Will the Promise of Drug-Induced Therapeutic Hypothermia Be Fulfilled?* Maximilian Mulder, MD Department of Neurology Department of Anesthesia and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore, MD Romergryko G. Geocadin, MD Department of Neurology Department of Anesthesia and Critical Care Medicine Department of Neurosurgery Department of Medicine Johns Hopkins University School of Medicine Baltimore, MD
T
herapeutic hypothermia (TH) has rapidly become one of the cornerstones of modern postresuscitation treatment of comatose cardiac arrest survivors (1, 2). The success of TH as an intervention is most like due to its pleiotropic action and its ability to ameliorate the brain injury at multiple points of cell injury cascade (3). TH induced by physical means, with its demonstrated ability to decrease mortality and improve neurologic outcomes in ventricular tachycardia and fibrillation (VT/VF) arrests, sets it apart from a long list of pharmacologie interventions with putative neuroprotective effects that failed to translate the outcome benefits from encouraging animal experiments into human clinical trials (4-8). In additional to its effect on VT/VF, TH seems likely to benefit patients with other forms of cardiac arrest (9, 10). The success of TH in cardiac arrest survivors has led to the adaptation and implementation of the therapy across medical institutions and renewed interest for TH in other acute neurologic illnesses, such as acute stroke, traumatic brain and spinal cord injuries, seizures and subarachnoid hemorrhage, and systemic illness such as myocardial infarction (11-15). This interest is accompanied by the realization of the limiting factors of TH induced by physical cooling, including cost and access to equipment and supplies, as well as the safety and stability of temperature control at different phases of the therapy.
*See also p. e42. Key Words: cannabinoid receptor agonist; neuroprotection; therapeutic hypothermia; WIN55, 21 2-2 Dr. Geocadin is supported, in part, by National Institutes of Health (grants 5R01 HL071 568 and R01 NS074425). He provided expert testimony for Medicolegal Firm and received support for travel from the American Heart Association. His institution received grant support from the NIH (coinvestigator in NIH grants). Dr. Mulder has disclosed that he does not have any potential conflicts of interest. Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3182a12275
Critical Care Medicine
Additional limitations include the difficulty of delivering TH in the field, during transport and in certain areas of the hospital. Considering the limitations of physically induced and maintained TH, alternate means to induce and maintain TH have been a promising endeavor. In this issue of Critical Care Medicine, Ma et al (16) build on their previous publications on pharmacologie induction of hypothermia by cannabinoid (CB) receptor agonists and attempt to clarify the mechanisms by which this intervention ameliorates injury (17-18). In those studies. Sun et al previously demonstrated the cardiac and neuroprotective properties of the nonselective CB receptor agonist WIN55,212-2 induced TH in rats ( 17). In the present study, they set out to determine if the cardiac protective effect as assessed by echocardiography and the neuroprotective effects assessed by neurologic functional outcome of WIN55,212-2 are provided by the reduction in temperature versus some nontemperature-related action provided by WIN55, 212-2. The experiment included 30 adult rats with induced VF that were resuscitated without pharmacologie intervention after 6 minutes of arrest. With investigator blinded, the rats were randomized into two treatment groups and one placebo control group (n = 10/group). Half an hour after return of spontaneous circulation, the rats received 2-hour infusions of WIN55,212-2 in the treatment groups or placebo in the control group. The difference between the two treatment groups consisted in allowing one group to become hypothermie (33.4°C ± 0.4°C) due to the study drug effect, while both the second treatment group and the control group were maintained at normothermia with heating lamps. The hypothermie group that received the CB receptor agonist reached temperatures of 35.1°C ± 0.1°C within an hour of initiating the infusion and reached target temperature of 33°C at 4 hours after starting the infusion. Hypothermie rats returned to normothermia at an average of 5 hours after one injection. After resuscitation, the study variables, such as