Editorials Cooperative sedation may be obtained through different pro tocols of sedation. In all instances, it requires a team approach dedicated to obtain patient cooperation and cognitive enhance ment, adequate physician and nurse staffing, and frequent assess ment of delirium. The pharmacological approach is im portant to consider but is only one factor of a multicomponent strategy to prevent or treat delirium.
REFERENCES 1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care M ed 2013; 4 1 :2 6 3 -3 0 6
Systematic Review and 4 3 :1 9 4 -2 0 4
Metaanalysis.
Crit
Care
M ed 2015;
6. Benbenbishty J, Adam S, Endacott R: Physical restraint use in inten sive care units across Europe: The PRICE study. Intensive Crit Care Nurs 2010; 2 6 :2 4 1 -2 4 5 7. McPherson JA, Wagner CE, Boehm LM, et al: Delirium in the cardio vascular ICU: Exploring modifiable risk factors. Crit Care Med 2013; 4 1 :4 0 5 -4 1 3 8. Pandharipande PP, Pun BT, Herr DL, et al: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechani cally ventilated patients: The M ENDS randomized controlled trial. JAMA 2007; 2 9 8 :2 6 4 4 -2 6 5 3 9. Andresen JM, Girard TD, Pandharipande PP, et al: Burst suppression on processed electroencephalography as a predictor of postcoma delirium in mechanically ventilated ICU patients. Crit Care M ed 2014; 4 2 :22 4 4 -2 25 1
2. Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators: Long-term cognitive impairment after critical illness. N Engl J M ed 2013; 3 6 9 :1 3 0 6 -1 3 1 6
10. Dieleman JM, Nierich AP, Rosseel PM, et al; Dexamethasone for Cardiac Surgery (DECS) Study Group: Intraoperative high-dose dexamethasone for cardiac surgery: A randomized controlled trial. JAMA 2012; 308:1761 -17 6 7
3. van Eijk MM, Roes KC, Honing ML, et al: Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: A multicentre, double-blind, placebocontrolled randomised trial. Lancet 2010; 3 7 6 :1 8 2 9 -18 3 7
11. Skrobik Y, Leger C, Cossette M, et al: Factors predisposing to coma and delirium: Fentanyl and midazolam exposure; CYP3A5, ABCB1, and A B C G 2 genetic polymorphisms; and inflammatory factors. C rit Care Med 2013; 4 1 :9 9 9 -1 008
4. Al-Qadheeb NS, Balk EM, Fraser GL, et al: Randomized ICU trials do not demonstrate an association between interventions that reduce delirium duration and short-term mortality: A systematic review and meta-analysis. Crit Care Med 2014; 4 2 :1 4 4 2 -1 4 5 4
1 2. Sauer AM, Slooter AJ, Veldhuijzen DS, et al: Intraoperative dexameth asone and delirium after cardiac surgery: A randomized clinical trial. Anesth Analg 2014; 1 1 9 :1 0 4 6 -1 0 5 2
5. Mu JL, Lee A, Joynt GM: Pharmacological Agents for the Prevention and Treatment of Delirium in Patients Undergoing Cardiac Surgery:
13. Inouye SK, Bogardus ST Jr, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J M e d t 999; 3 4 0 :6 6 9 -6 7 6
Tourniqueting the Limbs, the New Chest Compression in Cardiopulmonary Resuscitation* Nicolas Segal, MD, PhD Services des Urgences Universite Paris Diderot Sorbonne Paris Cite, UMRS 942, AP-HP Hopital Lariboisiere Paris, France s many as one third of a million out-of-hospital car diac arrests occur every year in the United States. D uring half a century, research focused on im proving the quality of chest compression to increase blood circula tion. Today, the treatm ent of this circulatory phase is p rob ably as good as it can be with the adjunction of mechanical chest compression, the use of impedance threshold device, and a better control of ventilation.
