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Should reperfusion be revisited?
American Journal of Emergency Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Editorial
Should reperfusion be revisited?☆ The article by Fei Han et al in this issue of the Journal may be an important bit of bench science. In a rodent model of global ischemia, they found that both the moderate-sized (cyclic non-ribosomal peptide) pharmaceutical drug cyclosporine and therapeutic hypothermia appear to blunt reperfusion related neuroinjury through similar mechanisms. Even more intriguingly, Fei Han et al provide a first indication that the pharmaceutical efficacy of cyclosporine and the physical efficacy of hypothermia may be somewhat additive. Before we can fully appreciate the potential importance of these results, a little bit of history is needed…. The possibility that much of the vital organ injury that follows ischemia may actually occur during reperfusion was inherent in the early insights of the Negofsky [1], Hossmann [2,3], and Siesjo [4]among others. The landmark studies of Kloner [5,6], Yellon, and others [7,8] clarified the hypothesis that this injury was fueled by the restoration of blood flow during resuscitation of patients in the setting of acute myocardial infarction, stroke, and cardiac arrest. The importance of reperfusion injury as a concept cannot be understated—if tissues enter a transiently stable state during ischemia, followed by injury during restoration of blood flow, then the opportunity to rescue patients clinically actually exists. If tissues were unalterably destined to complete the damage then vital organ ischemic injury would be untreatable. This makes “reperfusion injury” both an important pathophysiologic entity and a confusing bit of nomenclature. It begs the question—is not the worst possible outcome no reperfusion? We can address this conundrum with a definitional sleight of hand: “reperfusion injury” is the portion of the injury treatable after restoration of vital organ blood flow. In particular, therapies directed at reperfusion injury are intended to improve the outcome of penumbra regions that might actually have been better off with no reperfusion. Get it? Once we move past the definitional problems, our plate runneth over. At times it can seem as if almost every component of inflammation, metabolism, and cellular control mechanisms can be demonstrated to have some involvement in ischemia reperfusion injury. Peter Safer, in particular, was eloquent in his description of the multi-pathway cascade that typifies the phenomenon [9,10]. The last 40 years have at times felt like a flavor-of-the-month when it comes to describing the myriad molecular and cell signaling pathways involved in reperfusion injury. And that may be the problem. Once you comprehend how multifaceted the systems biology of reperfusion injury actually is, it is completely understandable that single-ligand pharmaceutical approaches have failed. While it has been relatively easy to demonstrate associations between reperfusion and any given molecular “change in concentration”,
☆ This editorial relates to the article published in this month's issue by Fei Han et al.
it has been difficult to determine which pathways are mechanistically important versus those that may simply be epiphenomenon. Calcium dishomeostasis, oxygen free radicals, lipid membrane damage, apoptosis; the list has gone on and on [5,11–13]. The challenge has been to identify a particular pathway that lies at the root of all these cascades. Even more concerning has been our inability to translate any of these molecular associations to effective bedside therapies. To date, other than the restoration of blood flow via thrombolytics or mechanical interventions, no drug directed at improving outcome in vital organ ischemia has clearly improved outcomes. The past few years has seen particular interest in the mitochondrial permeability transition pore (MPTP) as having a particularly important role in reperfusion injury [14–16]. As currently envisioned, the pore is a pathologic association of multiple molecular subunits that normally remain separate in the mitochondrial inner membrane. Once the components associate and form the pore, they allow pathologic flow of ions and proteins along with collapse of the proton motive gradient necessary for electron transport and energy production. These events also provide a pathway for initiation of programmed cell [17]. Look closely at the MPTP…see that subunit labeled cyclophilin D? It got that name because the drug cyclosporine fortuitously binds here. And the news gets even better—administration of cyclosporine appears to interfere with formation of the pore. In lab models, inhibition or depletion of cyclophilin D through either pharmacologic binding or even genetic knockout