heart rate, hemodynamic and echocardiographic variables, end-tidal carbon dioxide, urine output, survival and survival time, and neurologic deficit scores (NDSs), were recorded. The rats were euthanized after 72 hours to evaluate for cardiopulmonary resuscitation-related injuries, of which none were found. The study showed that the rats that received WIN55, 212-2 and were allowed to become hypothermie had significant improvement in survival and NDSs, as well as improved echocardiographic surrogates for cardiac function and perfusion. These results are in keeping with the group's previous findings, and the bradycardia and relative polyuria (cold diuresis) are findings consistent with a hypothermie state. The rats treated with WIN55, 212-2 which were not allowed to become hypothermic did not show any of the beneficial findings noted in the treatment group that were allowed to be become hypothermie. These findings demonstrate that the benefit derived from www.ccnnjournal.org
221
Editorials
treatment with WIN55, 212-2 is likely a result of temperature change and suggest that the protective effects are unlikely the result of direct pharmacologie effect of the drug considering that forced normothermia did not result in therapeutic benefit. Although it is promising to see this beneficial effect, it is crucial to compare the benefits of drug-induced hypothermia with that of physical cooling. Considering that we do not really know how physical cooling provides its benefit, a positive control arm is needed to understand if the benefits come from the reset of the brain's temperature set point with drugs or simply the physical induction of hypothermia, overriding the bodies temperature control mechanisms. This study has other limitations including short-term follow-up, lack of histopathologic examination, and the use of a small rodent model, which were also noted in some of their previous work evaluating the effects of other compounds (17-19). As promising as this research appears, it is important to remember that despite the numerous pharmacologie agents developed over the last few decades with putative neuroprotective effects, no agent has been successfully translated from preclinical development to clinical trials in humans with acute brain ischemia, be it focal or global. In light of these challenges, several recommendations for translational science and clinical resuscitation research have been published in an attempt to improve the research, optimize the chances of success, and help allow comparability of future studies (20-22). Some of the important considerations in the preclinical and translational work include the use of model systems that closely represents of the human condition, with the study designs that include adequate sample size, randomization, and blinding of drug allocation. These studies should demonstrate relevant dose response, define a therapeutic window, provide physiologic monitoring, show success and reproducibility across multiple species, and include outcome measures that are relevant and interpretable in light of the human condition. The development of these agents must also emphasize safety tolerability as well as no adverse behavioral effects. Although this study has incorporated some of these recommendations, WIN55, 212-2 has already raised concern for negative effects on cognitive function in rats (23). Several agents have been studied in this area, such as CB receptor agonists WIN55, 212-2 and HU-210, cholecystokinin octapeptide, poly(adenosine diphosphate-ribose) polymerase inhibitor GPI-6150 x, and transient receptor potential vanilloid type 1 agonist dihydrocapsaicin. All drugs are capable of inducing hypothermia and have putative neuroprotective mechanisms (17, 19, 24-26). After many failed translational and chnical trials in neuroprotection for focal and global brain ischemia, many investigators and institutions have understandably lost enthusiasm in this area of drug development. However, TH has shown that injury in global brain ischemia can be ameliorated. It is evident that the success of TH is again promoting interest in the development of pharmacologie neuroprotection. As we move forward with renewed enthusiasm in this area of research, let us do so in more insightful ways and equip ourselves with meaningful experiences so as to avoid the costly and frustrating pitfalls of the recent past. We owe this 222
WWW.ccmjournal.org
not only to ourselves, our field of research, and clinical practice but most importantly to our patients.
