SHOCK, Vol. 41, No. 1, pp. 85Y86, 2014
Editorial Comment WILL THE NEXT BREAKTHROUGH FOR NEUROPROTECTION AFTER CARDIAC ARREST COME OUT OF THIN AIR? Patrick M. Kochanek and Travis C. Jackson Department of Critical Care Medicine and Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Hypoxic ischemic encephalopathy resulting from cardiac arrest remains an enormous problem worldwide, across the spectrum of age and arrest etiologies (1, 2). Unfortunately, however, other than mild therapeutic hypothermia (3, 4), we have little in our armamentarium of therapies with which to attenuate the neuronal death and dysfunction that underlie the devastating outcomes that can be seen in survivors. In addition, although mild hypothermia has represented the first therapeutic breakthrough targeting brain injury in this condition, it shows efficacy in only a select number of cases. In this issue of Shock, Ristagno et al. (5) build on the prior work of a number of investigators such as Bruken et al. (6), Jawad et al. (7), Loetscher et al. (8), and Zhuang et al. (9) in experimental cardiac arrest in rats, cultured organotypic hippocampal slices, and other in vivo models such as perinatal asphyxia in rats. To this end, they tested the efficacy of inhaled argon gas in attenuating neuronal injury and neurological dysfunction in a pig outcome model of ventricular fibrillation cardiac arrest. Strengths of their work include the use of a large animal model, evaluation using an insult that specifically mimics the clinical condition, use of a postresuscitation administration paradigm, assessment of both behavioral and neuropathologic outcomes, demonstration of a reduction of serum levels of the brain injury marker neuron-specific enolase, and possible beneficial effects on the myocardium. Indeed, the three noble gases, argon, helium, and xenon, appear to perform similarly in this regard in some experimental models (9), and this work on argon has actually emerged from the more seminal studies with xenon from over a decade ago (10). It is noteworthy that in some but not all studies argon seems to perform best (7), and in general terms, argon and xenon are neuroprotective, whereas krypton and neon are not. A variety of mechanisms have been suggested to contribute to the neuroprotection produced by argon including triggering of +-aminobutyric acid (GABA) neurotransmission acting at the benzodiazepine binding sites of the GABAA receptor (8), increases in BCL-2 levels in brain (9), via effects at N-methyl-Daspartate receptors through argon’s ability to compete at the glycine-binding site, or possibly via effects on potassium channels (7, 9). The work of Ristagno et al. (5) has limitations, and there are some potential issues that could be complicating with the possible use of argon in the clinical setting of resuscitation. With regard to this study, importantly, the neuropathologic examination that was carried out was quite limited, and no
statistically significant beneficial effects were seen. Also, there were no uninjured controls for histological comparison. A more comprehensive survey of neuropathologic damage after cardiac arrest such as that carried out by Janata et al. (11) in rats or that of Ho¨gler et al. (12) in pigs should be carefully done in future studies to define the overall impact of this therapy on key brain targets such as CA1, cortical layer V, and Purkinje and striatal neurons. It is important to determine if there is a reduction in neuropathologic injury by this therapy and no unanticipated damage in remote brain regions, as was seen in the classic studies of Fix et al. (13) with the N-methyl-D-aspartate antagonist MK 801. In addition, the study examined a relatively small number of animals and followed outcome for only 72 h. It is well known from the studies of Dietrich et al. (14) that early neuroprotective effects of therapies can be lost at more delayed time points. Indeed, some therapies may only delay rather than mitigate neuronal death. In addition, all preclinical studies of cardiac arrest are confounded by the need for general anesthesia at or around the time of insult, and a possible favorable interaction between argon and other anesthetics such as pentobarbitalVas used in this studyVcould contribute to failure of clinical translation. The study also used a mixture of 70% argon and 30% oxygen for 4 h, and if that dose of argon is essential, it could be limiting in cases of cardiac arrest, which have pulmonary complications where an FIO2 greater than 0.3 is required. In addition, argon is 38% more dense than air, and even though the authors were able to generate similar blood