increases resistance to cell death [15,16,18]. However, we are still talking about ischemia reperfusion injury, so the translation from the bench to the clinic has been anything but smooth. In a pattern that should now seem familiar, efficacy in the lab and on near-term surrogate endpoints has been obtainable [15,16,18,19]; improved outcomes for patients? Not so much. Cyclosporine has been shown to reduce infarct size in laboratory models of coronary ischemia [20]. And in relatively small human trials in patients undergoing percuteaneous coronary intervention (PCI) for ST-elevation myocardial infarction, cyclosporine appeared to blunt the injury as measured by creatinine kinase and troponin [21]. Unfortunately, a more definitive trial found no significant difference in a composite endpoint composed of all cause mortality, worsening congestive heart failure, rehospitalization, and adverse remodeling [22]. The situation in neuroinjury has been similar. Early promise in the laboratory or Phase I trials [22–24] has failed to validate in Phase III trials in traumatic brain injury. In stroke, development of the drugs appears stuck at Phase II [25]. The failure of reperfusion therapies in the setting of acute myocardial infarction and PCI is particularly disappointing. Unlike resuscitation from cardiac arrest and stroke, in PCI we control reperfusion. Pharmacologic treatment can begin almost immediately, or even before the vessel is opened. The history of therapeutics for ischemia reperfusion injury is littered with agents that failed Phase III trials after promising laboratory and
0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Morrissette KM, Paradis NA, Should reperfusion be revisited?, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.02.070
2
K.M. Morrissette, N.A. Paradis / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Phase I/II studies; and cyclosporine now seems to be taking its place in this pantheon of failure [24,26]. Why? If the MPTP is central to reperfusion injury and we have an off the shelf drug to prevent its formation, shouldn't we be able to blunt the injury and improve the outcome of patients? The answer may lie in the numerous pathways and kinetics of ischemia reperfusion injury. By the time we get our hands on these patients, the primary initiating events may be long gone and all of the numerous downstream cascades widely activated. Adapting a useful metaphor—the genie is too completely out of the bottle. And so, is cyclosporine destined to join the long list of pharmaceuticals drugs that have failed to improve the clinical outcomes in vital organ ischemia reperfusion? Maybe not. After literally decades of the failure—along came therapeutic hypothermia and its apparent salutary effect after cardiac arrest [27]. While not clearly proven [28], it is clear to practitioners that something has changed in the outcome of patients suffering cardiac arrest. Good neurologic outcomes used to be so rare as to be topics of discussion. Now, some centers have survivors that number in the hundreds, without any other obvious change in therapy. Although, because it is relatively easy to apply, and without apparent significant toxicity, therapeutic hypothermia does violate the “too good to be true” rule of clinical medicine. Mechanistically, the efficacy of hypothermia is the opposite of single ligand pharmaceuticals—every molecule is affected. If it turns out to be true that it actually works for ischemia reperfusion injury, it will be because of the fortuitous circumstance that, net-net, this whole organism physical intervention improves outcome. And it is within that context that Fei Han et al results become particularly intriguing and exciting. If the salutary effect of therapeutic hypothermia and cyclosporine are even a bit addictive, is it possible this opens the window to revisit all of the failed pharmaceuticals in the setting of hypothermia co-treatment? But before our excitement gets the best of us, it is worth noting that the surrogates Fei Han et al measured showed only limited additive effect, and definitely no synergy. The possibility that the combination of therapeutic hypothermia and the mechanistically-attractive-but-clinical-trial-failing pharma agents may be effective for ischemia-reperfusion injury may be the most exciting thing to happen in the field in quite some time. The results of Fei Han et al indicate that this is possible, and that we may be at the beginning of a long and fruitful development cycle of effective therapies. They are to be congratulated for helping to open this door a bit wider. Katelin M. Morrissette MD Norman A. Paradis MD http://dx.doi.org/10.1016/j.ajem.2016.02.070 References [1] Negovsky VA, Gurvitch AM. Post-resuscitation disease—a new nosological entity. Its reality and significance. Resuscitation 1995;30:23–7.