A
*See also p. el2 . Key Words: cardiac arrest; cardiopulmonary resuscitation; ischemicreperfusion injury; remote postconditioning; remote preconditioning The author has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0000000000000729
Critical Care Medicine
In the last 10 years, research has shifted from treating the lesion that occurs during the circulatory phase to treating the ones happening during the metabolic phase. Several pathologic mechanisms occur concomitantly during this phase: reactive oxygen species production, energy production defect, hypoxia, sometimes hyperoxia, and inflammation. At the same time, several pathways of treatm ent have been studied: cyclosporine A and NIM 811 (1), sodium nitroprusside (2), ischemic post conditioning (3), oxygen level control (4), and steroids (5). In this issue of Critical Care Medicine, Xu et al (6) propose to use remote ischemic pre- and/or postconditioning to pre vent and treat ischemic/reperfusion injuries on rats. Precondi tioning has been described for the first time in 1986 by Murry et al (7), Zhao et al (8) describe postconditioning. The initial description of conditioning was performed only on the target organ suffering the injury, whereas in remote ischemic con ditioning (9), it is done on a limb at distance from the target organs (brain and heart during cardiac arrest). In their article, Xu et al (6) hypothesize that conditioning performed before cardiac arrest (preconditioning), during car diopulmonary resuscitation (CPR) (postconditioning), or after successful return of spontaneous circulation (postconditioning) can improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest. No real explanation is given to w w w .c c m jo u rn a l.o rg
257
Editorials
explain their hypothesis other than a deductive reasoning. Dur ing cardiac arrest, there are ischemic-reperfusion injuries, and it has been shown that remote ischemic conditioning work on ischemic-reperfusion injuries (10), so remote ischemic condi tioning should work on cardiac arrest. This is due to the lack of understanding science has on the pathway of ischemic-reperfu sion injury protection. The actual knowledge of the signalization of condition passes through activation of the phosphatidylinositol-3-OH kinase-Akt or extracellular-signal-regulated kinases 1/2 prosurvival kinases (the so-called reperfusion injury signal ing kinase pathway) (11) or glycogen synthase kinase 3P via its action on the mitochondrial permeability transition pore (12). Remote ischemic conditioning is an elegant treatment with several advantages compared with the others actually propose. Ischemic postconditioning needs pause during CPR, whereas remote ischemic conditioning allows continuous chest com pression. Cyclosporine, sodium nitroprusside, and steroids need an IV access, which does not allow their delivery during basic life support and delay their use to advanced life support. This is a major limitation considering that reperfusion injuries start at the initiation of reperfusion also known as when CPR begins. Furthermore, from a technical point of view, the trans lation of remote postconditioning to humans during CPR, if it happens 1 day, will be easy to perform. The main finding of this study is not that remote condi tioning works. It is that almost no difference is found between conditioning realized before the injury (preconditioning), conditioning realized at the beginning of CPR (early post conditioning), or after return of spontaneous circulation (late postconditioning). As explained previously, one of the fears concerning conditioning treatments is that it was necessary to apply them as soon as possible. This study gives the hope that we could treat ischemic-reperfusion injuries late in the CPR procedure and still have a major protective effect. Even if this study was not designed to explain the mechanism of conditioning, it raises more question than it gives answers. As far as we know, conditioning pathways are supposed to be intracellular without release of extracellular proteins. The fact that a remote stimulation on a limb during cardiac arrest could have an effect on other organs, in particular the heart and the brain, is quite astonishing. This study has, however, several limits. First, it is done on rats, a frequent model used in CPR research but which will
258
w w w .c c m jo u r n a l.o r g
need confirmation in larger animals before translation to human beings. The blood distribution is different in rat and humans. Optimal timing for conditioning, duration, or the pressure level to apply to the tourniquets is not known. The potential effect of remote ischemic condition could be critical if it was successfully translated to humans. Further studies will be necessary to confirm this model, and the comprehension of the mechanisms explaining those results should be a priority.
