivery and scaveng ing systems that allow for treatment with very small quan tities of the gas (12). Although these issues pose challenges, xenon has already been used safely in humans, which elimi nates a major barrier to its use. The era of xenon as a therapy for neuroprotection in TBI and other forms of CNS injury has not yet arrived, but it may be close at hand. January 2 0 1 5 * Volume 43 • Number 1
Editorials REFERENCES 1. Cullen SC, Gross EG: The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 1 1 3 :5 8 0 -5 8 2 2. Dickinson R, Franks NP: Bench-to-bedside review: Molecular phar macology and clinical use of inert gases in anesthesia and neuropro tection. Crit Care 2010; 14:229 3. Homi HM, Yokoo N, Ma D, et al: The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice. Anesthesiology 2003; 99 :876-881 4. Schmidt M, Marx T, Gloggl E, et al; Xenon attenuates cerebral dam age after ischemia in pigs. Anesthesiology 2005; 1 0 2 :9 2 9 -9 3 6 5. Ma D, Hossain M, Chow A, et al: Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005; 5 8 :1 8 2 -1 9 3 6. Yang YW, Cheng WP, Lu JK, et al: Timing of xenon-induced delayed postconditioning to protect against spinal cord ischaemia-reperfusion injury in rats. Br J Anaesth 2014; 1 1 3 :1 6 8 -1 7 6 7. Banks P, Franks NP, Dickinson R: Competitive inhibition at the gly cine site of the A/-methyl-o-aspartate receptor mediates xenon
neuroproteotion against hypoxia-ischemia. Anesthesiology 2010; 1 1 2 :61 4-6 22 8. Natale G, Cattano D, Abramo A, et al: Morphological evidence that xenon neuroprotects against /V-methyl-DL-aspartic acid-induced dam age in the rat arcuate nucleus: A time-dependent study. Ann N Y Acad Sci 2006; 1 0 7 4 :6 50 -658 9. Campos-Pires R, Armstrong SP, Sebastiani A, et al: Xenon Improves Neurologic Outcome and Reduces Secondary Injury Following Trauma in an In Vivo Model of Traumatic Brain Injury. Crit Care Med 2 0 1 5 ;4 3 :1 4 9 -1 5 8 10. Harris K, Armstrong SP, Campos-Pires R, et al: Neuroprotection against traumatic brain injury by xenon, but not argon, is medi ated by inhibition at the A/-methyl-D-aspartate receptor glycine site. Anesthesiology 2013; 1 1 9 :1 1 3 7 -1 1 4 8 11. Marklund N, Hillered L: Animal modelling of traumatic brain injury in preclinical drug development: Where do we go from here? Br J Pharmacol 2011; 1 6 4 :1 2 0 7 -1 2 2 9 12. Esencan E, Yuksel S, Tosun YB, et al: XENON in medical area: Emphasis on neuroprotection in hypoxia and anesthesia. Med Gas Res 2013; 3:4
Strength by Sheer Numbers: Electroencephalogram Gathers Momentum as a Positive Predictor* Tommaso Pellis, M D Anesthesia, Intensive Care and Emergency Medical Service Santa Maria Degli Angeli Hospital Pordenone, Italy
he introduction of therapeutic hypothermia, and then of the broader concept of temperature management, has profoundly changed the gameplay of prognostica tion after resuscitation. Physicians must now rely on a limodal approach and should refrain from the temptation of establishing prognosis earlier than 72 hours (1). Most recently, practical recommendations and a large postresuscitation trial on temperature management further delayed prognostication to 72 hours after reestablishing normothermia (2,3). As a con sequence, treating physicians, and families alike, face a painful stall in a possible end-of-life decision-making process. Recently, electroencephalogram has been investigated with growing interest for its potential role in providing clues to positive prognostication. In the contrary, in the multimodal approach to patients who do not regain consciousness, clinical
T
*See also p. 159. Key Words: cardiac arrest; neurologic outcome; postresuscitation care; prognostication; target temperature management Dr. Pellis lectured for Bard Medical. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM .0000000000000661
Critical Care Medicine
evaluation, somatosensory evoked potentials, biomarkers, and neuroimaging are all more reliable as negative than positive predictors (2,4). Another element that contributes to make extremely attrac tive the use of electroencephalogram is the timing with which it becomes informative. Despite hypothermia and ongoing sedation, several studies have highlighted early patterns of electroencephalogram activity associated with good outcome (5-7). In particular, a continuous background, even if slow, and reactivity should strongly reinforce motivation in con muttinuing aggressive postresuscitation care. The ramifications of the contribution of electroencephalogram as an early positive predictor should not be underestimated because in the first days the prevailing causes of death are postresuscitation myo cardial dysfunction and multiorgan failure (8). In this context, for example, electroencephalogram could positively contribute to the discussion on escalation of care such as with mechanical support. On the other hand, a perceived poor expectation may lead to early limitation of care, thus contributing to the main cause of death after resuscitation, which is neurological injury. Early positive indicators may counterbalance lurking skepti cism toward resuscitated patients. Yet, the available data so far suffered from the limitations deriving from low numbers and the retrospective nature of some studies (5-7, 9). In this scenario, Tjepkema-Cloostermans et al (10) should be complimented for presenting the largest prospective study so far on electroencephalogram for early prognostication. The authors analyzed a 5-minute section of a continuous electroencephalogram recording at 12 and 24 hours after cardiac arrest in 142 patients. A positive prediction w w w .c c m jo u r n a l.o r g
251
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