[2] Hossmann KA. Neuronal survival and revival during and after cerebral ischemia. Am J Emerg Med 1983;1:191–7. [3] Hossmann KA. Post-ischemic resuscitation of the brain: selective vulnerability versus global resistance. Prog Brain Res 1985;63:3–17. [4] Nevander G, Ingvar M, Auer R, Siesjö BK. Irreversible neuronal damage after short periods of status epilepticus. Acta Physiol Scand 1984;120:155–7. [5] Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974;54:1496–508. [6] Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest 1985;76:1713–9. [7] Sivaraman V, Mudalgiri NR, Salvo C, Kolvekar S, Hayward M, Yap J, et al. Postconditioning protects human atrial muscle through the activation of the RISK pathway. Basic Res Cardiol 2007;102:453–9. [8] Hausenloy DJ, Yellon DM. Time to take myocardial reperfusion injury seriously. N Engl J Med 2008;359:518–20. [9] Safar P, Peter S. Cerebral resuscitation after cardiac arrest: research initiatives and future directions. Ann Emerg Med 1993;22:324–49. [10] Safar P. Cerebral resuscitation after cardiac arrest: a review. Circulation 1986;74: IV138–53. [11] Brookes PS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. AJP Cell Physiol 2004;287:C817–33. [12] White BC, Sullivan JM, DeGracia DJ, O'Neil BJ, Neumar RW, Grossman LI, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000;179:1–33. [13] Chakraborti T, Das S, Mondal M, Roychoudhury S, Chakraborti S. Oxidant, mitochondria and calcium: an overview. Cell Signal 1999;11:77–85. [14] Halestrap A. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res 2004; 61:372–85. [15] Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 2006;34:232–7. [16] Hausenloy D. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia–reperfusion injury. Cardiovasc Res 2003;60: 617–25. [17] Xu L, Yenari MA, Steinberg GK, Giffard RG. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab 2002;22: 21–8. [18] Wang K, An T, Zhou L-Y, Liu C-Y, Zhang X-J, Feng C, et al. E2F1-regulated miR-30b suppresses cyclophilin D and protects heart from ischemia/ reperfusion injury and necrotic cell death. Cell Death Differ 2015;22: 743–54. [19] Osman MM, Lulic D, Glover L, Stahl CE, Lau T, van Loveren H, et al. Cyclosporine-A as a neuroprotective agent against stroke: its translation from laboratory research to clinical application. Neuropeptides 2011;45:359–68. [20] Lim WY, Messow CM, Berry C. Cyclosporin variably and inconsistently reduces infarct size in experimental models of reperfused myocardial infarction: a systematic review and meta-analysis. Br J Pharmacol 2012;165:2034–43. [21] Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359: 473–81. [22] Cung T-T, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 2015;373:1021–31. [23] Leger P-L, Pierre-Louis L, De Paulis D, Sonia B, Philippe B, Elisabeth C-L, et al. Evaluation of cyclosporine A in a stroke model in the immature rat brain. Exp Neurol 2011;230:58–66. [24] McConeghy KW, Jimmi H, Lindsey H, Cook AM. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs 2012;26:613–36. [25] Nighoghossian N, Berthezène Y, Mechtouff L, Derex L, Cho TH, Ritzenthaler T, et al. Cyclosporine in acute ischemic stroke. Neurology 2015;84:2216–23. [26] Song K, Wang S, Qi D. Effects of cyclosporine on reperfusion injury in patients: a meta-analysis of randomized controlled trials. Oxid Med Cell Longev 2015;2015: 1–6. [27] Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrestN Engl J Med 2002;346:549–56. [28] Nielsen N, Niklas N, Jørn W, Tobias C, David E, Yvan G, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med 2013;369: 2197–206.