REFERENCES 1. Nolan JP, Morley PT, Vanden Hoek TL, et al; International Liaison Committee on Resuscitation: Therapeutic hypothermia after cardiac arrest: An advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Oirculation 2003; 108;118-121 2. International Liaison Committee on Resuscitation: 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 2: Adult basic life support. Resuscitation 2005; 67:187-201 3. Froehler MT, Geocadin RG: Hypothermia for neuroproteotion after cardiac arrest: Mechanisms, clinical trials and patient care. J Neuroi Sc/2007; 261:118-126 4. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial I Study Group. N Engt J Med 1986; 314:397-403 5. Roine RC, Kaste M, Kinnunen A, et al: Nimodipine after resuscitation from out-of-hospital ventricular fibrillation. A placebo-controlled, double-blind, randomized trial. JAMA 1990; 264:3171-3177 6. A randomized clinioal trial of calcium entry blooker administration to comatose survivors of cardiac arrest design, methods, and patient characteristics. Brain Resuscitation Clinical Trial II Study Group. Oontrol Olin Trials 1 991 ; 1 2:525-545 7. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial II Study Group. N Engt J Med 1991; 324:1225-1231 8. Longstreth WT Jr, Fahrenbruch CE, CIsufka M, et al: Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology 2002; 59:506-514 9. Testori C, Sterz F, Behringer W, et al: Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. Resuscitation 2011 ; 82:1162-11 67 10. Lundbye JB, Rai M, Ramu B, et al: Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation 2012; 83:202-207 11. Lyden PD, Allgren RL, Ng K, et al: Intravascular Cooling in the Treatment of Stroke (ICTuS): Early clinical experience. J Stroke Oerebrovasc Dis 2005; 14:107-114 1 2. Ahmad F, Wang MY, Levi AD: Hypothermia for acute spinal cord injury-A review. World Neurosurg 2013 Jan 5. [Epub ahead of print] 13. Wang Y, Liu PP, Li LY, et al: Hypothermia reduces brain edema, spontaneous recurrent seizure attack, and learning memory deficits in the kainic acid treated rats. ONS Neurosci Ther 2011; 17:271-280 14. Anei R, Sakai H, lihara K, et al: Effectiveness of brain hypothermia treatment in patients with severe subarachnoid hemorrhage: Comparisons at a single facility. Neurot Med Ohir (Tokyo) 201 0; 50: 879-883 15. Schwartz BG, Kloner RA, Thomas JL, et al: Therapeutic hypothermia for acute myocardial infarction and cardiac arrest. Am J Oardiol 2012; 110:461-466 16. Ma L, Lu X, Xu J, et al: Improved Cardiac and Neurological Outcomes With Postresuscitation Infusion of Cannabinoid Receptor Agonist WIN55, 212-2 Depend on Hypothermia in a Rat Model of Cardiac Arrest. Orit Oare Med 2014; 42:e42-e48 17. Sun S, Tang W, Song F, et al: Pharmacologically induced hypothermia with cannabinoid receptor agonist WIN55, 21 2-2 after cardiopulmonary resuscitation. Orit Oare Med 2010; 38:2282-2286 18. Weng Y, Sun S, Park J, et al: Cannabinoid 1 (CB1 ) receptor mediates WIN55, 212-2 induced hypothermia and improved survival in a rat post-cardiac arrest model. Resuscitation 2012; 83:1145-1151 19. Weng Y, Sun S, Song F, et al: Cholecystokinin octapeptide induces hypothermia and improves outoomes in a rat model of cardiopulmonary resuscitation. Orit Oare Med 2011 ; 39:2407-241 2 January 2014 • Volume 42 • Number 1
Editorials 20. Becker LB, Weisfeldt ML, Weil MH, et al: The PULSE initiative: Scientific priorities and strategic planning for resuscitation research and life saving therapies. Circulation 2002; 105:2562-2570 21. Fisher M, Feuerstein G, Howells DW, et al; STAIR Group: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009; 40:2244-2250 22. Becker LB, Aufderheide TP, Geocadin RG, et al; American Heart Association Emergency Cardiovascular Care Committee; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation: Primary outcomes for resuscitation science studies: A consensus statement from the American Heart Association. Circulation 2011 ; 1 24:2158-2177 23. Ferraro L, Tomasini MC, Beggiato S, et al: Short- and long-term consequences of prenatal exposure to the cannabinoid agonist