gases between treatment groups in this preclinical study (presumably with adjustments in mechanical ventilation parameters), this poses additional concerns with regard to the need for adjustments in mechanical ventilation, particularly in the setting of lung injury after cardiac arrest. This is not a trivial concern, as exemplified by the recent study of the effect of 100% oxygen versus room air on outcome after cardiac arrest in children, for example, where pulmonary dysfunction was found to be extremely common (15). However, recent studies by Francis et al. (16) suggest that anesthesia with noble gases such as xenon could have favorable hemodynamic effects in shock states. Finally, argon was not tested in combination with mild hypothermia. It is unclear whether the effects of argon would augment, synergize, or cancel the benefits of hypothermia. However, recent work by Arola et al. (17) suggests feasibility of combining xenon with mild hypothermia after cardiac arrest in a clinical feasibility study in adults. Those findings are encouraging and suggest potential promise for argon as well in this regard. It certainly suggests feasibility in clinical studies. 85
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
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SHOCK VOL. 41, NO. 1
Surprisingly, argon is the third most abundant gas in our atmosphere, being more abundant at È0.9% than even carbon dioxide. Reflecting this is the fact that argon is produced in industry from room air and, unlike xenon, is quite inexpensiveVas pointed out by the authors (9 cents per liter). The late Dr. Peter SafarVoften called the father of modern day resuscitationVhad a catchphrase that he used to describe the key qualifications of an optimal new therapy in resuscitation, namely, Bsafe, effective, simple, and inexpensive.[ If the promise that seems to be emerging with argon is borne out in additional preclinical and clinical investigations, it might be that it meets those qualifications and that our next neuroprotective agent will appear out of thin air. REFERENCES 1. Sandroni C, Cavallaro F, Callaway CW, Sanna T, D’Arrigo S, Kuiper M, Della Marca G, Nolan JP: Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 1: patients not treated with therapeutic hypothermia [published online ahead of print]. Resuscitation 84(10):1310Y1323, 2013. 2. Akahane M, Tanabe S, Ogawa T, Koike S, Horiguchi H, Yasunaga H, Imamura T: Characteristics and outcomes of pediatric out-of-hospital cardiac arrest by scholastic age category. Pediatr Crit Care Med 14(2):130Y136, 2013. 3. Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW: Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation 83(2):188Y196, 2012. 4. Shankaran S, Laptook AR, McDonald SA, Higgins RD, Tyson JE, Ehrenkranz RA, Das A, Sant’Anna G, Goldberg RN, Bara R, et al.: Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: Temperature profile and outcomes of neonates undergoing whole body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatr Crit Care Med 13(2):53Y59, 2012. 5. Ristagno G, Flumagalli F, Russo I, Tantillo S, Zani D, Locatelli V, De Maglie M, Novelli D, Staszewsky L, Vago T, et al.: Post-resuscitation treatment with argon improves early neurological recovery in a porcine model of cardiac arrest. Shock 41(1):73Y79, 2013.
EDITORIAL COMMENT 6. Bruken A, Cizen A, Fera C, Meinhardt A, Weis J, Nolte K, Rossiant R, Pufe T, Marx G, Fries M: Argon reduces neurohistopathological damage and preserves functional recovery after cardiac arrest in rats. Br J Anaesth 110(Suppl 1): 106Y112, 2013. 7. Jawad N, Rizvi M, Gu J, Adeyi O, Tao G, Maze M, Ma D: Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury. Neuroscience Letters 460:232Y236, 2009. 8. Loetscher PD, Rossaint J, Rossaint R, Weis J, Fries M, Fahlenkamp A, Ryang YM, Grottke O, Coburn M: Argon: neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury. Crit Care Med 13(6):1578Y1587, 2009. 9. Zhuang L, Yang T, Zhao H, Fildalgo AR, Vizcaychipi MP, Sanders RD, Yu B, Takata M, Johnson MR, Ma D: The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats. Crit Care Med 40(6):1724Y1730, 2012. 10. Ma D, Wilhelm S, Maze M, Franks NP: Neuroprotective and neurotoxic properties of the Finert_ gas, xenon. Br J Anaesth 89(8):739Y746, 2002. 11. Janata A, Magnet IA, Drabek T, Stezoski JP, Janesko-Feldman K, Popp E, Garman RH, Tisherman SA, Kochanek PM: Extracorporeal versus conventional cardiopulmonary resuscitation after ventricular fibrillation cardiac arrest in rats: a feasibility trial. Crit Care Med 41(9):e211Ye222, 2013. 