Please cite this article as: Morrissette KM, Paradis NA, Should reperfusion be revisited?, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.02.070
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Editorial
Should reperfusion be revisited?☆ The article by Fei Han et al in this issue of the Journal may be an important bit of bench science. In a rodent model of global ischemia, they found that both the moderate-sized (cyclic non-ribosomal peptide) pharmaceutical drug cyclosporine and therapeutic hypothermia appear to blunt reperfusion related neuroinjury through similar mechanisms. Even more intriguingly, Fei Han et al provide a first indication that the pharmaceutical efficacy of cyclosporine and the physical efficacy of hypothermia may be somewhat additive. Before we can fully appreciate the potential importance of these results, a little bit of history is needed…. The possibility that much of the vital organ injury that follows ischemia may actually occur during reperfusion was inherent in the early insights of the Negofsky [1], Hossmann [2,3], and Siesjo [4]among others. The landmark studies of Kloner [5,6], Yellon, and others [7,8] clarified the hypothesis that this injury was fueled by the restoration of blood flow during resuscitation of patients in the setting of acute myocardial infarction, stroke, and cardiac arrest. The importance of reperfusion injury as a concept cannot be understated—if tissues enter a transiently stable state during ischemia, followed by injury during restoration of blood flow, then the opportunity to rescue patients clinically actually exists. If tissues were unalterably destined to complete the damage then vital organ ischemic injury would be untreatable. This makes “reperfusion injury” both an important pathophysiologic entity and a confusing bit of nomenclature. It begs the question—is not the worst possible outcome no reperfusion? We can address this conundrum with a definitional sleight of hand: “reperfusion injury” is the portion of the injury treatable after restoration of vital organ blood flow. In particular, therapies directed at reperfusion injury are intended to improve the outcome of penumbra regions that might actually have been better off with no reperfusion. Get it? Once we move past the definitional problems, our plate runneth over. At times it can seem as if almost every component of inflammation, metabolism, and cellular control mechanisms can be demonstrated to have some involvement in ischemia reperfusion injury. Peter Safer, in particular, was eloquent in his description of the multi-pathway cascade that typifies the phenomenon [9,10]. The last 40 years have at times felt like a flavor-of-the-month when it comes to describing the myriad molecular and cell signaling pathways involved in reperfusion injury. And that may be the problem. Once you comprehend how multifaceted the systems biology of reperfusion injury actually is, it is completely understandable that single-ligand pharmaceutical approaches have failed. While it has been relatively easy to demonstrate associations between reperfusion and any given molecular “change in concentration”,
☆ This editorial relates to the article published in this month's issue by Fei Han et al.
it has been difficult to determine which pathways are mechanistically important versus those that may simply be epiphenomenon. Calcium dishomeostasis, oxygen free radicals, lipid membrane damage, apoptosis; the list has gone on and on [5,11–13]. The challenge has been to identify a particular pathway that lies at the root of all these cascades. Even more concerning has been our inability to translate any of these molecular associations to effective bedside therapies. To date, other than the restoration of blood flow via thrombolytics or mechanical interventions, no drug directed at improving outcome in vital organ ischemia has clearly improved outcomes. The past few years has seen particular interest in the mitochondrial permeability transition pore (MPTP) as having a particularly important role in reperfusion injury [14–16]. As currently envisioned, the pore is a pathologic association of multiple molecular subunits that normally remain separate in the mitochondrial inner membrane. Once the components associate and form the pore, they allow pathologic flow of ions and proteins along with collapse of the proton motive gradient necessary for electron transport and energy production. These events also provide a pathway for initiation of programmed cell [17]. Look closely at the MPTP…see that subunit labeled cyclophilin D? It got that name because the drug cyclosporine fortuitously binds here. And the news gets even better—administration of cyclosporine appears to interfere with formation of the pore. In lab models, inhibition or depletion of cyclophilin D through either pharmacologic binding or even