WIN55,212-2 on rat glutamate transmission and cognitive functions. J Neural Transm 2009; 11 6:1017-1027 24. Leker RR, Gai N, Mechouiam R, et al: Drug-induced hypothermia reduces ischémie damage: Effects of the cannabinoid HU-210. Stroke 2003; 34:2000-2006 25. Feng Y, LeBlanc MH: Drug-induced hypothermia begun 5 minutes after injury with a poly(adenosine 5'-diphosphate-ribose) polymerase inhibitor reduces hypoxic brain injury in rat pups. Cdt Care Med 2002; 30:2420-2424 26. Fosgerau K, Weber UJ, Gotfredsen JW, et al: Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist. BMC Cardiovasc Disord 2010; 10:51
Compartmentalization of Lung Injury—Atelectasis Versus Overstretch* Maurizio Cereda, MD Departnnent of Anesthesiclogy and Critical Care University of Pennsylvania Philadelphia, PA
Stretch") or low V.^. with neither PEEP nor recruitment maneuvers (termed "atelectasis") (3). While both strategies caused lung injury, substantial levels of circulating inflammatory mediators were detected only in the "high-stretch" group; furthermore, circulating mediators depended on marginated pulmonary vascuBrian P. Kavanagh, MB, FRCPC lar monocytes. The study was performed in isolated, perñised mouse lungs that were not preinjured; naturally, extrapolation Department of Critical Care Medicine; and to clinical care requires considerable caution. Department of Anesthesia Hospital for Sick Children This study (3) has important strengths: the authors were University of Toronto able to separate some effects of high V.^. from those of ateleeToronto, ON, Canada tasis; this is crucial because while many studies report on the effects of high V.^, atelectasis can be difficult to study. In small mammals, extensive atelectasis can be fatal (4), likely because xtensive experimental evidence suggests that protecof acute right heart failure (5); the current investigators (3) tive ventilation in acute respiratory distress syndrome (ARDS) has two components: minimization of tidal bypassed this problem by using an artificial pump to perfuse stretch (avoidance of excessive tidal volume [V.^]) and recruit- the lung. Atelectasis per se resulted in minimal circulating mediators, and this led the investigators to discover a cellular ment of atelectatic lung ("open" lung) (1). Although the basis (i.e., marginated monoeytes) for the mediators induced importance of Vj. has been proved (2), many clinical trials have by high V.J. failed to show benefit from various efforts to "open" injured The higher V.^ here is massive by clinical standards; howlungs in ARDS. In trying to understand this problem, the artiever, mouse models of ventilator-induced lung injury (VILI) cle by Wakabayashi et al in this issue of Critical Care Medicine require V. J . of up to 50 mL/kg body weight—an order of magprovides helpful insight (3). nitude greater than targeted in patients with ARDS. In addiLung injury was induced in one of two ways: high V.^ with low tion, although others (6) have used a similar model to show levels of positive end-expiratory pressure (PEEP) (termed "high that lung-derived circulating mediators augment lung injury, causal linkage of individual mediators to VILI (or systemic *See also p. e49. organ failure) is a challenge. Key Words: acute respiratory distress syndrome; alveolar recruitment; ateiectasis; mechanical ventilation; ventilator-associated lung injury What is not clear from this study is why lung stretch actiDr. Cereda is supported by a grant from the Foundation for Anesthesia vates lung monocytes but atelectasis does not. The answer Education and Research and the Society of Critical Care Anesthesiolomay lie in the different anatomical basis for injury induced gists. Dr. Kavanagh holds the Dr. Geoffrey Barker Chair in Critical Care by stretch versus that induced by atelectasis. According to the Medicine and his research is supported by operating grants from the Canadian Institutes of Health Research. original concept of "atelectrauma," mechanical stress generDr. Cereda received grant support from the Foundation for Anesthesia ated by repetitive airway opening and closing causes injury Education and Research. Dr. Kavanagh disclosed that he does not have and inflammation (7) and earlier data record the coexisany potential conflicts of interest. tence—but not colocalization—of atelectasis and injury (8). Copyright © 2013 by the Society of Critical Care Medicine and Lippincott However, stereologic analysis from an in vivo small animal Williams & Wilkins model characterized by dorsal atelectasis and ventral aeration DOI:10.1097/CCM.0b013e3182a264ed
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Critical Care Medicine