REFERENCES 1. Cour M, Loufouat J, Paillard M, et al: Inhibition of mitochondrial per meability transition to prevent the post-cardiac arrest syndrome: A pre-clinical study. Eur Heart J 2011; 3 2 :2 2 6 -2 3 5 2. Yannopoulos D, Matsuura T, Schultz J, et al: Sodium nitroprusside enhanced cardiopulmonary resuscitation improves survival with good neurological function in a porcine model of prolonged cardiac arrest. Crit Care Med 2011; 3 9 :1 2 6 9 -1 2 7 4 3. Segal N, Matsuura T, Caldwell E, et al: Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation. Resuscitation 2012; 8 3 :1 3 9 7 -1 4 0 3 4. Fullerton JN: Oxygen in resuscitation: A game of two halves. Resuscitation 2013; 8 4 :7 1 5 -7 1 7 5. Mentzelopoulos SD, Malachias S, Chamos C, et al: Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: A randomized clinical trial. JAMA 2013; 3 1 0 :2 7 0 -2 7 9 6. Xu J, Sun S, Lu X, et al: Remote Ischemic Pre- and Postconditioning Improve Postresuscitation Myocardial and Cerebral Function in a Rat Model of Cardiac Arrest and Resuscitation. Crit Care Med 2015; 4 3 :e 1 2 -e 1 8 7. Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36 8. Zhao ZQ, Corvera JS, Halkos ME, et al: Inhibition of myocardial injury by ischemic postconditioning during reperfusion: Comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003; 28 5 :H 5 7 9 -H 5 8 8 9. Andreka G, Vertesaljai M, Szantho G, et al: Remote ischaemic post conditioning protects the heart during acute myocardial infarction in pigs. Heart 2007; 9 3 :7 4 9 -7 5 2 10. Dave KR, Saul I, Prado R, et al: Remote organ ischemic precondition ing protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett 2006; 4 0 4 :1 7 0 -1 7 5 11. Davidson SM, Hausenloy D, Duchen MR, et al: Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem Cell Biol 2006; 3 8 :4 1 4 -4 1 9 12. Wagner C, Tillack D, Simonis G, et al: Ischemic post-conditioning reduces infarct size of the in vivo rat heart: Role of PI3-K, mTOR, GSK-3beta, and apoptosis. Mol Cell Biochem 2010; 3 3 9 :1 3 5 -1 4 7
January 2015 • Volume 43 • Number 1
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.
REFERENCES 1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care M ed 2013; 4 1 :2 6 3 -3 0 6
Systematic Review and 4 3 :1 9 4 -2 0 4
Metaanalysis.
Crit
Care
M ed 2015;
6. Benbenbishty J, Adam S, Endacott R: Physical restraint use in inten sive care units across Europe: The PRICE study. Intensive Crit Care Nurs 2010; 2 6 :2 4 1 -2 4 5 7. McPherson JA, Wagner CE, Boehm LM, et al: Delirium in the cardio vascular ICU: Exploring modifiable risk factors. Crit Care Med 2013; 4 1 :4 0 5 -4 1 3 8. Pandharipande PP, Pun BT, Herr DL, et al: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechani cally ventilated patients: The M ENDS randomized controlled trial. JAMA 2007; 2 9 8 :2 6 4 4 -2 6 5 3 9. Andresen JM, Girard TD, Pandharipande PP, et al: Burst suppression on processed electroencephalography as a predictor of postcoma delirium in mechanically ventilated ICU patients. Crit Care M ed 2014; 4 2 :22 4 4 -2 25 1
2. Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators: Long-term cognitive impairment after critical illness. N Engl J M ed 2013; 3 6 9 :1 3 0 6 -1 3 1 6
10. Dieleman JM, Nierich AP, Rosseel PM, et al; Dexamethasone for Cardiac Surgery (DECS) Study Group: Intraoperative high-dose dexamethasone for cardiac surgery: A randomized controlled trial. JAMA 2012; 308:1761 -17 6 7
3. van Eijk MM, Roes KC, Honing ML, et al: Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: A multicentre, double-blind, placebocontrolled randomised trial. Lancet 2010; 3 7 6 :1 8 2 9 -18 3 7
11. Skrobik Y, Leger C, Cossette M, et al: Factors predisposing to coma and delirium: Fentanyl and midazolam exposure; CYP3A5, ABCB1, and A B C G 2 genetic polymorphisms; and inflammatory factors. C rit Care Med 2013; 4 1 :9 9 9 -1 008
4. Al-Qadheeb NS, Balk EM, Fraser GL, et al: Randomized ICU trials do not demonstrate an association between interventions that reduce delirium duration and short-term mortality: A systematic review and meta-analysis. Crit Care Med 2014; 4 2 :1 4 4 2 -1 4 5 4