genetic knockout increases resistance to cell death [15,16,18]. However, we are still talking about ischemia reperfusion injury, so the translation from the bench to the clinic has been anything but smooth. In a pattern that should now seem familiar, efficacy in the lab and on near-term surrogate endpoints has been obtainable [15,16,18,19]; improved outcomes for patients? Not so much. Cyclosporine has been shown to reduce infarct size in laboratory models of coronary ischemia [20]. And in relatively small human trials in patients undergoing percuteaneous coronary intervention (PCI) for ST-elevation myocardial infarction, cyclosporine appeared to blunt the injury as measured by creatinine kinase and troponin [21]. Unfortunately, a more definitive trial found no significant difference in a composite endpoint composed of all cause mortality, worsening congestive heart failure, rehospitalization, and adverse remodeling [22]. The situation in neuroinjury has been similar. Early promise in the laboratory or Phase I trials [22–24] has failed to validate in Phase III trials in traumatic brain injury. In stroke, development of the drugs appears stuck at Phase II [25]. The failure of reperfusion therapies in the setting of acute myocardial infarction and PCI is particularly disappointing. Unlike resuscitation from cardiac arrest and stroke, in PCI we control reperfusion. Pharmacologic treatment can begin almost immediately, or even before the vessel is opened. The history of therapeutics for ischemia reperfusion injury is littered with agents that failed Phase III trials after promising laboratory and
0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Morrissette KM, Paradis NA, Should reperfusion be revisited?, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.02.070
2
K.M. Morrissette, N.A. Paradis / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Phase I/II studies; and cyclosporine now seems to be taking its place in this pantheon of failure [24,26]. Why? If the MPTP is central to reperfusion injury and we have an off the shelf drug to prevent its formation, shouldn't we be able to blunt the injury and improve the outcome of patients? The answer may lie in the numerous pathways and kinetics of ischemia reperfusion injury. By the time we get our hands on these patients, the primary initiating events may be long gone and all of the numerous downstream cascades widely activated. Adapting a useful metaphor—the genie is too completely out of the bottle. And so, is cyclosporine destined to join the long list of pharmaceuticals drugs that have failed to improve the clinical outcomes in vital organ ischemia reperfusion? Maybe not. After literally decades of the failure—along came therapeutic hypothermia and its apparent salutary effect after cardiac arrest [27]. While not clearly proven [28], it is clear to practitioners that something has changed in the outcome of patients suffering cardiac arrest. Good neurologic outcomes used to be so rare as to be topics of discussion. Now, some centers have survivors that number in the hundreds, without any other obvious change in therapy. Although, because it is relatively easy to apply, and without apparent significant toxicity, therapeutic hypothermia does violate the “too good to be true” rule of clinical medicine. Mechanistically, the efficacy of hypothermia is the opposite of single ligand pharmaceuticals—every molecule is affected. If it turns out to be true that it actually works for ischemia reperfusion injury, it will be because of the fortuitous circumstance that, net-net, this whole organism physical intervention improves outcome. And it is within that context that Fei Han et al results become particularly intriguing and exciting. If the salutary effect of therapeutic hypothermia and cyclosporine are even a bit addictive, is it possible this opens the window to revisit all of the failed pharmaceuticals in the setting of hypothermia co-treatment? But before our excitement gets the best of us, it is worth noting that the surrogates Fei Han et al measured showed only limited additive effect, and definitely no synergy. The possibility that the combination of therapeutic hypothermia and the mechanistically-attractive-but-clinical-trial-failing pharma agents may be effective for ischemia-reperfusion injury may be the most exciting thing to happen in the field in quite some time. The results of Fei Han et al indicate that this is possible, and that we may be at the beginning of a long and fruitful development cycle of effective therapies. They are to be congratulated for helping to open this door a bit wider. Katelin M. Morrissette MD Norman A. Paradis MD http://dx.doi.org/10.1016/j.ajem.2016.02.070 References [1] Negovsky VA, Gurvitch AM. Post-resuscitation disease—a new nosological entity. Its reality and significance. Resuscitation 1995;30:23–7.