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T
herapeutic hypothermia (TH) has rapidly become one of the cornerstones of modern postresuscitation treatment of comatose cardiac arrest survivors (1, 2). The success of TH as an intervention is most like due to its pleiotropic action and its ability to ameliorate the brain injury at multiple points of cell injury cascade (3). TH induced by physical means, with its demonstrated ability to decrease mortality and improve neurologic outcomes in ventricular tachycardia and fibrillation (VT/VF) arrests, sets it apart from a long list of pharmacologie interventions with putative neuroprotective effects that failed to translate the outcome benefits from encouraging animal experiments into human clinical trials (4-8). In additional to its effect on VT/VF, TH seems likely to benefit patients with other forms of cardiac arrest (9, 10). The success of TH in cardiac arrest survivors has led to the adaptation and implementation of the therapy across medical institutions and renewed interest for TH in other acute neurologic illnesses, such as acute stroke, traumatic brain and spinal cord injuries, seizures and subarachnoid hemorrhage, and systemic illness such as myocardial infarction (11-15). This interest is accompanied by the realization of the limiting factors of TH induced by physical cooling, including cost and access to equipment and supplies, as well as the safety and stability of temperature control at different phases of the therapy.
*See also p. e42. Key Words: cannabinoid receptor agonist; neuroprotection; therapeutic hypothermia; WIN55, 21 2-2 Dr. Geocadin is supported, in part, by National Institutes of Health (grants 5R01 HL071 568 and R01 NS074425). He provided expert testimony for Medicolegal Firm and received support for travel from the American Heart Association. His institution received grant support from the NIH (coinvestigator in NIH grants). Dr. Mulder has disclosed that he does not have any potential conflicts of interest. Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3182a12275
Critical Care Medicine
Additional limitations include the difficulty of delivering TH in the field, during transport and in certain areas of the hospital. Considering the limitations of physically induced and maintained TH, alternate means to induce and maintain TH have been a promising endeavor. In this issue of Critical Care Medicine, Ma et al (16) build on their previous publications on pharmacologie induction of hypothermia by cannabinoid (CB) receptor agonists and attempt to clarify the mechanisms by which this intervention ameliorates injury (17-18). In those studies. Sun et al previously demonstrated the cardiac and neuroprotective properties of the nonselective CB receptor agonist WIN55,212-2 induced TH in rats ( 17). In the present study, they set out to determine if the cardiac protective effect as assessed by echocardiography and the neuroprotective effects assessed by neurologic functional outcome of WIN55,212-2 are provided by the reduction in temperature versus some nontemperature-related action provided by WIN55, 212-2. The experiment included 30 adult rats with induced VF that were resuscitated without pharmacologie intervention after 6 minutes of arrest. With investigator blinded, the rats were randomized into two treatment groups and one placebo control group (n = 10/group). Half an hour after return of spontaneous circulation, the rats received 2-hour infusions of WIN55,212-2 in the treatment groups or placebo in the control group. The difference between the two treatment groups consisted in allowing one group to become hypothermie (33.4°C ± 0.4°C) due to the study drug effect, while both the second treatment group and the control group were maintained at normothermia with heating lamps. The hypothermie group that received the CB receptor agonist reached temperatures of 35.1°C ± 0.1°C within an hour of initiating the infusion and reached target temperature of 33°C at 4 hours after starting the infusion. Hypothermie rats returned to normothermia at an average of 5 hours after one injection. After resuscitation, the study variables, such as heart rate, hemodynamic and echocardiographic variables, end-tidal carbon dioxide, urine output, survival and survival time, and neurologic deficit scores (NDSs), were