12. Ho¨gler S, Sterz F, Sipos W, Schratter A, Weihs W, Holzer M, Janata A, Losert U, Behringer W, Tichy A, et al.: Distribution of neuropathological lesions in pig brains after different durations of cardiac arrest. Resuscitation 81(11):1577Y1583, 2010. 13. Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N, Wozniak DF, Olney JW: Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex. Exp Neurol 123(2):204Y215, 1993. 14. Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD: Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 13(4):541Y549, 1993. 15. Del Castillo J, Lo´pez-Herce J, Matamoros M, Can˜adas S, Rodriguez-Calvo A, Cechetti C, Rodriguez-Nu´n˜ez A, Alvarez AC; Iberoamerican Pediatric Cardiac Arrest Study Network RIBEPCI: Hyperoxia, hypocapnia and hypercapnia as outcome factors after cardiac arrest in children. Resuscitation 83(12):1456Y1461, 2012. 16. Francis RC, Philippi-Ho¨hne C, Klein A, Pickerodt PA, Reyle-Hahn MS, Boemke W: Xenon/remifentanil anesthesia protects against adverse effects of losartan on hemodynamic challenges induced by anesthesia and acute blood loss. Shock 34(6):628Y635, 2010. 17. Arola OJ, Laitio RM, Roine RO, Gro¨nlund J, Saraste A, Pietila¨ M, Airaksinen J, Perttila¨ J, Scheinin H, Olkkola KT, et al.: Feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out-ofhospital cardiac arrest. Crit Care Med 41(9):2116Y2124, 2013.
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
Editorial Comment WILL THE NEXT BREAKTHROUGH FOR NEUROPROTECTION AFTER CARDIAC ARREST COME OUT OF THIN AIR? Patrick M. Kochanek and Travis C. Jackson Department of Critical Care Medicine and Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Hypoxic ischemic encephalopathy resulting from cardiac arrest remains an enormous problem worldwide, across the spectrum of age and arrest etiologies (1, 2). Unfortunately, however, other than mild therapeutic hypothermia (3, 4), we have little in our armamentarium of therapies with which to attenuate the neuronal death and dysfunction that underlie the devastating outcomes that can be seen in survivors. In addition, although mild hypothermia has represented the first therapeutic breakthrough targeting brain injury in this condition, it shows efficacy in only a select number of cases. In this issue of Shock, Ristagno et al. (5) build on the prior work of a number of investigators such as Bruken et al. (6), Jawad et al. (7), Loetscher et al. (8), and Zhuang et al. (9) in experimental cardiac arrest in rats, cultured organotypic hippocampal slices, and other in vivo models such as perinatal asphyxia in rats. To this end, they tested the efficacy of inhaled argon gas in attenuating neuronal injury and neurological dysfunction in a pig outcome model of ventricular fibrillation cardiac arrest. Strengths of their work include the use of a large animal model, evaluation using an insult that specifically mimics the clinical condition, use of a postresuscitation administration paradigm, assessment of both behavioral and neuropathologic outcomes, demonstration of a reduction of serum levels of the brain injury marker neuron-specific enolase, and possible beneficial effects on the myocardium. Indeed, the three noble gases, argon, helium, and xenon, appear to perform similarly in this regard in some experimental models (9), and this work on argon has actually emerged from the more seminal studies with xenon from over a decade ago (10). It is noteworthy that in some but not all studies argon seems to perform best (7), and in general terms, argon and xenon are neuroprotective, whereas krypton and neon are not. A variety of mechanisms have been suggested to contribute to the neuroprotection produced by argon including triggering of +-aminobutyric acid (GABA) neurotransmission acting at the benzodiazepine binding sites of the GABAA receptor (8), increases in BCL-2 levels in brain (9), via effects at N-methyl-Daspartate receptors through argon’s ability to compete at the glycine-binding site, or possibly via effects on potassium channels (7, 9). The work of Ristagno et al. (5) has limitations, and there are some potential issues that could be complicating with the possible use of argon in the clinical setting of resuscitation. With regard to this study, importantly, the neuropathologic examination that was carried out was quite limited, and no