[2] Hossmann KA. Neuronal survival and revival during and after cerebral ischemia. Am J Emerg Med 1983;1:191–7. [3] Hossmann KA. Post-ischemic resuscitation of the brain: selective vulnerability versus global resistance. Prog Brain Res 1985;63:3–17. [4] Nevander G, Ingvar M, Auer R, Siesjö BK. Irreversible neuronal damage after short periods of status epilepticus. Acta Physiol Scand 1984;120:155–7. [5] Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974;54:1496–508. [6] Braunwald E, Kloner RA. Myocardial reperfusion: a double-edged sword? J Clin Invest 1985;76:1713–9. [7] Sivaraman V, Mudalgiri NR, Salvo C, Kolvekar S, Hayward M, Yap J, et al. Postconditioning protects human atrial muscle through the activation of the RISK pathway. Basic Res Cardiol 2007;102:453–9. [8] Hausenloy DJ, Yellon DM. Time to take myocardial reperfusion injury seriously. N Engl J Med 2008;359:518–20. [9] Safar P, Peter S. Cerebral resuscitation after cardiac arrest: research initiatives and future directions. Ann Emerg Med 1993;22:324–49. [10] Safar P. Cerebral resuscitation after cardiac arrest: a review. Circulation 1986;74: IV138–53. [11] Brookes PS. Calcium, ATP, and ROS: a mitochondrial love-hate triangle. AJP Cell Physiol 2004;287:C817–33. [12] White BC, Sullivan JM, DeGracia DJ, O'Neil BJ, Neumar RW, Grossman LI, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000;179:1–33. [13] Chakraborti T, Das S, Mondal M, Roychoudhury S, Chakraborti S. Oxidant, mitochondria and calcium: an overview. Cell Signal 1999;11:77–85. [14] Halestrap A. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res 2004; 61:372–85. [15] Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 2006;34:232–7. [16] Hausenloy D. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia–reperfusion injury. Cardiovasc Res 2003;60: 617–25. [17] Xu L, Yenari MA, Steinberg GK, Giffard RG. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab 2002;22: 21–8. [18] Wang K, An T, Zhou L-Y, Liu C-Y, Zhang X-J, Feng C, et al. E2F1-regulated miR-30b suppresses cyclophilin D and protects heart from ischemia/ reperfusion injury and necrotic cell death. Cell Death Differ 2015;22: 743–54. [19] Osman MM, Lulic D, Glover L, Stahl CE, Lau T, van Loveren H, et al. Cyclosporine-A as a neuroprotective agent against stroke: its translation from laboratory research to clinical application. Neuropeptides 2011;45:359–68. [20] Lim WY, Messow CM, Berry C. Cyclosporin variably and inconsistently reduces infarct size in experimental models of reperfused myocardial infarction: a systematic review and meta-analysis. Br J Pharmacol 2012;165:2034–43. [21] Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359: 473–81. [22] Cung T-T, Morel O, Cayla G, Rioufol G, Garcia-Dorado D, Angoulvant D, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 2015;373:1021–31. [23] Leger P-L, Pierre-Louis L, De Paulis D, Sonia B, Philippe B, Elisabeth C-L, et al. Evaluation of cyclosporine A in a stroke model in the immature rat brain. Exp Neurol 2011;230:58–66. [24] McConeghy KW, Jimmi H, Lindsey H, Cook AM. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs 2012;26:613–36. [25] Nighoghossian N, Berthezène Y, Mechtouff L, Derex L, Cho TH, Ritzenthaler T, et al. Cyclosporine in acute ischemic stroke. Neurology 2015;84:2216–23. [26] Song K, Wang S, Qi D. Effects of cyclosporine on reperfusion injury in patients: a meta-analysis of randomized controlled trials. Oxid Med Cell Longev 2015;2015: 1–6. [27] Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrestN Engl J Med 2002;346:549–56. [28] Nielsen N, Niklas N, Jørn W, Tobias C, David E, Yvan G, et al. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med 2013;369: 2197–206.
Please cite this article as: Morrissette KM, Paradis NA, Should reperfusion be revisited?, Am J Emerg Med (2016), http://dx.doi.org/10.1016/ j.ajem.2016.02.070