recorded. The rats were euthanized after 72 hours to evaluate for cardiopulmonary resuscitation-related injuries, of which none were found. The study showed that the rats that received WIN55, 212-2 and were allowed to become hypothermie had significant improvement in survival and NDSs, as well as improved echocardiographic surrogates for cardiac function and perfusion. These results are in keeping with the group's previous findings, and the bradycardia and relative polyuria (cold diuresis) are findings consistent with a hypothermie state. The rats treated with WIN55, 212-2 which were not allowed to become hypothermic did not show any of the beneficial findings noted in the treatment group that were allowed to be become hypothermie. These findings demonstrate that the benefit derived from www.ccnnjournal.org
221
Editorials
treatment with WIN55, 212-2 is likely a result of temperature change and suggest that the protective effects are unlikely the result of direct pharmacologie effect of the drug considering that forced normothermia did not result in therapeutic benefit. Although it is promising to see this beneficial effect, it is crucial to compare the benefits of drug-induced hypothermia with that of physical cooling. Considering that we do not really know how physical cooling provides its benefit, a positive control arm is needed to understand if the benefits come from the reset of the brain's temperature set point with drugs or simply the physical induction of hypothermia, overriding the bodies temperature control mechanisms. This study has other limitations including short-term follow-up, lack of histopathologic examination, and the use of a small rodent model, which were also noted in some of their previous work evaluating the effects of other compounds (17-19). As promising as this research appears, it is important to remember that despite the numerous pharmacologie agents developed over the last few decades with putative neuroprotective effects, no agent has been successfully translated from preclinical development to clinical trials in humans with acute brain ischemia, be it focal or global. In light of these challenges, several recommendations for translational science and clinical resuscitation research have been published in an attempt to improve the research, optimize the chances of success, and help allow comparability of future studies (20-22). Some of the important considerations in the preclinical and translational work include the use of model systems that closely represents of the human condition, with the study designs that include adequate sample size, randomization, and blinding of drug allocation. These studies should demonstrate relevant dose response, define a therapeutic window, provide physiologic monitoring, show success and reproducibility across multiple species, and include outcome measures that are relevant and interpretable in light of the human condition. The development of these agents must also emphasize safety tolerability as well as no adverse behavioral effects. Although this study has incorporated some of these recommendations, WIN55, 212-2 has already raised concern for negative effects on cognitive function in rats (23). Several agents have been studied in this area, such as CB receptor agonists WIN55, 212-2 and HU-210, cholecystokinin octapeptide, poly(adenosine diphosphate-ribose) polymerase inhibitor GPI-6150 x, and transient receptor potential vanilloid type 1 agonist dihydrocapsaicin. All drugs are capable of inducing hypothermia and have putative neuroprotective mechanisms (17, 19, 24-26). After many failed translational and chnical trials in neuroprotection for focal and global brain ischemia, many investigators and institutions have understandably lost enthusiasm in this area of drug development. However, TH has shown that injury in global brain ischemia can be ameliorated. It is evident that the success of TH is again promoting interest in the development of pharmacologie neuroprotection. As we move forward with renewed enthusiasm in this area of research, let us do so in more insightful ways and equip ourselves with meaningful experiences so as to avoid the costly and frustrating pitfalls of the recent past. We owe this 222
WWW.ccmjournal.org
not only to ourselves, our field of research, and clinical practice but most importantly to our patients.