statistically significant beneficial effects were seen. Also, there were no uninjured controls for histological comparison. A more comprehensive survey of neuropathologic damage after cardiac arrest such as that carried out by Janata et al. (11) in rats or that of Ho¨gler et al. (12) in pigs should be carefully done in future studies to define the overall impact of this therapy on key brain targets such as CA1, cortical layer V, and Purkinje and striatal neurons. It is important to determine if there is a reduction in neuropathologic injury by this therapy and no unanticipated damage in remote brain regions, as was seen in the classic studies of Fix et al. (13) with the N-methyl-D-aspartate antagonist MK 801. In addition, the study examined a relatively small number of animals and followed outcome for only 72 h. It is well known from the studies of Dietrich et al. (14) that early neuroprotective effects of therapies can be lost at more delayed time points. Indeed, some therapies may only delay rather than mitigate neuronal death. In addition, all preclinical studies of cardiac arrest are confounded by the need for general anesthesia at or around the time of insult, and a possible favorable interaction between argon and other anesthetics such as pentobarbitalVas used in this studyVcould contribute to failure of clinical translation. The study also used a mixture of 70% argon and 30% oxygen for 4 h, and if that dose of argon is essential, it could be limiting in cases of cardiac arrest, which have pulmonary complications where an FIO2 greater than 0.3 is required. In addition, argon is 38% more dense than air, and even though the authors were able to generate similar blood gases between treatment groups in this preclinical study (presumably with adjustments in mechanical ventilation parameters), this poses additional concerns with regard to the need for adjustments in mechanical ventilation, particularly in the setting of lung injury after cardiac arrest. This is not a trivial concern, as exemplified by the recent study of the effect of 100% oxygen versus room air on outcome after cardiac arrest in children, for example, where pulmonary dysfunction was found to be extremely common (15). However, recent studies by Francis et al. (16) suggest that anesthesia with noble gases such as xenon could have favorable hemodynamic effects in shock states. Finally, argon was not tested in combination with mild hypothermia. It is unclear whether the effects of argon would augment, synergize, or cancel the benefits of hypothermia. However, recent work by Arola et al. (17) suggests feasibility of combining xenon with mild hypothermia after cardiac arrest in a clinical feasibility study in adults. Those findings are encouraging and suggest potential promise for argon as well in this regard. It certainly suggests feasibility in clinical studies. 85
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
86
SHOCK VOL. 41, NO. 1
Surprisingly, argon is the third most abundant gas in our atmosphere, being more abundant at È0.9% than even carbon dioxide. Reflecting this is the fact that argon is produced in industry from room air and, unlike xenon, is quite inexpensiveVas pointed out by the authors (9 cents per liter). The late Dr. Peter SafarVoften called the father of modern day resuscitationVhad a catchphrase that he used to describe the key qualifications of an optimal new therapy in resuscitation, namely, Bsafe, effective, simple, and inexpensive.[ If the promise that seems to be emerging with argon is borne out in additional preclinical and clinical investigations, it might be that it meets those qualifications and that our next neuroprotective agent will appear out of thin air. REFERENCES 1. Sandroni C, Cavallaro F, Callaway CW, Sanna T, D’Arrigo S, Kuiper M, Della Marca G, Nolan JP: Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 1: patients not treated with therapeutic hypothermia [published online ahead of print]. Resuscitation 84(10):1310Y1323, 2013. 2. Akahane M, Tanabe S, Ogawa T, Koike S, Horiguchi H, Yasunaga H, Imamura T: Characteristics and outcomes of pediatric out-of-hospital cardiac arrest by scholastic age category. Pediatr Crit Care Med 14(2):130Y136, 2013. 3. Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW: Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: A systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation 83(2):188Y196, 2012. 4. Shankaran S, Laptook AR, McDonald SA, Higgins RD, Tyson JE, Ehrenkranz RA, Das A, Sant’Anna G, Goldberg RN, Bara R, et al.: Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network: Temperature profile and outcomes of neonates undergoing whole body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatr Crit Care Med 13(2):53Y59, 2012. 5. Ristagno G, Flumagalli F, Russo I, Tantillo S, Zani D, Locatelli V, De Maglie M, Novelli D, Staszewsky L, Vago T, et al.: Post-resuscitation treatment with argon improves early neurological recovery in a porcine model of cardiac arrest. Shock 41(1):73Y79, 2013.