1 2. Sauer AM, Slooter AJ, Veldhuijzen DS, et al: Intraoperative dexameth asone and delirium after cardiac surgery: A randomized clinical trial. Anesth Analg 2014; 1 1 9 :1 0 4 6 -1 0 5 2
5. Mu JL, Lee A, Joynt GM: Pharmacological Agents for the Prevention and Treatment of Delirium in Patients Undergoing Cardiac Surgery:
13. Inouye SK, Bogardus ST Jr, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J M e d t 999; 3 4 0 :6 6 9 -6 7 6
Tourniqueting the Limbs, the New Chest Compression in Cardiopulmonary Resuscitation* Nicolas Segal, MD, PhD Services des Urgences Universite Paris Diderot Sorbonne Paris Cite, UMRS 942, AP-HP Hopital Lariboisiere Paris, France s many as one third of a million out-of-hospital car diac arrests occur every year in the United States. D uring half a century, research focused on im proving the quality of chest compression to increase blood circula tion. Today, the treatm ent of this circulatory phase is p rob ably as good as it can be with the adjunction of mechanical chest compression, the use of impedance threshold device, and a better control of ventilation.
A
*See also p. el2 . Key Words: cardiac arrest; cardiopulmonary resuscitation; ischemicreperfusion injury; remote postconditioning; remote preconditioning The author has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0000000000000729
Critical Care Medicine
In the last 10 years, research has shifted from treating the lesion that occurs during the circulatory phase to treating the ones happening during the metabolic phase. Several pathologic mechanisms occur concomitantly during this phase: reactive oxygen species production, energy production defect, hypoxia, sometimes hyperoxia, and inflammation. At the same time, several pathways of treatm ent have been studied: cyclosporine A and NIM 811 (1), sodium nitroprusside (2), ischemic post conditioning (3), oxygen level control (4), and steroids (5). In this issue of Critical Care Medicine, Xu et al (6) propose to use remote ischemic pre- and/or postconditioning to pre vent and treat ischemic/reperfusion injuries on rats. Precondi tioning has been described for the first time in 1986 by Murry et al (7), Zhao et al (8) describe postconditioning. The initial description of conditioning was performed only on the target organ suffering the injury, whereas in remote ischemic con ditioning (9), it is done on a limb at distance from the target organs (brain and heart during cardiac arrest). In their article, Xu et al (6) hypothesize that conditioning performed before cardiac arrest (preconditioning), during car diopulmonary resuscitation (CPR) (postconditioning), or after successful return of spontaneous circulation (postconditioning) can improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest. No real explanation is given to w w w .c c m jo u rn a l.o rg
257
Editorials
explain their hypothesis other than a deductive reasoning. Dur ing cardiac arrest, there are ischemic-reperfusion injuries, and it has been shown that remote ischemic conditioning work on ischemic-reperfusion injuries (10), so remote ischemic condi tioning should work on cardiac arrest. This is due to the lack of understanding science has on the pathway of ischemic-reperfu sion injury protection. The actual knowledge of the signalization of condition passes through activation of the phosphatidylinositol-3-OH kinase-Akt or extracellular-signal-regulated kinases 1/2 prosurvival kinases (the so-called reperfusion injury signal ing kinase pathway) (11) or glycogen synthase kinase 3P via its action on the mitochondrial permeability transition pore (12). Remote ischemic conditioning is an elegant treatment with several advantages compared with the others actually propose. Ischemic postconditioning needs pause during CPR, whereas remote ischemic conditioning allows continuous chest com pression. Cyclosporine, sodium nitroprusside, and steroids need an IV access, which does not allow their delivery during basic life support and delay their use to advanced life support. This is a major limitation considering that reperfusion injuries start at the initiation of reperfusion also known as when CPR begins. Furthermore, from a technical point of