REFERENCES 1. Nolan JP, Morley PT, Vanden Hoek TL, et al; International Liaison Committee on Resuscitation: Therapeutic hypothermia after cardiac arrest: An advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Oirculation 2003; 108;118-121 2. International Liaison Committee on Resuscitation: 2005 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Part 2: Adult basic life support. Resuscitation 2005; 67:187-201 3. Froehler MT, Geocadin RG: Hypothermia for neuroproteotion after cardiac arrest: Mechanisms, clinical trials and patient care. J Neuroi Sc/2007; 261:118-126 4. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial I Study Group. N Engt J Med 1986; 314:397-403 5. Roine RC, Kaste M, Kinnunen A, et al: Nimodipine after resuscitation from out-of-hospital ventricular fibrillation. A placebo-controlled, double-blind, randomized trial. JAMA 1990; 264:3171-3177 6. A randomized clinioal trial of calcium entry blooker administration to comatose survivors of cardiac arrest design, methods, and patient characteristics. Brain Resuscitation Clinical Trial II Study Group. Oontrol Olin Trials 1 991 ; 1 2:525-545 7. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. Brain Resuscitation Clinical Trial II Study Group. N Engt J Med 1991; 324:1225-1231 8. Longstreth WT Jr, Fahrenbruch CE, CIsufka M, et al: Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest. Neurology 2002; 59:506-514 9. Testori C, Sterz F, Behringer W, et al: Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. Resuscitation 2011 ; 82:1162-11 67 10. Lundbye JB, Rai M, Ramu B, et al: Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms. Resuscitation 2012; 83:202-207 11. Lyden PD, Allgren RL, Ng K, et al: Intravascular Cooling in the Treatment of Stroke (ICTuS): Early clinical experience. J Stroke Oerebrovasc Dis 2005; 14:107-114 1 2. Ahmad F, Wang MY, Levi AD: Hypothermia for acute spinal cord injury-A review. World Neurosurg 2013 Jan 5. [Epub ahead of print] 13. Wang Y, Liu PP, Li LY, et al: Hypothermia reduces brain edema, spontaneous recurrent seizure attack, and learning memory deficits in the kainic acid treated rats. ONS Neurosci Ther 2011; 17:271-280 14. Anei R, Sakai H, lihara K, et al: Effectiveness of brain hypothermia treatment in patients with severe subarachnoid hemorrhage: Comparisons at a single facility. Neurot Med Ohir (Tokyo) 201 0; 50: 879-883 15. Schwartz BG, Kloner RA, Thomas JL, et al: Therapeutic hypothermia for acute myocardial infarction and cardiac arrest. Am J Oardiol 2012; 110:461-466 16. Ma L, Lu X, Xu J, et al: Improved Cardiac and Neurological Outcomes With Postresuscitation Infusion of Cannabinoid Receptor Agonist WIN55, 212-2 Depend on Hypothermia in a Rat Model of Cardiac Arrest. Orit Oare Med 2014; 42:e42-e48 17. Sun S, Tang W, Song F, et al: Pharmacologically induced hypothermia with cannabinoid receptor agonist WIN55, 21 2-2 after cardiopulmonary resuscitation. Orit Oare Med 2010; 38:2282-2286 18. Weng Y, Sun S, Park J, et al: Cannabinoid 1 (CB1 ) receptor mediates WIN55, 212-2 induced hypothermia and improved survival in a rat post-cardiac arrest model. Resuscitation 2012; 83:1145-1151 19. Weng Y, Sun S, Song F, et al: Cholecystokinin octapeptide induces hypothermia and improves outoomes in a rat model of cardiopulmonary resuscitation. Orit Oare Med 2011 ; 39:2407-241 2 January 2014 • Volume 42 • Number 1
Editorials 20. Becker LB, Weisfeldt ML, Weil MH, et al: The PULSE initiative: Scientific priorities and strategic planning for resuscitation research and life saving therapies. Circulation 2002; 105:2562-2570 21. Fisher M, Feuerstein G, Howells DW, et al; STAIR Group: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 2009; 40:2244-2250 22. Becker LB, Aufderheide TP, Geocadin RG, et al; American Heart Association Emergency Cardiovascular Care Committee; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation: Primary outcomes for resuscitation science studies: A consensus statement from the American Heart Association. Circulation 2011 ; 1 24:2158-2177 23. Ferraro L, Tomasini MC, Beggiato S, et al: Short- and long-term consequences of prenatal exposure to the cannabinoid agonist