EDITORIAL COMMENT 6. Bruken A, Cizen A, Fera C, Meinhardt A, Weis J, Nolte K, Rossiant R, Pufe T, Marx G, Fries M: Argon reduces neurohistopathological damage and preserves functional recovery after cardiac arrest in rats. Br J Anaesth 110(Suppl 1): 106Y112, 2013. 7. Jawad N, Rizvi M, Gu J, Adeyi O, Tao G, Maze M, Ma D: Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury. Neuroscience Letters 460:232Y236, 2009. 8. Loetscher PD, Rossaint J, Rossaint R, Weis J, Fries M, Fahlenkamp A, Ryang YM, Grottke O, Coburn M: Argon: neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury. Crit Care Med 13(6):1578Y1587, 2009. 9. Zhuang L, Yang T, Zhao H, Fildalgo AR, Vizcaychipi MP, Sanders RD, Yu B, Takata M, Johnson MR, Ma D: The protective profile of argon, helium, and xenon in a model of neonatal asphyxia in rats. Crit Care Med 40(6):1724Y1730, 2012. 10. Ma D, Wilhelm S, Maze M, Franks NP: Neuroprotective and neurotoxic properties of the Finert_ gas, xenon. Br J Anaesth 89(8):739Y746, 2002. 11. Janata A, Magnet IA, Drabek T, Stezoski JP, Janesko-Feldman K, Popp E, Garman RH, Tisherman SA, Kochanek PM: Extracorporeal versus conventional cardiopulmonary resuscitation after ventricular fibrillation cardiac arrest in rats: a feasibility trial. Crit Care Med 41(9):e211Ye222, 2013. 12. Ho¨gler S, Sterz F, Sipos W, Schratter A, Weihs W, Holzer M, Janata A, Losert U, Behringer W, Tichy A, et al.: Distribution of neuropathological lesions in pig brains after different durations of cardiac arrest. Resuscitation 81(11):1577Y1583, 2010. 13. Fix AS, Horn JW, Wightman KA, Johnson CA, Long GG, Storts RW, Farber N, Wozniak DF, Olney JW: Neuronal vacuolization and necrosis induced by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK(+)801 (dizocilpine maleate): a light and electron microscopic evaluation of the rat retrosplenial cortex. Exp Neurol 123(2):204Y215, 1993. 14. Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD: Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 13(4):541Y549, 1993. 15. Del Castillo J, Lo´pez-Herce J, Matamoros M, Can˜adas S, Rodriguez-Calvo A, Cechetti C, Rodriguez-Nu´n˜ez A, Alvarez AC; Iberoamerican Pediatric Cardiac Arrest Study Network RIBEPCI: Hyperoxia, hypocapnia and hypercapnia as outcome factors after cardiac arrest in children. Resuscitation 83(12):1456Y1461, 2012. 16. Francis RC, Philippi-Ho¨hne C, Klein A, Pickerodt PA, Reyle-Hahn MS, Boemke W: Xenon/remifentanil anesthesia protects against adverse effects of losartan on hemodynamic challenges induced by anesthesia and acute blood loss. Shock 34(6):628Y635, 2010. 17. Arola OJ, Laitio RM, Roine RO, Gro¨nlund J, Saraste A, Pietila¨ M, Airaksinen J, Perttila¨ J, Scheinin H, Olkkola KT, et al.: Feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out-ofhospital cardiac arrest. Crit Care Med 41(9):2116Y2124, 2013.
Copyright © 2013 by the Shock Society. Unauthorized reproduction of this article is prohibited.