view, the trans lation of remote postconditioning to humans during CPR, if it happens 1 day, will be easy to perform. The main finding of this study is not that remote condi tioning works. It is that almost no difference is found between conditioning realized before the injury (preconditioning), conditioning realized at the beginning of CPR (early post conditioning), or after return of spontaneous circulation (late postconditioning). As explained previously, one of the fears concerning conditioning treatments is that it was necessary to apply them as soon as possible. This study gives the hope that we could treat ischemic-reperfusion injuries late in the CPR procedure and still have a major protective effect. Even if this study was not designed to explain the mechanism of conditioning, it raises more question than it gives answers. As far as we know, conditioning pathways are supposed to be intracellular without release of extracellular proteins. The fact that a remote stimulation on a limb during cardiac arrest could have an effect on other organs, in particular the heart and the brain, is quite astonishing. This study has, however, several limits. First, it is done on rats, a frequent model used in CPR research but which will
258
w w w .c c m jo u r n a l.o r g
need confirmation in larger animals before translation to human beings. The blood distribution is different in rat and humans. Optimal timing for conditioning, duration, or the pressure level to apply to the tourniquets is not known. The potential effect of remote ischemic condition could be critical if it was successfully translated to humans. Further studies will be necessary to confirm this model, and the comprehension of the mechanisms explaining those results should be a priority.
REFERENCES 1. Cour M, Loufouat J, Paillard M, et al: Inhibition of mitochondrial per meability transition to prevent the post-cardiac arrest syndrome: A pre-clinical study. Eur Heart J 2011; 3 2 :2 2 6 -2 3 5 2. Yannopoulos D, Matsuura T, Schultz J, et al: Sodium nitroprusside enhanced cardiopulmonary resuscitation improves survival with good neurological function in a porcine model of prolonged cardiac arrest. Crit Care Med 2011; 3 9 :1 2 6 9 -1 2 7 4 3. Segal N, Matsuura T, Caldwell E, et al: Ischemic postconditioning at the initiation of cardiopulmonary resuscitation facilitates functional cardiac and cerebral recovery after prolonged untreated ventricular fibrillation. Resuscitation 2012; 8 3 :1 3 9 7 -1 4 0 3 4. Fullerton JN: Oxygen in resuscitation: A game of two halves. Resuscitation 2013; 8 4 :7 1 5 -7 1 7 5. Mentzelopoulos SD, Malachias S, Chamos C, et al: Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: A randomized clinical trial. JAMA 2013; 3 1 0 :2 7 0 -2 7 9 6. Xu J, Sun S, Lu X, et al: Remote Ischemic Pre- and Postconditioning Improve Postresuscitation Myocardial and Cerebral Function in a Rat Model of Cardiac Arrest and Resuscitation. Crit Care Med 2015; 4 3 :e 1 2 -e 1 8 7. Murry CE, Jennings RB, Reimer KA: Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36 8. Zhao ZQ, Corvera JS, Halkos ME, et al: Inhibition of myocardial injury by ischemic postconditioning during reperfusion: Comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003; 28 5 :H 5 7 9 -H 5 8 8 9. Andreka G, Vertesaljai M, Szantho G, et al: Remote ischaemic post conditioning protects the heart during acute myocardial infarction in pigs. Heart 2007; 9 3 :7 4 9 -7 5 2 10. Dave KR, Saul I, Prado R, et al: Remote organ ischemic precondition ing protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett 2006; 4 0 4 :1 7 0 -1 7 5 11. Davidson SM, Hausenloy D, Duchen MR, et al: Signalling via the reperfusion injury signalling kinase (RISK) pathway links closure of the mitochondrial permeability transition pore to cardioprotection. Int J Biochem Cell Biol 2006; 3 8 :4 1 4 -4 1 9 12. Wagner C, Tillack D, Simonis G, et al: Ischemic post-conditioning reduces infarct size of the in vivo rat heart: Role of PI3-K, mTOR, GSK-3beta, and apoptosis. Mol Cell Biochem 2010; 3 3 9 :1 3 5 -1 4 7
January 2015 • Volume 43 • Number 1
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.