WIN55,212-2 on rat glutamate transmission and cognitive functions. J Neural Transm 2009; 11 6:1017-1027 24. Leker RR, Gai N, Mechouiam R, et al: Drug-induced hypothermia reduces ischémie damage: Effects of the cannabinoid HU-210. Stroke 2003; 34:2000-2006 25. Feng Y, LeBlanc MH: Drug-induced hypothermia begun 5 minutes after injury with a poly(adenosine 5'-diphosphate-ribose) polymerase inhibitor reduces hypoxic brain injury in rat pups. Cdt Care Med 2002; 30:2420-2424 26. Fosgerau K, Weber UJ, Gotfredsen JW, et al: Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist. BMC Cardiovasc Disord 2010; 10:51
Compartmentalization of Lung Injury—Atelectasis Versus Overstretch* Maurizio Cereda, MD Departnnent of Anesthesiclogy and Critical Care University of Pennsylvania Philadelphia, PA
Stretch") or low V.^. with neither PEEP nor recruitment maneuvers (termed "atelectasis") (3). While both strategies caused lung injury, substantial levels of circulating inflammatory mediators were detected only in the "high-stretch" group; furthermore, circulating mediators depended on marginated pulmonary vascuBrian P. Kavanagh, MB, FRCPC lar monocytes. The study was performed in isolated, perñised mouse lungs that were not preinjured; naturally, extrapolation Department of Critical Care Medicine; and to clinical care requires considerable caution. Department of Anesthesia Hospital for Sick Children This study (3) has important strengths: the authors were University of Toronto able to separate some effects of high V.^. from those of ateleeToronto, ON, Canada tasis; this is crucial because while many studies report on the effects of high V.^, atelectasis can be difficult to study. In small mammals, extensive atelectasis can be fatal (4), likely because xtensive experimental evidence suggests that protecof acute right heart failure (5); the current investigators (3) tive ventilation in acute respiratory distress syndrome (ARDS) has two components: minimization of tidal bypassed this problem by using an artificial pump to perfuse stretch (avoidance of excessive tidal volume [V.^]) and recruit- the lung. Atelectasis per se resulted in minimal circulating mediators, and this led the investigators to discover a cellular ment of atelectatic lung ("open" lung) (1). Although the basis (i.e., marginated monoeytes) for the mediators induced importance of Vj. has been proved (2), many clinical trials have by high V.J. failed to show benefit from various efforts to "open" injured The higher V.^ here is massive by clinical standards; howlungs in ARDS. In trying to understand this problem, the artiever, mouse models of ventilator-induced lung injury (VILI) cle by Wakabayashi et al in this issue of Critical Care Medicine require V. J . of up to 50 mL/kg body weight—an order of magprovides helpful insight (3). nitude greater than targeted in patients with ARDS. In addiLung injury was induced in one of two ways: high V.^ with low tion, although others (6) have used a similar model to show levels of positive end-expiratory pressure (PEEP) (termed "high that lung-derived circulating mediators augment lung injury, causal linkage of individual mediators to VILI (or systemic *See also p. e49. organ failure) is a challenge. Key Words: acute respiratory distress syndrome; alveolar recruitment; ateiectasis; mechanical ventilation; ventilator-associated lung injury What is not clear from this study is why lung stretch actiDr. Cereda is supported by a grant from the Foundation for Anesthesia vates lung monocytes but atelectasis does not. The answer Education and Research and the Society of Critical Care Anesthesiolomay lie in the different anatomical basis for injury induced gists. Dr. Kavanagh holds the Dr. Geoffrey Barker Chair in Critical Care by stretch versus that induced by atelectasis. According to the Medicine and his research is supported by operating grants from the Canadian Institutes of Health Research. original concept of "atelectrauma," mechanical stress generDr. Cereda received grant support from the Foundation for Anesthesia ated by repetitive airway opening and closing causes injury Education and Research. Dr. Kavanagh disclosed that he does not have and inflammation (7) and earlier data record the coexisany potential conflicts of interest. tence—but not colocalization—of atelectasis and injury (8). Copyright © 2013 by the Society of Critical Care Medicine and Lippincott However, stereologic analysis from an in vivo small animal Williams & Wilkins model characterized by dorsal atelectasis and ventral aeration DOI:10.1097/CCM.0b013e3182a264ed
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